Breast Cancer

Key clinical point: Immediate reconstruction after neoadjuvant chemotherapy in women with T4 breast cancer is associated with higher odds for complication resulting in unplanned reoperations and a longer time to postmastectomy radiotherapy.

Major finding: Unplanned reoperations for complications were more common after immediate vs. delayed and no reconstruction (22% vs. 7.3% and 4.4%, respectively; P less than .001). The median time to initiation of postmastectomy radiotherapy was longer after immediate reconstruction vs. delayed and no reconstruction (60 days vs. 42 days and 49 days, respectively; P less than .001). The median time to the first recurrence was 18 months and was not significantly different between the groups (P = .13).

Study details: A retrospective study of 269 consecutive women with stage T4 breast cancer treated with surgery, chemotherapy, and radiotherapy between 2007 and 2019.

Disclosure: This study was supported in part by the National Institutes of Health. Dr. Morrow received speaking honoraria from Roche. The other authors did not disclose any conflicts of interest.

Source: Pawloski KR et al. J Am Coll Surg. 2021 Apr 24. doi: 10.1016/j.jamcollsurg.2021.04.016.

Key clinical point: Immediate reconstruction after neoadjuvant chemotherapy in women with T4 breast cancer is associated with higher odds for complication resulting in unplanned reoperations and a longer time to postmastectomy radiotherapy.

Major finding: Unplanned reoperations for complications were more common after immediate vs. delayed and no reconstruction (22% vs. 7.3% and 4.4%, respectively; P less than .001). The median time to initiation of postmastectomy radiotherapy was longer after immediate reconstruction vs. delayed and no reconstruction (60 days vs. 42 days and 49 days, respectively; P less than .001). The median time to the first recurrence was 18 months and was not significantly different between the groups (P = .13).

Study details: A retrospective study of 269 consecutive women with stage T4 breast cancer treated with surgery, chemotherapy, and radiotherapy between 2007 and 2019.

Disclosure: This study was supported in part by the National Institutes of Health. Dr. Morrow received speaking honoraria from Roche. The other authors did not disclose any conflicts of interest.

Source: Pawloski KR et al. J Am Coll Surg. 2021 Apr 24. doi: 10.1016/j.jamcollsurg.2021.04.016.

Key clinical point: Immediate reconstruction after neoadjuvant chemotherapy in women with T4 breast cancer is associated with higher odds for complication resulting in unplanned reoperations and a longer time to postmastectomy radiotherapy.

Major finding: Unplanned reoperations for complications were more common after immediate vs. delayed and no reconstruction (22% vs. 7.3% and 4.4%, respectively; P less than .001). The median time to initiation of postmastectomy radiotherapy was longer after immediate reconstruction vs. delayed and no reconstruction (60 days vs. 42 days and 49 days, respectively; P less than .001). The median time to the first recurrence was 18 months and was not significantly different between the groups (P = .13).

Study details: A retrospective study of 269 consecutive women with stage T4 breast cancer treated with surgery, chemotherapy, and radiotherapy between 2007 and 2019.

Disclosure: This study was supported in part by the National Institutes of Health. Dr. Morrow received speaking honoraria from Roche. The other authors did not disclose any conflicts of interest.

Source: Pawloski KR et al. J Am Coll Surg. 2021 Apr 24. doi: 10.1016/j.jamcollsurg.2021.04.016.

Key clinical point: The presence and extent of coronary artery calcium (CAC), as automatically quantified on routinely performed computed tomography scans, are associated with cardiovascular and coronary artery diseases.

Major finding: The risk for cardiovascular disease increased with a higher CAC score (adjusted hazard ratio, 1.8, 2.1, and 3.4 for CAC scores 11-100, 101-400, and greater than 400, respectively). The risk for coronary artery disease also increased with an increase in CAC score (adjusted hazard ratio, 2.8, 4.3, and 7.8 for CAC scores 11-100, 101-400, and greater than 400, respectively).

Study details: A multicenter cohort study of 15,915 patients with breast cancer who received radiotherapy between 2005 and 2016. The CAC scores were automatically extracted from computed tomography scans using a deep learning algorithm.

Disclosure: This study was funded by the Dutch Cancer Society. The authors received grants, lecture fees, and research support from various sources. Dr. Leiner and Dr. Isgum owned shares of Quantib-U BV and/or a patent with royalties planned. No other conflicts of interest were reported.

Source: Gal R et al. JAMA Oncol. 2021 May 6. doi: 10.1001/jamaoncol.2021.1144.

Key clinical point: The presence and extent of coronary artery calcium (CAC), as automatically quantified on routinely performed computed tomography scans, are associated with cardiovascular and coronary artery diseases.

Major finding: The risk for cardiovascular disease increased with a higher CAC score (adjusted hazard ratio, 1.8, 2.1, and 3.4 for CAC scores 11-100, 101-400, and greater than 400, respectively). The risk for coronary artery disease also increased with an increase in CAC score (adjusted hazard ratio, 2.8, 4.3, and 7.8 for CAC scores 11-100, 101-400, and greater than 400, respectively).

Study details: A multicenter cohort study of 15,915 patients with breast cancer who received radiotherapy between 2005 and 2016. The CAC scores were automatically extracted from computed tomography scans using a deep learning algorithm.

