Breast Cancer

Aromatase inhibitor-induced arthralgia substantially improved in women who received omega-3 fatty acid capsules, as well as in those who took placebo, according to a study published online May 4 in the Journal of Clinical Oncology.

Brief Pain Inventory (BPI) worst pain scores were significantly lower than were baseline scores after treatment with O3-FAs and placebo. On the 10-point scale, the median scores reported by women taking O3-FAs were lower by 1.69, 1.74, and 2.23 at 6, 12, and 24 weeks, respectively (P < .001). For those taking placebo, the scores also were significantly lower: 1.36, 1.50, and 1.81 points at 6, 12, and 24 weeks respectively (P < .001). Differences between the groups were not significant, reported Dr. Dawn Hershman of the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, and associates (J. Clin. Onc. 2015 May 4 [doi: 10.1200/JCO.2014.59.5595]).

©Clayton Hansen/iStockphoto.com

“The improvement in symptoms in both the treatment and placebo groups was unexpected. The magnitude of the expected placebo effect reported in the literature can vary from 6% to 59% and can be higher in symptom-management studies. We found an effect >50%,” Dr. Hershman and associates wrote.

The large placebo effect may have resulted from a number of factors, including the natural history of arthralgia (which can improve over time), the soy/corn oil ingredients in the placebo capsule, or O3-FA contamination in the placebo arm due to supplementation by patients.

There are no proven therapies for AI-associated arthralgia, and its mechanism is unclear. Evidence suggests that inflammation may play a role. Given that studies have shown O3-FAs may benefit symptoms of rheumatoid arthritis, this multicenter, placebo controlled trial evaluated whether O3-FAs reduce pain and stiffness in 249 women undergoing adjuvant AI therapy for early-stage breast cancer.

At week 12, patients who received O3-FAs had significantly decreased serum triglyceride levels (–22.1 mg/dL, P < .001) and increased HDL (2.9 mg/dL, P < .007). Triglyceride and HDL levels for the placebo arm did not significantly change, which suggests that O3-FA contamination in the placebo arm was not a factor in the high placebo effect. Other serum measures (cholesterol, CRP, and LDL) did not significantly change for either group, Dr. Hershman and associates said.

tor@frontlinemedcom.com

Aromatase inhibitor-induced arthralgia substantially improved in women who received omega-3 fatty acid capsules, as well as in those who took placebo, according to a study published online May 4 in the Journal of Clinical Oncology.

Brief Pain Inventory (BPI) worst pain scores were significantly lower than were baseline scores after treatment with O3-FAs and placebo. On the 10-point scale, the median scores reported by women taking O3-FAs were lower by 1.69, 1.74, and 2.23 at 6, 12, and 24 weeks, respectively (P < .001). For those taking placebo, the scores also were significantly lower: 1.36, 1.50, and 1.81 points at 6, 12, and 24 weeks respectively (P < .001). Differences between the groups were not significant, reported Dr. Dawn Hershman of the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, and associates (J. Clin. Onc. 2015 May 4 [doi: 10.1200/JCO.2014.59.5595]).

©Clayton Hansen/iStockphoto.com

“The improvement in symptoms in both the treatment and placebo groups was unexpected. The magnitude of the expected placebo effect reported in the literature can vary from 6% to 59% and can be higher in symptom-management studies. We found an effect >50%,” Dr. Hershman and associates wrote.

The large placebo effect may have resulted from a number of factors, including the natural history of arthralgia (which can improve over time), the soy/corn oil ingredients in the placebo capsule, or O3-FA contamination in the placebo arm due to supplementation by patients.

There are no proven therapies for AI-associated arthralgia, and its mechanism is unclear. Evidence suggests that inflammation may play a role. Given that studies have shown O3-FAs may benefit symptoms of rheumatoid arthritis, this multicenter, placebo controlled trial evaluated whether O3-FAs reduce pain and stiffness in 249 women undergoing adjuvant AI therapy for early-stage breast cancer.

At week 12, patients who received O3-FAs had significantly decreased serum triglyceride levels (–22.1 mg/dL, P < .001) and increased HDL (2.9 mg/dL, P < .007). Triglyceride and HDL levels for the placebo arm did not significantly change, which suggests that O3-FA contamination in the placebo arm was not a factor in the high placebo effect. Other serum measures (cholesterol, CRP, and LDL) did not significantly change for either group, Dr. Hershman and associates said.

tor@frontlinemedcom.com

Aromatase inhibitor-induced arthralgia substantially improved in women who received omega-3 fatty acid capsules, as well as in those who took placebo, according to a study published online May 4 in the Journal of Clinical Oncology.

Brief Pain Inventory (BPI) worst pain scores were significantly lower than were baseline scores after treatment with O3-FAs and placebo. On the 10-point scale, the median scores reported by women taking O3-FAs were lower by 1.69, 1.74, and 2.23 at 6, 12, and 24 weeks, respectively (P < .001). For those taking placebo, the scores also were significantly lower: 1.36, 1.50, and 1.81 points at 6, 12, and 24 weeks respectively (P < .001). Differences between the groups were not significant, reported Dr. Dawn Hershman of the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, and associates (J. Clin. Onc. 2015 May 4 [doi: 10.1200/JCO.2014.59.5595]).