Disclosure: This study was funded by the Dutch Cancer Society. The authors received grants, lecture fees, and research support from various sources. Dr. Leiner and Dr. Isgum owned shares of Quantib-U BV and/or a patent with royalties planned. No other conflicts of interest were reported.

Source: Gal R et al. JAMA Oncol. 2021 May 6. doi: 10.1001/jamaoncol.2021.1144.

Key clinical point: The presence and extent of coronary artery calcium (CAC), as automatically quantified on routinely performed computed tomography scans, are associated with cardiovascular and coronary artery diseases.

Major finding: The risk for cardiovascular disease increased with a higher CAC score (adjusted hazard ratio, 1.8, 2.1, and 3.4 for CAC scores 11-100, 101-400, and greater than 400, respectively). The risk for coronary artery disease also increased with an increase in CAC score (adjusted hazard ratio, 2.8, 4.3, and 7.8 for CAC scores 11-100, 101-400, and greater than 400, respectively).

Study details: A multicenter cohort study of 15,915 patients with breast cancer who received radiotherapy between 2005 and 2016. The CAC scores were automatically extracted from computed tomography scans using a deep learning algorithm.

Disclosure: This study was funded by the Dutch Cancer Society. The authors received grants, lecture fees, and research support from various sources. Dr. Leiner and Dr. Isgum owned shares of Quantib-U BV and/or a patent with royalties planned. No other conflicts of interest were reported.

Source: Gal R et al. JAMA Oncol. 2021 May 6. doi: 10.1001/jamaoncol.2021.1144.

Key clinical point: Breast-conserving surgery (BCS) with radiotherapy yields superior survival vs. mastectomy in patients with early-stage breast cancer.

Major finding: At a median follow-up of 6.28 years, mastectomy without radiotherapy vs. BCS with radiotherapy was associated with worse overall survival (OS; hazard ratio [HR], 1.79; P less than .001) and breast cancer-specific survival (BCSS; HR, 1.66; P less than .001). Mastectomy with radiotherapy also showed lower OS (HR, 1.24; P less than .001) and BCSS (HR, 1.28; P=.001) vs. BCS and radiotherapy.

Study details: A cohort study of 48,986 patients with primary invasive T1-2 N0-2 breast cancer who underwent breast surgery between 2008 and 2017.

Disclosure: This work was funded by the Swedish Breast Cancer Association. Dr de Boniface was supported by an investigator award from the Swedish Cancer Society, and Ms Johansson was supported by a research grant from the Swedish Research Council. The authors did not declare any conflict of interest.

Source: de Boniface J et al. JAMA Surg. 2021 May 5. doi: 10.1001/jamasurg.2021.1438.

Key clinical point: Breast-conserving surgery (BCS) with radiotherapy yields superior survival vs. mastectomy in patients with early-stage breast cancer.

Major finding: At a median follow-up of 6.28 years, mastectomy without radiotherapy vs. BCS with radiotherapy was associated with worse overall survival (OS; hazard ratio [HR], 1.79; P less than .001) and breast cancer-specific survival (BCSS; HR, 1.66; P less than .001). Mastectomy with radiotherapy also showed lower OS (HR, 1.24; P less than .001) and BCSS (HR, 1.28; P=.001) vs. BCS and radiotherapy.

Study details: A cohort study of 48,986 patients with primary invasive T1-2 N0-2 breast cancer who underwent breast surgery between 2008 and 2017.

Disclosure: This work was funded by the Swedish Breast Cancer Association. Dr de Boniface was supported by an investigator award from the Swedish Cancer Society, and Ms Johansson was supported by a research grant from the Swedish Research Council. The authors did not declare any conflict of interest.

Source: de Boniface J et al. JAMA Surg. 2021 May 5. doi: 10.1001/jamasurg.2021.1438.

Key clinical point: Breast-conserving surgery (BCS) with radiotherapy yields superior survival vs. mastectomy in patients with early-stage breast cancer.

Major finding: At a median follow-up of 6.28 years, mastectomy without radiotherapy vs. BCS with radiotherapy was associated with worse overall survival (OS; hazard ratio [HR], 1.79; P less than .001) and breast cancer-specific survival (BCSS; HR, 1.66; P less than .001). Mastectomy with radiotherapy also showed lower OS (HR, 1.24; P less than .001) and BCSS (HR, 1.28; P=.001) vs. BCS and radiotherapy.

Study details: A cohort study of 48,986 patients with primary invasive T1-2 N0-2 breast cancer who underwent breast surgery between 2008 and 2017.

Disclosure: This work was funded by the Swedish Breast Cancer Association. Dr de Boniface was supported by an investigator award from the Swedish Cancer Society, and Ms Johansson was supported by a research grant from the Swedish Research Council. The authors did not declare any conflict of interest.

Source: de Boniface J et al. JAMA Surg. 2021 May 5. doi: 10.1001/jamasurg.2021.1438.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.

Adjuvant T-DM1 is recommended for patients with HER2-positive early breast cancer with residual disease after neoadjuvant therapy based on phase 3 results. The KATHERINE study found a significant reduction for the risk of recurrence and death with adjuvant T-DM1 vs trastuzumab. Subgroup analyses from KATHERINE showed similar benefits with T-DM1 irrespective of type of neoadjuvant regimen. Furthermore, T-DM1 appeared to benefit small node-negative tumors and particularly those tumors considered high-risk (Mamounas). In the phase 3 TRAIN-2 study, similar pCR rates (68% vs 67%), as well as 3 year event-free (94% vs 93%) and overall (98% vs 98%) survival, were observed for non-anthracycline and anthracycline-containing regimens. These findings highlight the broad applicability of T-DM1 in the adjuvant setting, the rationale to support de-escalation and omission of anthracyclines for HER2-positive tumors, and the importance of tailoring therapy based on response.

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC). Effective therapies for this population represent an unmet clinical need. The phase 2 PATRICIA study demonstrated activity of pertuzumab plus high-dose trastuzumab (6mg/kg weekly) for patients with HER2-positive MBC and central nervous system (CNS) progression after radiotherapy. In 37 patients evaluable for efficacy, the CNS objective response rate was 11%, clinical benefit rate at 4 and 6 months was 68% and 51%, respectively, and 2 patients had stable disease for over 2 years (Lin). Data supports the role of other HER2-targeted therapies for CNS disease including T-DM1, neratinib, and tucatinib. Among 291 patients with brain metastases in HER2CLIMB, the combination of tucatinib, capecitabine, and trastuzumab improved median overall survival (18 vs 12 months) and CNS progression-free survival (9.9 vs 4.2 months), compared with capecitabine plus trastuzumab. Further investigation exploring other novel therapy combinations and biomarkers will help further improve outcomes for these patients.

Adjuvant endocrine therapy decreases the risk for recurrence and improves survival for women diagnosed with HR-positive breast cancer. For young women, endocrine therapy options include tamoxifen, as well as ovarian suppression plus tamoxifen, or an aromatase inhibitor. Recommended duration of therapy is at least 5 years and can extend to 10 years. These treatments and duration may present challenges related to childbearing attempts and raise fertility concerns among young women.  In the Young Women’s Breast Cancer Study, among 643 women aged 40 years or younger and diagnosed with early stage HR-positive breast cancer, one-third reported fertility concerns impacting endocrine therapy decisions. Those who reported fertility concerns were more likely to exhibit non-initiation or non-persistence to endocrine therapy (40% vs 20%). Among women with fertility concerns, 7% did not initiate endocrine therapy, and 33% were non-persistent over 5 years (Sella). It is essential to integrate early oncofertility dialogue to help achieve optimal endocrine therapy and address family planning goals.

Studies have shown sugar-sweetened beverages (SSB) increase the risk for insulin resistance, diabetes, and heart disease. In a subsample of Women’s Health Initiative participants, higher levels of insulin resistance were shown to be linked to an increased incidence of breast cancer and all-cause mortality after breast cancer. Researchers found that among 8,863 women diagnosed with early breast cancer, those who consumed SSB after diagnosis had higher breast cancer-specific mortality and all-cause mortality. Additionally, replacing SSB with coffee, tea or water was linked to a decrease in mortality (Farvid). These findings support discussion of lifestyle and dietary behaviors in the survivorship setting, as these modifiable risk factors can potentially have significant health implications.

References:

van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol. 2020;38S:ASCO #501.

Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619.

Pan K, Chlebowski RT, Mortimer JE, et al. Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative. Cancer. 2020;126(16):3638-3647.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

In the past, chemotherapy was the go-to treatment for patients with HR+/HER2- breast cancer with visceral metastases, which most commonly involve lung and liver. Dr Adam M. Brufsky, of the University of Pittsburgh School of Medicine, reports that the advent of CDK4/6 inhibitors offers an opportunity for several different courses of action appropriate to subgroups within this population of patients.

Three CDK4/6 inhibitors are FDA approved for clinical practice. Dr Brufsky summarizes results from three studies of CDK4/6 inhibitors — abemaciclib, ribociclib, and palbociclib — where these agents were used as second-line therapy after progression on a nonsteroidal aromatase inhibitor. In combination with fulvestrant, all three offered significant benefits in progression-free survival (PFS) and two in overall survival (OS). Among those who derived survival benefit were patients who had visceral metatases, who constituted 56%, 27% and 60% of the respective studies.

For patients who show progression on CDK4/6 inhibitors, additional treatment can be determined by genomic sequencing. Combination therapy with alpelisib and fulvestrant has been shown to lengthen PFS in patients whose tumors have PIK3 mutations. Patients without PIK3 mutations can be treated with fulvestrant or a combination of fulvestrant and everolimus.

--

Adam M. Brufsky, MD, PhD, Professor, Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine; Associate Chief, Department of Medicine, Division of Hematology-Oncology, UPMC-Hillman Cancer Center, Pittsburgh, Pennsylvania. 

Adam M. Brufsky, MD, PhD, has disclosed the following relevant financial relationships: 
Received income in an amount equal to or greater than $250 from: Seattle Genetics; Roche; AstraZeneca; Puma; Daiichi Sankyo.