©Clayton Hansen/iStockphoto.com

“The improvement in symptoms in both the treatment and placebo groups was unexpected. The magnitude of the expected placebo effect reported in the literature can vary from 6% to 59% and can be higher in symptom-management studies. We found an effect >50%,” Dr. Hershman and associates wrote.

The large placebo effect may have resulted from a number of factors, including the natural history of arthralgia (which can improve over time), the soy/corn oil ingredients in the placebo capsule, or O3-FA contamination in the placebo arm due to supplementation by patients.

There are no proven therapies for AI-associated arthralgia, and its mechanism is unclear. Evidence suggests that inflammation may play a role. Given that studies have shown O3-FAs may benefit symptoms of rheumatoid arthritis, this multicenter, placebo controlled trial evaluated whether O3-FAs reduce pain and stiffness in 249 women undergoing adjuvant AI therapy for early-stage breast cancer.

At week 12, patients who received O3-FAs had significantly decreased serum triglyceride levels (–22.1 mg/dL, P < .001) and increased HDL (2.9 mg/dL, P < .007). Triglyceride and HDL levels for the placebo arm did not significantly change, which suggests that O3-FA contamination in the placebo arm was not a factor in the high placebo effect. Other serum measures (cholesterol, CRP, and LDL) did not significantly change for either group, Dr. Hershman and associates said.

tor@frontlinemedcom.com

Combining the poly(ADP-ribose) polymerase inhibitor olaparib and the investigational P13K inhibitor BKM 120 was safe and active in triple-negative breast cancer and ovarian cancer in a phase I trial.

Patients with both BRCA-mutant and BRCA-wildtype breast cancer responded to the combination. One patient with germline BRCA-wildtype triple-negative breast cancer (TNBC) and lung metastases had a partial response and remained on treatment for 20 cycles, or nearly 2 years, study author Dr. Ursula Matulonis reported at the annual meeting of the American Association for Cancer Research.

Rationale for the study lay in data from mouse models showing that combination olaparib and BKM120 was more effective than either drug alone in BRCA-mutant breast cancer and BRCA-wildtype TNBC. Similarities also exist between high-grade serous ovarian cancer and TNBC, including an association with germline BRCA mutations, sensitivity to platinum agents, and high copy number alteration rates, she said in a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly [ADP-ribose] polymerase) inhibitor, was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

The phase I, dose-escalation study enrolled 70 patients with a diagnosis of recurrent high-grade serous ovarian cancer or TNBC but also allowed documented germline BRCA mutation carriers regardless of histology.

The histology was high-grade serous in 90% of the 46 ovarian cancer patients, while 2% had high-grade endometrioid disease, 4% carcinosarcoma, and 4% poorly differentiated carcinoma. Most of the 24 breast cancer patients (63%) had TNBC, while 29% had estrogen receptor–positive/progesterone receptor–positive disease and 8% had ER+/PR– breast cancer.

Germline BRCA mutations were present in 77% of ovarian and 58% of breast cancer patients. The median age in the two groups was 60 years and 47.5 years, respectively. Prior PARP or P13kinase pathway inhibitors were allowed during dose escalation.

Among ovarian cancer patients, 12 (26%) had a partial response and 22 (48%) had stable disease. Responses were similar in the breast cancer group, with 5 (21%) partial responses and 12 (50%) patients with stable disease, said Dr. Matulonis of the Dana-Farber Cancer Center and Harvard Medical School, both in Boston.

Ten dosing regimens were evaluated in the study, beginning with an initial dose of BKM120 60 mg once daily and olaparib 100 mg twice daily, both given orally on a continuous basis. This elicited two dose-limiting toxicities (DLTs) – grade 3 hyperglycemia and grade 3 transaminitis – and prompted the investigators to back down to dose levels of 40 mg and 50 mg, respectively.

No DLTs occurred until dosing reached BKM120 60 mg and olaparib 300 mg, at which point one grade-4 transaminitis and one grade-3 depression were reported in cycle 2, she said. Dose levels of 50 mg and 300 mg, respectively, were selected for the expansion cohort.

As for why the two DLTs occurred at the initial dose but the same doses were later used without incident, Dr. Matulonis said that one of the patients with a DLT fell out of well-controlled diabetes and the other had liver metastases that accelerated during treatment.

Overall, the most common nonhematologic toxicities of any grade were nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Related hematologic toxicities of any grade were anemia in 23.5%, neutropenia in 12%, and thrombocytopenia and leukopenia, both in 10% of patients.

“Combinations of biologic agents will require establishment of target patient populations using biomarkers in order to predict sensitivity as well as determine mechanisms of resistance,” Dr. Matulonis concluded.

Next-generation sequencing is ongoing for BKM120/olaparib patients and mechanisms of response and resistance are being studied in human ovarian mouse models, she added.