In the past, chemotherapy was the go-to treatment for patients with HR+/HER2- breast cancer with visceral metastases, which most commonly involve lung and liver. Dr Adam M. Brufsky, of the University of Pittsburgh School of Medicine, reports that the advent of CDK4/6 inhibitors offers an opportunity for several different courses of action appropriate to subgroups within this population of patients.

Three CDK4/6 inhibitors are FDA approved for clinical practice. Dr Brufsky summarizes results from three studies of CDK4/6 inhibitors — abemaciclib, ribociclib, and palbociclib — where these agents were used as second-line therapy after progression on a nonsteroidal aromatase inhibitor. In combination with fulvestrant, all three offered significant benefits in progression-free survival (PFS) and two in overall survival (OS). Among those who derived survival benefit were patients who had visceral metatases, who constituted 56%, 27% and 60% of the respective studies.

For patients who show progression on CDK4/6 inhibitors, additional treatment can be determined by genomic sequencing. Combination therapy with alpelisib and fulvestrant has been shown to lengthen PFS in patients whose tumors have PIK3 mutations. Patients without PIK3 mutations can be treated with fulvestrant or a combination of fulvestrant and everolimus.

--

Adam M. Brufsky, MD, PhD, Professor, Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine; Associate Chief, Department of Medicine, Division of Hematology-Oncology, UPMC-Hillman Cancer Center, Pittsburgh, Pennsylvania. 

Adam M. Brufsky, MD, PhD, has disclosed the following relevant financial relationships: 
Received income in an amount equal to or greater than $250 from: Seattle Genetics; Roche; AstraZeneca; Puma; Daiichi Sankyo.

In the past, chemotherapy was the go-to treatment for patients with HR+/HER2- breast cancer with visceral metastases, which most commonly involve lung and liver. Dr Adam M. Brufsky, of the University of Pittsburgh School of Medicine, reports that the advent of CDK4/6 inhibitors offers an opportunity for several different courses of action appropriate to subgroups within this population of patients.

Three CDK4/6 inhibitors are FDA approved for clinical practice. Dr Brufsky summarizes results from three studies of CDK4/6 inhibitors — abemaciclib, ribociclib, and palbociclib — where these agents were used as second-line therapy after progression on a nonsteroidal aromatase inhibitor. In combination with fulvestrant, all three offered significant benefits in progression-free survival (PFS) and two in overall survival (OS). Among those who derived survival benefit were patients who had visceral metatases, who constituted 56%, 27% and 60% of the respective studies.

For patients who show progression on CDK4/6 inhibitors, additional treatment can be determined by genomic sequencing. Combination therapy with alpelisib and fulvestrant has been shown to lengthen PFS in patients whose tumors have PIK3 mutations. Patients without PIK3 mutations can be treated with fulvestrant or a combination of fulvestrant and everolimus.

--

Adam M. Brufsky, MD, PhD, Professor, Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine; Associate Chief, Department of Medicine, Division of Hematology-Oncology, UPMC-Hillman Cancer Center, Pittsburgh, Pennsylvania. 

Adam M. Brufsky, MD, PhD, has disclosed the following relevant financial relationships: 
Received income in an amount equal to or greater than $250 from: Seattle Genetics; Roche; AstraZeneca; Puma; Daiichi Sankyo.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

The landscape for therapies targeting HER2-positive metastatic breast cancer (MBC) has evolved rapidly in the past few years. In a 12-month window, the U.S. Food and Drug Administration approved four agents targeting human epidermal growth factor 2 (HER2)–positive MBC, starting with trastuzumab deruxtecan in December 2019, followed by neratinib and tucatinib a few months later, and margetuximab last December.

Although first-line therapy for the majority of patients continues to be the CLEOPATRA regimen — the monoclonal antibodies trastuzumab and pertuzumab plus a taxane, such as docetaxel or paclitaxel — the influx of agents approved in the metastatic setting has opened up new avenues for second-line therapy and beyond.

“We have been really fortunate to see a number of highly effective new therapies approved for HER2-positive MBC in the past year, and this has given us even more options to offer our patients,” remarked Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

What considerations do experts weigh when sequencing HER2-positive MBC?

For Kelly McCann, MD, PhD, the order largely depends on balancing two factors: regimens that will provide the best efficacy in terms of patient survival and quality of life. “In the metastatic setting, I know I’m going to end up using all of the available medications one after the other, so the order that allows patients to continue living their best life for as long as possible is essential,” commented Dr. McCann, a hematologist/oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles.

A new second-line option?

Before the wave of drug approvals for metastatic HER2-positive disease last year, oncologists routinely looked to trastuzumab emtansine (T-DM1) as second-line therapy.

But tucatinib may also now be considered in the second-line setting, after results from the HER2CLIMB trial. The decision between tucatinib and T-DM1 largely comes down to the presence or absence of brain metastases.

“T-DM1 is well-tolerated, so it’s still my go-to in the second-line setting unless my patient has a brain metastasis, in which case I opt for tucatinib,” Dr. McCann noted, adding that the HER2-specific oral tyrosine kinase inhibitor (TKI) not only crosses the blood-brain barrier but is also effective in patients with untreated brain metastases.