The study was funded by Stand Up to Cancer, the Kathryn Fox Samway Foundation, and participating centers. Olaparib was provided by AstraZeneca and BKM120 by Novartis. Dr. Matulonis reported research funding from AstraZeneca, as well as renumeration for attending a speaker’s bureau.

pwendling@frontlinemedcom.com

On Twitter @pwendl

Combining the poly(ADP-ribose) polymerase inhibitor olaparib and the investigational P13K inhibitor BKM 120 was safe and active in triple-negative breast cancer and ovarian cancer in a phase I trial.

Patients with both BRCA-mutant and BRCA-wildtype breast cancer responded to the combination. One patient with germline BRCA-wildtype triple-negative breast cancer (TNBC) and lung metastases had a partial response and remained on treatment for 20 cycles, or nearly 2 years, study author Dr. Ursula Matulonis reported at the annual meeting of the American Association for Cancer Research.

Rationale for the study lay in data from mouse models showing that combination olaparib and BKM120 was more effective than either drug alone in BRCA-mutant breast cancer and BRCA-wildtype TNBC. Similarities also exist between high-grade serous ovarian cancer and TNBC, including an association with germline BRCA mutations, sensitivity to platinum agents, and high copy number alteration rates, she said in a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly [ADP-ribose] polymerase) inhibitor, was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

The phase I, dose-escalation study enrolled 70 patients with a diagnosis of recurrent high-grade serous ovarian cancer or TNBC but also allowed documented germline BRCA mutation carriers regardless of histology.

The histology was high-grade serous in 90% of the 46 ovarian cancer patients, while 2% had high-grade endometrioid disease, 4% carcinosarcoma, and 4% poorly differentiated carcinoma. Most of the 24 breast cancer patients (63%) had TNBC, while 29% had estrogen receptor–positive/progesterone receptor–positive disease and 8% had ER+/PR– breast cancer.

Germline BRCA mutations were present in 77% of ovarian and 58% of breast cancer patients. The median age in the two groups was 60 years and 47.5 years, respectively. Prior PARP or P13kinase pathway inhibitors were allowed during dose escalation.

Among ovarian cancer patients, 12 (26%) had a partial response and 22 (48%) had stable disease. Responses were similar in the breast cancer group, with 5 (21%) partial responses and 12 (50%) patients with stable disease, said Dr. Matulonis of the Dana-Farber Cancer Center and Harvard Medical School, both in Boston.

Ten dosing regimens were evaluated in the study, beginning with an initial dose of BKM120 60 mg once daily and olaparib 100 mg twice daily, both given orally on a continuous basis. This elicited two dose-limiting toxicities (DLTs) – grade 3 hyperglycemia and grade 3 transaminitis – and prompted the investigators to back down to dose levels of 40 mg and 50 mg, respectively.

No DLTs occurred until dosing reached BKM120 60 mg and olaparib 300 mg, at which point one grade-4 transaminitis and one grade-3 depression were reported in cycle 2, she said. Dose levels of 50 mg and 300 mg, respectively, were selected for the expansion cohort.

As for why the two DLTs occurred at the initial dose but the same doses were later used without incident, Dr. Matulonis said that one of the patients with a DLT fell out of well-controlled diabetes and the other had liver metastases that accelerated during treatment.

Overall, the most common nonhematologic toxicities of any grade were nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Related hematologic toxicities of any grade were anemia in 23.5%, neutropenia in 12%, and thrombocytopenia and leukopenia, both in 10% of patients.

“Combinations of biologic agents will require establishment of target patient populations using biomarkers in order to predict sensitivity as well as determine mechanisms of resistance,” Dr. Matulonis concluded.

Next-generation sequencing is ongoing for BKM120/olaparib patients and mechanisms of response and resistance are being studied in human ovarian mouse models, she added.

The study was funded by Stand Up to Cancer, the Kathryn Fox Samway Foundation, and participating centers. Olaparib was provided by AstraZeneca and BKM120 by Novartis. Dr. Matulonis reported research funding from AstraZeneca, as well as renumeration for attending a speaker’s bureau.

pwendling@frontlinemedcom.com

On Twitter @pwendl

Combining the poly(ADP-ribose) polymerase inhibitor olaparib and the investigational P13K inhibitor BKM 120 was safe and active in triple-negative breast cancer and ovarian cancer in a phase I trial.

Patients with both BRCA-mutant and BRCA-wildtype breast cancer responded to the combination. One patient with germline BRCA-wildtype triple-negative breast cancer (TNBC) and lung metastases had a partial response and remained on treatment for 20 cycles, or nearly 2 years, study author Dr. Ursula Matulonis reported at the annual meeting of the American Association for Cancer Research.

Rationale for the study lay in data from mouse models showing that combination olaparib and BKM120 was more effective than either drug alone in BRCA-mutant breast cancer and BRCA-wildtype TNBC. Similarities also exist between high-grade serous ovarian cancer and TNBC, including an association with germline BRCA mutations, sensitivity to platinum agents, and high copy number alteration rates, she said in a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly [ADP-ribose] polymerase) inhibitor, was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

The phase I, dose-escalation study enrolled 70 patients with a diagnosis of recurrent high-grade serous ovarian cancer or TNBC but also allowed documented germline BRCA mutation carriers regardless of histology.