In HER2CLIMB, tucatinib exhibited strong efficacy in patients with advanced HER2-positive disease, including those with previously treated or untreated brain metastases. The randomized controlled trial, which paired tucatinib with trastuzumab and capecitabine, showed median progression-free survival of 7.8 months in 410 patients with HER2-positive MBC compared with 5.6 months in the 202 patients receiving the placebo regimen. The tucatinib cohort showed an overall survival advantage compared with the placebo group (21.9 vs 17.4 months).

Perhaps the most notable finding occurred in patients with brain or central nervous system (CNS) involvement, which develops in as many as half of patients with HER-positive MBC and is associated with shorter survival. In the HER2CLIMB trial, median progression-free survival was 7.6 months in patients with brain metastases compared with 5.4 months in the placebo group.

A follow-up exploratory analysis, which focused on 291 patients with brain metastases, found that adding tucatinib reduced the risk for intracranial progression by two thirds and death by almost half. In patients with active brain metastases, median progression-free survival reached 9.5 months vs 4.1 months in the placebo group. Those with stable metastases also benefited from tucatinib, with median progression-free survival of 13.9 vs 5.6 months in the placebo group.

On the basis of the results, the authors concluded that this randomized trial was the first to demonstrate improvements in both CNS progression–free survival and overall survival in patients with HER2-positive MBC and brain metastases.

Evolving options in the third-line setting and after

For third-line therapy and beyond, oncologists have an array of newer agents to choose from alongside longer-standing options — which include trastuzumab plus lapatinib, trastuzumab or lapatinib plus capecitabine, as well as T-DM1, if not given as second-line therapy.

According to Dr. McCann, the antibody-drug conjugate trastuzumab deruxtecan has been a particularly exciting addition to third-line treatment. In the phase 2 DESTINY-01 trial, more than 60% of a heavily pretreated population showed an objective response to trastuzumab deruxtecan, with a median response duration of almost 15 months and a median progression-free survival of 16.4 months. Longer-term follow-up results, presented in December at the 2020 San Antonio Breast Cancer Symposium, revealed progression-free survival of 19.4 months and preliminary median overall survival of 24.6 months.

Neratinib, the second TKI to bridge the blood-brain barrier in HER2-positive disease, was also approved for third-line use; however, Sayeh Lavasani, MD, MS, said she is more likely to consider this agent later in the sequence, potentially in the fourth-line setting and beyond, given the more robust outcomes observed in the HER2CLIMB tucatinib trial.

“Neratinib improved progression-free survival and time to intervention for CNS metastasis but, unlike tucatinib, did not demonstrate an overall survival benefit,” remarked Dr. Lavasani, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

More specifically, the phase 3 NALA trial, which randomly assigned patients to receive neratinib plus capecitabine or lapatinib plus capecitabine, reported progression-free survival of 8.8 months in the neratinib group compared with 6.6 months in the control arm but no significant gains in overall survival (hazard ratio, 0.88; P = .2098).

The fourth recently approved drug, margetuximab, has not yet made a significant mark on sequencing decisions for Dr. McCann.

“Margetuximab could have been a potential game changer, but clinical trial results were underwhelming,” she said.

In the phase 3 randomized clinical SOPHIA trial, margetuximab plus chemotherapy prolonged median progression-free survival by just over 1 month compared with trastuzumab plus chemotherapy. Preliminary overall survival data showed a slight, but not significant, benefit in the margetuximab group (21.6 vs 19.8 months).

For Dr. Lavasani, the presence of brain metastases is the most important consideration when weighing sequencing options. “For some of my patients with HER2-positive MBC, it’s ultimately disease progression in the brain that takes their life,” she said.

Aside from CNS metastases, specific sequencing choices may vary on the basis of drug-related tolerance as well as patient preferences. “It is critical to get a patient’s input in treatment selection,” Dr. Nanda remarked. “Given the number of effective treatments for HER2-positive MBC and the lack of data to guide how to sequence these regimens, it is important to ask patients what their preferences are.”

Dr. McCann agreed, noting that “a patient with HER2-positive MBC typically has a life expectancy measured in years, which is also why sequencing should be influenced by quality of life considerations.”

Convenience, side-effect profile, and financial toxicity should factor into clinical decision-making, according to Dr. Nanda. Some patients may, for instance, prefer a combination of tucatinib, capecitabine, and trastuzumab over trastuzumab deruxtecan to avoid hair loss and the risk for interstitial lung disease, which has been reported in more than 13% of patients, whereas others may prefer trastuzumab deruxtecan to avoid the possibility of diarrhea.

Taxanes come with a high risk for infusion reactions — which occur in about 30% of patients — and can cause neuropathy as well as hair loss and severe gastrointestinal side effects. In first-line care, Dr. McCann typically stops the taxane at some point for toxicity reasons and continues with trastuzumab plus pertuzumab until disease progression.

Even with an array of new options for treating metastatic HER2-positive disease, ultimately drug resistance does occur, Dr. Lavasani cautioned. Several ongoing trials are exploring new combinations of existing drugs to see whether those variations move the needle on survival outcomes. The HER2CLIMB-04 trial, for instance, is pairing tucatinib with trastuzumab deruxtecan, whereas HER2CLIMB-02 is pairing tucatinib with T-DM1.

But given progress in drug development in just the past few years, Lisa A. Carey, MD, deputy director of Clinical Sciences at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, sees a promising future for treating metastatic HER2-positive disease. “There is so much going on in the HER2-positive MBC therapeutics space that almost every 6 months, oncologists have to regroup and reevaluate treatment and sequencing, which is a great position to be in,” Dr. Carey noted.

A version of this article first appeared on Medscape.com .

The landscape for therapies targeting HER2-positive metastatic breast cancer (MBC) has evolved rapidly in the past few years. In a 12-month window, the U.S. Food and Drug Administration approved four agents targeting human epidermal growth factor 2 (HER2)–positive MBC, starting with trastuzumab deruxtecan in December 2019, followed by neratinib and tucatinib a few months later, and margetuximab last December.

Although first-line therapy for the majority of patients continues to be the CLEOPATRA regimen — the monoclonal antibodies trastuzumab and pertuzumab plus a taxane, such as docetaxel or paclitaxel — the influx of agents approved in the metastatic setting has opened up new avenues for second-line therapy and beyond.

“We have been really fortunate to see a number of highly effective new therapies approved for HER2-positive MBC in the past year, and this has given us even more options to offer our patients,” remarked Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

What considerations do experts weigh when sequencing HER2-positive MBC?

For Kelly McCann, MD, PhD, the order largely depends on balancing two factors: regimens that will provide the best efficacy in terms of patient survival and quality of life. “In the metastatic setting, I know I’m going to end up using all of the available medications one after the other, so the order that allows patients to continue living their best life for as long as possible is essential,” commented Dr. McCann, a hematologist/oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles.

A new second-line option?

Before the wave of drug approvals for metastatic HER2-positive disease last year, oncologists routinely looked to trastuzumab emtansine (T-DM1) as second-line therapy.

But tucatinib may also now be considered in the second-line setting, after results from the HER2CLIMB trial. The decision between tucatinib and T-DM1 largely comes down to the presence or absence of brain metastases.

“T-DM1 is well-tolerated, so it’s still my go-to in the second-line setting unless my patient has a brain metastasis, in which case I opt for tucatinib,” Dr. McCann noted, adding that the HER2-specific oral tyrosine kinase inhibitor (TKI) not only crosses the blood-brain barrier but is also effective in patients with untreated brain metastases.

In HER2CLIMB, tucatinib exhibited strong efficacy in patients with advanced HER2-positive disease, including those with previously treated or untreated brain metastases. The randomized controlled trial, which paired tucatinib with trastuzumab and capecitabine, showed median progression-free survival of 7.8 months in 410 patients with HER2-positive MBC compared with 5.6 months in the 202 patients receiving the placebo regimen. The tucatinib cohort showed an overall survival advantage compared with the placebo group (21.9 vs 17.4 months).

Perhaps the most notable finding occurred in patients with brain or central nervous system (CNS) involvement, which develops in as many as half of patients with HER-positive MBC and is associated with shorter survival. In the HER2CLIMB trial, median progression-free survival was 7.6 months in patients with brain metastases compared with 5.4 months in the placebo group.

A follow-up exploratory analysis, which focused on 291 patients with brain metastases, found that adding tucatinib reduced the risk for intracranial progression by two thirds and death by almost half. In patients with active brain metastases, median progression-free survival reached 9.5 months vs 4.1 months in the placebo group. Those with stable metastases also benefited from tucatinib, with median progression-free survival of 13.9 vs 5.6 months in the placebo group.

On the basis of the results, the authors concluded that this randomized trial was the first to demonstrate improvements in both CNS progression–free survival and overall survival in patients with HER2-positive MBC and brain metastases.

Evolving options in the third-line setting and after

For third-line therapy and beyond, oncologists have an array of newer agents to choose from alongside longer-standing options — which include trastuzumab plus lapatinib, trastuzumab or lapatinib plus capecitabine, as well as T-DM1, if not given as second-line therapy.

According to Dr. McCann, the antibody-drug conjugate trastuzumab deruxtecan has been a particularly exciting addition to third-line treatment. In the phase 2 DESTINY-01 trial, more than 60% of a heavily pretreated population showed an objective response to trastuzumab deruxtecan, with a median response duration of almost 15 months and a median progression-free survival of 16.4 months. Longer-term follow-up results, presented in December at the 2020 San Antonio Breast Cancer Symposium, revealed progression-free survival of 19.4 months and preliminary median overall survival of 24.6 months.

Neratinib, the second TKI to bridge the blood-brain barrier in HER2-positive disease, was also approved for third-line use; however, Sayeh Lavasani, MD, MS, said she is more likely to consider this agent later in the sequence, potentially in the fourth-line setting and beyond, given the more robust outcomes observed in the HER2CLIMB tucatinib trial.

“Neratinib improved progression-free survival and time to intervention for CNS metastasis but, unlike tucatinib, did not demonstrate an overall survival benefit,” remarked Dr. Lavasani, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

More specifically, the phase 3 NALA trial, which randomly assigned patients to receive neratinib plus capecitabine or lapatinib plus capecitabine, reported progression-free survival of 8.8 months in the neratinib group compared with 6.6 months in the control arm but no significant gains in overall survival (hazard ratio, 0.88; P = .2098).