The histology was high-grade serous in 90% of the 46 ovarian cancer patients, while 2% had high-grade endometrioid disease, 4% carcinosarcoma, and 4% poorly differentiated carcinoma. Most of the 24 breast cancer patients (63%) had TNBC, while 29% had estrogen receptor–positive/progesterone receptor–positive disease and 8% had ER+/PR– breast cancer.

Germline BRCA mutations were present in 77% of ovarian and 58% of breast cancer patients. The median age in the two groups was 60 years and 47.5 years, respectively. Prior PARP or P13kinase pathway inhibitors were allowed during dose escalation.

Among ovarian cancer patients, 12 (26%) had a partial response and 22 (48%) had stable disease. Responses were similar in the breast cancer group, with 5 (21%) partial responses and 12 (50%) patients with stable disease, said Dr. Matulonis of the Dana-Farber Cancer Center and Harvard Medical School, both in Boston.

Ten dosing regimens were evaluated in the study, beginning with an initial dose of BKM120 60 mg once daily and olaparib 100 mg twice daily, both given orally on a continuous basis. This elicited two dose-limiting toxicities (DLTs) – grade 3 hyperglycemia and grade 3 transaminitis – and prompted the investigators to back down to dose levels of 40 mg and 50 mg, respectively.

No DLTs occurred until dosing reached BKM120 60 mg and olaparib 300 mg, at which point one grade-4 transaminitis and one grade-3 depression were reported in cycle 2, she said. Dose levels of 50 mg and 300 mg, respectively, were selected for the expansion cohort.

As for why the two DLTs occurred at the initial dose but the same doses were later used without incident, Dr. Matulonis said that one of the patients with a DLT fell out of well-controlled diabetes and the other had liver metastases that accelerated during treatment.

Overall, the most common nonhematologic toxicities of any grade were nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Related hematologic toxicities of any grade were anemia in 23.5%, neutropenia in 12%, and thrombocytopenia and leukopenia, both in 10% of patients.

“Combinations of biologic agents will require establishment of target patient populations using biomarkers in order to predict sensitivity as well as determine mechanisms of resistance,” Dr. Matulonis concluded.

Next-generation sequencing is ongoing for BKM120/olaparib patients and mechanisms of response and resistance are being studied in human ovarian mouse models, she added.

The study was funded by Stand Up to Cancer, the Kathryn Fox Samway Foundation, and participating centers. Olaparib was provided by AstraZeneca and BKM120 by Novartis. Dr. Matulonis reported research funding from AstraZeneca, as well as renumeration for attending a speaker’s bureau.

pwendling@frontlinemedcom.com

On Twitter @pwendl

Compared with usual care, a moderate- to high-intensity exercise intervention had beneficial effects on chemotherapy completion rates, symptom burden, and return-to-work rates among women with breast cancer who were undergoing adjuvant chemotherapy, according to a study published online April 27 in the Journal of Clinical Oncology.

For the multicenter Physical Exercise During Adjuvant Chemotherapy Effectiveness Study (PACES), 230 women (mean age 51 years) with breast cancer who were undergoing adjuvant chemotherapy were randomized to participate in a high- to moderate-intensity exercise program supervised by physical therapists (n = 76), a low-intensity home-based program (n = 77), or the usual care group (n = 77).

©Luka8au/thinkstockphotos.com

Dose adjustments in the chemotherapy regimen were less frequent in the moderate- to high-intensity exercise group (12%) than in the usual care or low-intensity groups (both 34%, P = .002). Patients in the exercise interventions were more likely to return to work by the 6-month follow up than those with usual care, wrote Ms. Hanna van Waart, a doctoral candidate at the Netherlands Cancer Institute, Amsterdam, and colleagues (J. Clin. Oncol. 2015 Apr. 27 [doi:10.1200/JCO.2014.59.1081]).

“This not only has financial implications, but also carries meaning in terms of quality of life and a sense of return to normalcy,” they wrote.

At completion of chemotherapy, patients from both activity groups reported significantly better physical functioning, less nausea and vomiting, and less pain than did those in the usual care group.

Compared with usual care, a moderate- to high-intensity exercise intervention had beneficial effects on chemotherapy completion rates, symptom burden, and return-to-work rates among women with breast cancer who were undergoing adjuvant chemotherapy, according to a study published online April 27 in the Journal of Clinical Oncology.

For the multicenter Physical Exercise During Adjuvant Chemotherapy Effectiveness Study (PACES), 230 women (mean age 51 years) with breast cancer who were undergoing adjuvant chemotherapy were randomized to participate in a high- to moderate-intensity exercise program supervised by physical therapists (n = 76), a low-intensity home-based program (n = 77), or the usual care group (n = 77).

©Luka8au/thinkstockphotos.com

Dose adjustments in the chemotherapy regimen were less frequent in the moderate- to high-intensity exercise group (12%) than in the usual care or low-intensity groups (both 34%, P = .002). Patients in the exercise interventions were more likely to return to work by the 6-month follow up than those with usual care, wrote Ms. Hanna van Waart, a doctoral candidate at the Netherlands Cancer Institute, Amsterdam, and colleagues (J. Clin. Oncol. 2015 Apr. 27 [doi:10.1200/JCO.2014.59.1081]).