The fourth recently approved drug, margetuximab, has not yet made a significant mark on sequencing decisions for Dr. McCann.

“Margetuximab could have been a potential game changer, but clinical trial results were underwhelming,” she said.

In the phase 3 randomized clinical SOPHIA trial, margetuximab plus chemotherapy prolonged median progression-free survival by just over 1 month compared with trastuzumab plus chemotherapy. Preliminary overall survival data showed a slight, but not significant, benefit in the margetuximab group (21.6 vs 19.8 months).

For Dr. Lavasani, the presence of brain metastases is the most important consideration when weighing sequencing options. “For some of my patients with HER2-positive MBC, it’s ultimately disease progression in the brain that takes their life,” she said.

Aside from CNS metastases, specific sequencing choices may vary on the basis of drug-related tolerance as well as patient preferences. “It is critical to get a patient’s input in treatment selection,” Dr. Nanda remarked. “Given the number of effective treatments for HER2-positive MBC and the lack of data to guide how to sequence these regimens, it is important to ask patients what their preferences are.”

Dr. McCann agreed, noting that “a patient with HER2-positive MBC typically has a life expectancy measured in years, which is also why sequencing should be influenced by quality of life considerations.”

Convenience, side-effect profile, and financial toxicity should factor into clinical decision-making, according to Dr. Nanda. Some patients may, for instance, prefer a combination of tucatinib, capecitabine, and trastuzumab over trastuzumab deruxtecan to avoid hair loss and the risk for interstitial lung disease, which has been reported in more than 13% of patients, whereas others may prefer trastuzumab deruxtecan to avoid the possibility of diarrhea.

Taxanes come with a high risk for infusion reactions — which occur in about 30% of patients — and can cause neuropathy as well as hair loss and severe gastrointestinal side effects. In first-line care, Dr. McCann typically stops the taxane at some point for toxicity reasons and continues with trastuzumab plus pertuzumab until disease progression.

Even with an array of new options for treating metastatic HER2-positive disease, ultimately drug resistance does occur, Dr. Lavasani cautioned. Several ongoing trials are exploring new combinations of existing drugs to see whether those variations move the needle on survival outcomes. The HER2CLIMB-04 trial, for instance, is pairing tucatinib with trastuzumab deruxtecan, whereas HER2CLIMB-02 is pairing tucatinib with T-DM1.

But given progress in drug development in just the past few years, Lisa A. Carey, MD, deputy director of Clinical Sciences at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, sees a promising future for treating metastatic HER2-positive disease. “There is so much going on in the HER2-positive MBC therapeutics space that almost every 6 months, oncologists have to regroup and reevaluate treatment and sequencing, which is a great position to be in,” Dr. Carey noted.

A version of this article first appeared on Medscape.com .

The landscape for therapies targeting HER2-positive metastatic breast cancer (MBC) has evolved rapidly in the past few years. In a 12-month window, the U.S. Food and Drug Administration approved four agents targeting human epidermal growth factor 2 (HER2)–positive MBC, starting with trastuzumab deruxtecan in December 2019, followed by neratinib and tucatinib a few months later, and margetuximab last December.

Although first-line therapy for the majority of patients continues to be the CLEOPATRA regimen — the monoclonal antibodies trastuzumab and pertuzumab plus a taxane, such as docetaxel or paclitaxel — the influx of agents approved in the metastatic setting has opened up new avenues for second-line therapy and beyond.

“We have been really fortunate to see a number of highly effective new therapies approved for HER2-positive MBC in the past year, and this has given us even more options to offer our patients,” remarked Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

What considerations do experts weigh when sequencing HER2-positive MBC?

For Kelly McCann, MD, PhD, the order largely depends on balancing two factors: regimens that will provide the best efficacy in terms of patient survival and quality of life. “In the metastatic setting, I know I’m going to end up using all of the available medications one after the other, so the order that allows patients to continue living their best life for as long as possible is essential,” commented Dr. McCann, a hematologist/oncologist in the department of medicine at the David Geffen School of Medicine, University of California, Los Angeles.

A new second-line option?

Before the wave of drug approvals for metastatic HER2-positive disease last year, oncologists routinely looked to trastuzumab emtansine (T-DM1) as second-line therapy.

But tucatinib may also now be considered in the second-line setting, after results from the HER2CLIMB trial. The decision between tucatinib and T-DM1 largely comes down to the presence or absence of brain metastases.

“T-DM1 is well-tolerated, so it’s still my go-to in the second-line setting unless my patient has a brain metastasis, in which case I opt for tucatinib,” Dr. McCann noted, adding that the HER2-specific oral tyrosine kinase inhibitor (TKI) not only crosses the blood-brain barrier but is also effective in patients with untreated brain metastases.

In HER2CLIMB, tucatinib exhibited strong efficacy in patients with advanced HER2-positive disease, including those with previously treated or untreated brain metastases. The randomized controlled trial, which paired tucatinib with trastuzumab and capecitabine, showed median progression-free survival of 7.8 months in 410 patients with HER2-positive MBC compared with 5.6 months in the 202 patients receiving the placebo regimen. The tucatinib cohort showed an overall survival advantage compared with the placebo group (21.9 vs 17.4 months).