“This not only has financial implications, but also carries meaning in terms of quality of life and a sense of return to normalcy,” they wrote.

At completion of chemotherapy, patients from both activity groups reported significantly better physical functioning, less nausea and vomiting, and less pain than did those in the usual care group.

Compared with usual care, a moderate- to high-intensity exercise intervention had beneficial effects on chemotherapy completion rates, symptom burden, and return-to-work rates among women with breast cancer who were undergoing adjuvant chemotherapy, according to a study published online April 27 in the Journal of Clinical Oncology.

For the multicenter Physical Exercise During Adjuvant Chemotherapy Effectiveness Study (PACES), 230 women (mean age 51 years) with breast cancer who were undergoing adjuvant chemotherapy were randomized to participate in a high- to moderate-intensity exercise program supervised by physical therapists (n = 76), a low-intensity home-based program (n = 77), or the usual care group (n = 77).

©Luka8au/thinkstockphotos.com

Dose adjustments in the chemotherapy regimen were less frequent in the moderate- to high-intensity exercise group (12%) than in the usual care or low-intensity groups (both 34%, P = .002). Patients in the exercise interventions were more likely to return to work by the 6-month follow up than those with usual care, wrote Ms. Hanna van Waart, a doctoral candidate at the Netherlands Cancer Institute, Amsterdam, and colleagues (J. Clin. Oncol. 2015 Apr. 27 [doi:10.1200/JCO.2014.59.1081]).

“This not only has financial implications, but also carries meaning in terms of quality of life and a sense of return to normalcy,” they wrote.

At completion of chemotherapy, patients from both activity groups reported significantly better physical functioning, less nausea and vomiting, and less pain than did those in the usual care group.

Mylan N.V. has announced a voluntary recall of specific lots of injectable products for conditions including rheumatoid arthritis, severe psoriasis, lung cancer, breast cancer, ovarian cancer, and acute nonlymphocytic leukemia because foreign particles were observed during testing of retention samples, according to a statement issued by the company on April 23.

The specific lot numbers can be found on the company’s website.

Affected products include methotrexate injection, USP 25 mg/mL, which is indicated for adult rheumatoid arthritis, severe psoriasis, and some neoplastic diseases. According to Mylan, the contaminated lot was distributed in the United States between Jan. 16, 2014, and March 25, 2014.

Other recalled injectable products include gemcitabine, USP 200 mg, an intravenous product for ovarian cancer, breast cancer, non–small cell lung cancer, and pancreatic cancer; carboplatin 10 mg/mL, indicated for advanced ovarian cancer; and cytarabine, indicated for remission induction in acute nonlymphocytic leukemia in adults and children. The lots for these products were distributed in the United States in various periods of several months during 2014.

The recall is being conducted with the knowledge of the Food and Drug Administration, and any adverse events or quality problems should be reported to the FDA’s MedWatch adverse event reporting program.

hsplete@frontlinemedcom.com

Mylan N.V. has announced a voluntary recall of specific lots of injectable products for conditions including rheumatoid arthritis, severe psoriasis, lung cancer, breast cancer, ovarian cancer, and acute nonlymphocytic leukemia because foreign particles were observed during testing of retention samples, according to a statement issued by the company on April 23.

The specific lot numbers can be found on the company’s website.

Affected products include methotrexate injection, USP 25 mg/mL, which is indicated for adult rheumatoid arthritis, severe psoriasis, and some neoplastic diseases. According to Mylan, the contaminated lot was distributed in the United States between Jan. 16, 2014, and March 25, 2014.

Other recalled injectable products include gemcitabine, USP 200 mg, an intravenous product for ovarian cancer, breast cancer, non–small cell lung cancer, and pancreatic cancer; carboplatin 10 mg/mL, indicated for advanced ovarian cancer; and cytarabine, indicated for remission induction in acute nonlymphocytic leukemia in adults and children. The lots for these products were distributed in the United States in various periods of several months during 2014.

The recall is being conducted with the knowledge of the Food and Drug Administration, and any adverse events or quality problems should be reported to the FDA’s MedWatch adverse event reporting program.

hsplete@frontlinemedcom.com

Mylan N.V. has announced a voluntary recall of specific lots of injectable products for conditions including rheumatoid arthritis, severe psoriasis, lung cancer, breast cancer, ovarian cancer, and acute nonlymphocytic leukemia because foreign particles were observed during testing of retention samples, according to a statement issued by the company on April 23.

The specific lot numbers can be found on the company’s website.

Affected products include methotrexate injection, USP 25 mg/mL, which is indicated for adult rheumatoid arthritis, severe psoriasis, and some neoplastic diseases. According to Mylan, the contaminated lot was distributed in the United States between Jan. 16, 2014, and March 25, 2014.

Other recalled injectable products include gemcitabine, USP 200 mg, an intravenous product for ovarian cancer, breast cancer, non–small cell lung cancer, and pancreatic cancer; carboplatin 10 mg/mL, indicated for advanced ovarian cancer; and cytarabine, indicated for remission induction in acute nonlymphocytic leukemia in adults and children. The lots for these products were distributed in the United States in various periods of several months during 2014.

The recall is being conducted with the knowledge of the Food and Drug Administration, and any adverse events or quality problems should be reported to the FDA’s MedWatch adverse event reporting program.

hsplete@frontlinemedcom.com

Women with breast cancer and BRCA1 mutations had a lower risk of mortality if they underwent oophorectomy, and the benefit was apparent beyond age 50, investigators reported online April 23 in JAMA Oncology.

In the entire cohort that included women with BRCA1 and BRCA2 mutations, breast cancer–related mortality was reduced 56%, and all-cause mortality (including 9 deaths due to ovarian cancer) was reduced 65% with oophorectomy (adjusted HR, 0.35; 95% CI, 0.22-0.56; P < .001).

Dr. Kelly Metcalfe of the Women’s College Research Institute, Toronto, and her colleagues provided evidence in support of BRCA1 testing in women with early-stage breast cancer at the time of diagnosis.

“The data presented here suggest that oophorectomy should be discussed with the patient [with a BRCA1 mutation] shortly after diagnosis. We recommend that the operation be performed in the first year of treatment to maximize the benefit,” the investigators wrote (JAMA Oncol. 2015 Apr. 23 [doi:10.1001/jamaoncol.2015.0658]).

The historical cohort study evaluated 676 women with BRCA1 or BRCA2 mutations and early-stage breast cancer diagnosed between 1975 and 2008. In order to examine the impact of subsequent oophorectomy on mortality risk due to breast cancer, a requirement for inclusion was that both ovaries be intact at the time of diagnosis. The subsequent oophorectomy group included 345 women.

Among the women who underwent oophorectomy, women with a BRCA1 mutation had a significantly reduced risk of breast cancer–related death, but the association was not significant for those with BRCA2 mutations. However, the number of BRCA2 carriers was much smaller than the number of BRCA1 carriers, and the 95% CI range was wide (0.23-1.43). A larger sample is required to determine the strength of an association.

Regardless of BRCA1/2 mutation status, in patients with estrogen receptor–negative breast cancer, oophorectomy had a protective effect (HR, 0.07; 95% CI, 0.01-0.51; P = .009).

Among 14 women over age 50 with estrogen receptor–negative cancer who did not undergo oophorectomy, 3 (21%) died; of the 15 who underwent the surgery, none died. Based on this finding, and a previous study indicating a protective effect of oophorectomy on the risk of primary breast cancer in women over 50, the researchers concluded that “the postmenopausal ovary remains active in terms of androgen production and that this affects cancer risk and progression, either directly or through aromatization to estrogen.”

Women with breast cancer and BRCA1 mutations had a lower risk of mortality if they underwent oophorectomy, and the benefit was apparent beyond age 50, investigators reported online April 23 in JAMA Oncology.

In the entire cohort that included women with BRCA1 and BRCA2 mutations, breast cancer–related mortality was reduced 56%, and all-cause mortality (including 9 deaths due to ovarian cancer) was reduced 65% with oophorectomy (adjusted HR, 0.35; 95% CI, 0.22-0.56; P < .001).

Dr. Kelly Metcalfe of the Women’s College Research Institute, Toronto, and her colleagues provided evidence in support of BRCA1 testing in women with early-stage breast cancer at the time of diagnosis.

“The data presented here suggest that oophorectomy should be discussed with the patient [with a BRCA1 mutation] shortly after diagnosis. We recommend that the operation be performed in the first year of treatment to maximize the benefit,” the investigators wrote (JAMA Oncol. 2015 Apr. 23 [doi:10.1001/jamaoncol.2015.0658]).

The historical cohort study evaluated 676 women with BRCA1 or BRCA2 mutations and early-stage breast cancer diagnosed between 1975 and 2008. In order to examine the impact of subsequent oophorectomy on mortality risk due to breast cancer, a requirement for inclusion was that both ovaries be intact at the time of diagnosis. The subsequent oophorectomy group included 345 women.

Among the women who underwent oophorectomy, women with a BRCA1 mutation had a significantly reduced risk of breast cancer–related death, but the association was not significant for those with BRCA2 mutations. However, the number of BRCA2 carriers was much smaller than the number of BRCA1 carriers, and the 95% CI range was wide (0.23-1.43). A larger sample is required to determine the strength of an association.

Regardless of BRCA1/2 mutation status, in patients with estrogen receptor–negative breast cancer, oophorectomy had a protective effect (HR, 0.07; 95% CI, 0.01-0.51; P = .009).

Among 14 women over age 50 with estrogen receptor–negative cancer who did not undergo oophorectomy, 3 (21%) died; of the 15 who underwent the surgery, none died. Based on this finding, and a previous study indicating a protective effect of oophorectomy on the risk of primary breast cancer in women over 50, the researchers concluded that “the postmenopausal ovary remains active in terms of androgen production and that this affects cancer risk and progression, either directly or through aromatization to estrogen.”

Women with breast cancer and BRCA1 mutations had a lower risk of mortality if they underwent oophorectomy, and the benefit was apparent beyond age 50, investigators reported online April 23 in JAMA Oncology.