Perhaps the most notable finding occurred in patients with brain or central nervous system (CNS) involvement, which develops in as many as half of patients with HER-positive MBC and is associated with shorter survival. In the HER2CLIMB trial, median progression-free survival was 7.6 months in patients with brain metastases compared with 5.4 months in the placebo group.

A follow-up exploratory analysis, which focused on 291 patients with brain metastases, found that adding tucatinib reduced the risk for intracranial progression by two thirds and death by almost half. In patients with active brain metastases, median progression-free survival reached 9.5 months vs 4.1 months in the placebo group. Those with stable metastases also benefited from tucatinib, with median progression-free survival of 13.9 vs 5.6 months in the placebo group.

On the basis of the results, the authors concluded that this randomized trial was the first to demonstrate improvements in both CNS progression–free survival and overall survival in patients with HER2-positive MBC and brain metastases.

Evolving options in the third-line setting and after

For third-line therapy and beyond, oncologists have an array of newer agents to choose from alongside longer-standing options — which include trastuzumab plus lapatinib, trastuzumab or lapatinib plus capecitabine, as well as T-DM1, if not given as second-line therapy.

According to Dr. McCann, the antibody-drug conjugate trastuzumab deruxtecan has been a particularly exciting addition to third-line treatment. In the phase 2 DESTINY-01 trial, more than 60% of a heavily pretreated population showed an objective response to trastuzumab deruxtecan, with a median response duration of almost 15 months and a median progression-free survival of 16.4 months. Longer-term follow-up results, presented in December at the 2020 San Antonio Breast Cancer Symposium, revealed progression-free survival of 19.4 months and preliminary median overall survival of 24.6 months.

Neratinib, the second TKI to bridge the blood-brain barrier in HER2-positive disease, was also approved for third-line use; however, Sayeh Lavasani, MD, MS, said she is more likely to consider this agent later in the sequence, potentially in the fourth-line setting and beyond, given the more robust outcomes observed in the HER2CLIMB tucatinib trial.

“Neratinib improved progression-free survival and time to intervention for CNS metastasis but, unlike tucatinib, did not demonstrate an overall survival benefit,” remarked Dr. Lavasani, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

More specifically, the phase 3 NALA trial, which randomly assigned patients to receive neratinib plus capecitabine or lapatinib plus capecitabine, reported progression-free survival of 8.8 months in the neratinib group compared with 6.6 months in the control arm but no significant gains in overall survival (hazard ratio, 0.88; P = .2098).

The fourth recently approved drug, margetuximab, has not yet made a significant mark on sequencing decisions for Dr. McCann.

“Margetuximab could have been a potential game changer, but clinical trial results were underwhelming,” she said.

In the phase 3 randomized clinical SOPHIA trial, margetuximab plus chemotherapy prolonged median progression-free survival by just over 1 month compared with trastuzumab plus chemotherapy. Preliminary overall survival data showed a slight, but not significant, benefit in the margetuximab group (21.6 vs 19.8 months).

For Dr. Lavasani, the presence of brain metastases is the most important consideration when weighing sequencing options. “For some of my patients with HER2-positive MBC, it’s ultimately disease progression in the brain that takes their life,” she said.

Aside from CNS metastases, specific sequencing choices may vary on the basis of drug-related tolerance as well as patient preferences. “It is critical to get a patient’s input in treatment selection,” Dr. Nanda remarked. “Given the number of effective treatments for HER2-positive MBC and the lack of data to guide how to sequence these regimens, it is important to ask patients what their preferences are.”

Dr. McCann agreed, noting that “a patient with HER2-positive MBC typically has a life expectancy measured in years, which is also why sequencing should be influenced by quality of life considerations.”

Convenience, side-effect profile, and financial toxicity should factor into clinical decision-making, according to Dr. Nanda. Some patients may, for instance, prefer a combination of tucatinib, capecitabine, and trastuzumab over trastuzumab deruxtecan to avoid hair loss and the risk for interstitial lung disease, which has been reported in more than 13% of patients, whereas others may prefer trastuzumab deruxtecan to avoid the possibility of diarrhea.

Taxanes come with a high risk for infusion reactions — which occur in about 30% of patients — and can cause neuropathy as well as hair loss and severe gastrointestinal side effects. In first-line care, Dr. McCann typically stops the taxane at some point for toxicity reasons and continues with trastuzumab plus pertuzumab until disease progression.

Even with an array of new options for treating metastatic HER2-positive disease, ultimately drug resistance does occur, Dr. Lavasani cautioned. Several ongoing trials are exploring new combinations of existing drugs to see whether those variations move the needle on survival outcomes. The HER2CLIMB-04 trial, for instance, is pairing tucatinib with trastuzumab deruxtecan, whereas HER2CLIMB-02 is pairing tucatinib with T-DM1.

But given progress in drug development in just the past few years, Lisa A. Carey, MD, deputy director of Clinical Sciences at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, sees a promising future for treating metastatic HER2-positive disease. “There is so much going on in the HER2-positive MBC therapeutics space that almost every 6 months, oncologists have to regroup and reevaluate treatment and sequencing, which is a great position to be in,” Dr. Carey noted.

A version of this article first appeared on Medscape.com .

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.