In the entire cohort that included women with BRCA1 and BRCA2 mutations, breast cancer–related mortality was reduced 56%, and all-cause mortality (including 9 deaths due to ovarian cancer) was reduced 65% with oophorectomy (adjusted HR, 0.35; 95% CI, 0.22-0.56; P < .001).

Dr. Kelly Metcalfe of the Women’s College Research Institute, Toronto, and her colleagues provided evidence in support of BRCA1 testing in women with early-stage breast cancer at the time of diagnosis.

“The data presented here suggest that oophorectomy should be discussed with the patient [with a BRCA1 mutation] shortly after diagnosis. We recommend that the operation be performed in the first year of treatment to maximize the benefit,” the investigators wrote (JAMA Oncol. 2015 Apr. 23 [doi:10.1001/jamaoncol.2015.0658]).

The historical cohort study evaluated 676 women with BRCA1 or BRCA2 mutations and early-stage breast cancer diagnosed between 1975 and 2008. In order to examine the impact of subsequent oophorectomy on mortality risk due to breast cancer, a requirement for inclusion was that both ovaries be intact at the time of diagnosis. The subsequent oophorectomy group included 345 women.

Among the women who underwent oophorectomy, women with a BRCA1 mutation had a significantly reduced risk of breast cancer–related death, but the association was not significant for those with BRCA2 mutations. However, the number of BRCA2 carriers was much smaller than the number of BRCA1 carriers, and the 95% CI range was wide (0.23-1.43). A larger sample is required to determine the strength of an association.

Regardless of BRCA1/2 mutation status, in patients with estrogen receptor–negative breast cancer, oophorectomy had a protective effect (HR, 0.07; 95% CI, 0.01-0.51; P = .009).

Among 14 women over age 50 with estrogen receptor–negative cancer who did not undergo oophorectomy, 3 (21%) died; of the 15 who underwent the surgery, none died. Based on this finding, and a previous study indicating a protective effect of oophorectomy on the risk of primary breast cancer in women over 50, the researchers concluded that “the postmenopausal ovary remains active in terms of androgen production and that this affects cancer risk and progression, either directly or through aromatization to estrogen.”

Background Treatment-related symptoms and decreased health-related quality of life (HRQoL) frequently occur during chemotherapy for breast cancer. Although research findings suggest that yoga can reduce symptoms and improve HRQoL after treatment, potential benefits of yoga during chemotherapy have received minimal attention.

Objective To estimate accrual, adherence, study retention, and preliminary efficacy of a yoga intervention compared with an active control group for breast cancer patients during chemotherapy.

Methods Women with stage I-III breast cancer were recruited from 3 community cancer clinics and randomized to 10 weeks of gentle yoga or wellness education. Depressive symptoms, fatigue, sleep, and HRQoL were assessed at baseline, mid-intervention (Week 5), and after intervention (Week 10).

Results 40 women aged 29-83 years (median, 48 years; 88% white) were randomized to yoga (n = 22) or wellness education (n = 18). The groups did not differ significantly on baseline characteristics, adherence, or study retention. Participant feedback was positive and comparable between groups. Meaningful within-group differences were identified for sleep adequacy and quantity in yoga participants and for somnolence in wellness-education participants.

Limitations Small sample size and lack of a usual-care control group.

Conclusions This study established feasibility of a community-based randomized trial of yoga and an active comparison group for women undergoing chemotherapy for breast cancer. Preliminary efficacy estimates suggest that yoga improves sleep adequacy. Symptom severity and interference remained stable during chemotherapy for the yoga group and showed a trend toward increasing in the control group. The study highlighted obstacles to multisite yoga research during cancer treatment.

Funding/sponsorship National Cancer Institute (3U10 CA081851, PI: Shaw; R25 CA122061, PI: Avis); Translational Science Institute, Wake Forest School of Medicine

Click on the PDF icon at the top of this introduction to read the full article.

Background Treatment-related symptoms and decreased health-related quality of life (HRQoL) frequently occur during chemotherapy for breast cancer. Although research findings suggest that yoga can reduce symptoms and improve HRQoL after treatment, potential benefits of yoga during chemotherapy have received minimal attention.

Objective To estimate accrual, adherence, study retention, and preliminary efficacy of a yoga intervention compared with an active control group for breast cancer patients during chemotherapy.

Methods Women with stage I-III breast cancer were recruited from 3 community cancer clinics and randomized to 10 weeks of gentle yoga or wellness education. Depressive symptoms, fatigue, sleep, and HRQoL were assessed at baseline, mid-intervention (Week 5), and after intervention (Week 10).

Results 40 women aged 29-83 years (median, 48 years; 88% white) were randomized to yoga (n = 22) or wellness education (n = 18). The groups did not differ significantly on baseline characteristics, adherence, or study retention. Participant feedback was positive and comparable between groups. Meaningful within-group differences were identified for sleep adequacy and quantity in yoga participants and for somnolence in wellness-education participants.

Limitations Small sample size and lack of a usual-care control group.

Conclusions This study established feasibility of a community-based randomized trial of yoga and an active comparison group for women undergoing chemotherapy for breast cancer. Preliminary efficacy estimates suggest that yoga improves sleep adequacy. Symptom severity and interference remained stable during chemotherapy for the yoga group and showed a trend toward increasing in the control group. The study highlighted obstacles to multisite yoga research during cancer treatment.

Funding/sponsorship National Cancer Institute (3U10 CA081851, PI: Shaw; R25 CA122061, PI: Avis); Translational Science Institute, Wake Forest School of Medicine

Click on the PDF icon at the top of this introduction to read the full article.

Background Treatment-related symptoms and decreased health-related quality of life (HRQoL) frequently occur during chemotherapy for breast cancer. Although research findings suggest that yoga can reduce symptoms and improve HRQoL after treatment, potential benefits of yoga during chemotherapy have received minimal attention.

Objective To estimate accrual, adherence, study retention, and preliminary efficacy of a yoga intervention compared with an active control group for breast cancer patients during chemotherapy.

Methods Women with stage I-III breast cancer were recruited from 3 community cancer clinics and randomized to 10 weeks of gentle yoga or wellness education. Depressive symptoms, fatigue, sleep, and HRQoL were assessed at baseline, mid-intervention (Week 5), and after intervention (Week 10).

Results 40 women aged 29-83 years (median, 48 years; 88% white) were randomized to yoga (n = 22) or wellness education (n = 18). The groups did not differ significantly on baseline characteristics, adherence, or study retention. Participant feedback was positive and comparable between groups. Meaningful within-group differences were identified for sleep adequacy and quantity in yoga participants and for somnolence in wellness-education participants.

Limitations Small sample size and lack of a usual-care control group.

Conclusions This study established feasibility of a community-based randomized trial of yoga and an active comparison group for women undergoing chemotherapy for breast cancer. Preliminary efficacy estimates suggest that yoga improves sleep adequacy. Symptom severity and interference remained stable during chemotherapy for the yoga group and showed a trend toward increasing in the control group. The study highlighted obstacles to multisite yoga research during cancer treatment.

Funding/sponsorship National Cancer Institute (3U10 CA081851, PI: Shaw; R25 CA122061, PI: Avis); Translational Science Institute, Wake Forest School of Medicine

Click on the PDF icon at the top of this introduction to read the full article.

The US Food and Drug Administration (FDA) recently approved NEPA, an oral fixed-dose combination of netupitant and palonosetron for treatment of chemotherapy-induced nausea and vomiting (CINV). Palonosetron is a pharmacologically distinct, best-in-class serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor antagonist, which prevents CINV during the acute phase (0-24 h) after administration of chemotherapy, and netupitant is a potent and selective neurokinin-1 (NK-1) receptor antagonist, which prevents CINV during both the acute and delayed (25-120 h) phases. The 2 agents have also been shown potentially to act synergistically in inhibiting NK-1 receptor activity.

Click on the PDF icon at the top of this introduction to read the full article.

The US Food and Drug Administration (FDA) recently approved NEPA, an oral fixed-dose combination of netupitant and palonosetron for treatment of chemotherapy-induced nausea and vomiting (CINV). Palonosetron is a pharmacologically distinct, best-in-class serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor antagonist, which prevents CINV during the acute phase (0-24 h) after administration of chemotherapy, and netupitant is a potent and selective neurokinin-1 (NK-1) receptor antagonist, which prevents CINV during both the acute and delayed (25-120 h) phases. The 2 agents have also been shown potentially to act synergistically in inhibiting NK-1 receptor activity.

Click on the PDF icon at the top of this introduction to read the full article.

The US Food and Drug Administration (FDA) recently approved NEPA, an oral fixed-dose combination of netupitant and palonosetron for treatment of chemotherapy-induced nausea and vomiting (CINV). Palonosetron is a pharmacologically distinct, best-in-class serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor antagonist, which prevents CINV during the acute phase (0-24 h) after administration of chemotherapy, and netupitant is a potent and selective neurokinin-1 (NK-1) receptor antagonist, which prevents CINV during both the acute and delayed (25-120 h) phases. The 2 agents have also been shown potentially to act synergistically in inhibiting NK-1 receptor activity.

Click on the PDF icon at the top of this introduction to read the full article.

Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.

MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).

© 2015 AACR/Todd Buchanan

This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.

“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”

There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.

TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.

TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.

MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.

The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.

The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.

At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.

Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.

“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”

Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.

MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.

Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.

Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.

A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.

pwendling@frontlinemedcom.com

On Twitter @pwendl

Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.

MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).

© 2015 AACR/Todd Buchanan

This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.

“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”

There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.

TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.

TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.

MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.

The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.

The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.

At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.

Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.

“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”

Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.

MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.

Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.

Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.

A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.

pwendling@frontlinemedcom.com

On Twitter @pwendl

Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.

MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).

© 2015 AACR/Todd Buchanan

This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.

“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”

There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.

TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.

TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.

MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.

The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.

The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.

At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.

Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.

“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”

Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.

MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.

Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.

Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.

A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.

pwendling@frontlinemedcom.com

On Twitter @pwendl