FDA News

FDA approves pembrolizumab for hepatocellular carcinoma, lung cancer indications

The FDA approved pembrolizumab for two additional indications.

The agency granted accelerated approval to pembrolizumab (Keytruda, Merck) — an anti-PD-1 therapy — for treatment of patients with hepatocellular carcinoma who previously received sorafenib (Nexavar, Bayer).

The agent also now is approved for use in combination with carboplatin and either paclitaxel or nab-paclitaxel for first-line treatment of metastatic squamous non-small cell lung cancer.

HCC indication

The FDA based the HCC indication on results of the single-arm, open-label KEYNOTE-224 trial.

Balazs Halmos, MD, MS
Balazs Halmos

The trial included 104 patients (median age, 68 years; 83% men; 81% white; 14% Asian) with HCC who experienced disease progression during or after sorafenib treatment or who were intolerant to sorafenib.

All patients had ECOG performance status of 0 (61%) or 1 (39%), and all had Child-Pugh class A liver impairment (A5, 72%; A6, 22%; B7, 5%; and B8, 1%).

In addition, 21% were hepatitis B virus seropositive, 25% were hepatitis C virus seropositive and 9% were seropositive for both.

Sixty-four percent of patients had extrahepatic disease, 17% had vascular invasion and 9% had both.

Patients received pembrolizumab 200 mg every 3 weeks for up to 24 months, or until disease progression or unacceptable toxicity.

Objective response rate and duration of response served as the primary efficacy outcomes.

Median pembrolizumab exposure was 4.2 months (range, 1 day to 1.5 years).

Researchers reported an ORR of 17% (95% CI, 11-26), including a 1% complete response rate and 16% partial response rate.

Among the 18 patients who achieved a response, 16 (89%) remained in response for at least 6 months, and 10 (56%) remained in response for at least 12 months.

Adverse reactions among pembrolizumab-treated patients with HCC appeared similar to those observed in other studies of the agent for treatment of melanoma or NSCLC, with the exception of increased incidence of ascites (grade 3/grade 4, 8%) and immune-mediated hepatitis (2.9%).

Grade 3 or grade 4 laboratory abnormalities that occurred more frequently in the KEYNOTE-224 trial included elevated alanine transaminase (20%), elevated aspartate transaminase (9%) and hyperbilirubinemia (10%).

“Hepatocellular carcinoma is the most common type of liver cancer in adults and, [although] we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease,” Andrew X. Zhu, MD, PhD, lead investigator of KEYNOTE-224, director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, said in a Merck-issued press release. “[This] approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib.”

NSCLC indication

The lung cancer approval makes pembrolizumab the first anti-PD-1 therapy approved for first-line treatment of squamous NSCLC regardless of tumor PD-L1 expression.

“[This] approval expands our current lung cancer indications to include combination treatment in patients with squamous cell carcinoma, a type of lung cancer that is particularly difficult to treat,” Roger M. Perlmutter, MD, PhD, president of Merck Research Laboratories, said in a company-issued press release. “Approval by the FDA has the potential to mean that Keytruda can be used to improve survival for more patients with this debilitating disease.”

The FDA based the approval on results of the randomized phase 3 KEYNOTE-407 trial, which included 559 patients with metastatic squamous NSCLC who had received no prior systemic treatment for metastatic disease. Patients could participate regardless of tumor PD-L1 expression status.

Researchers randomly assigned 278 patients to receive 200 mg pembrolizumab and carboplatin every 3 weeks for four cycles, plus paclitaxel every 3 weeks for four cycles or nab-paclitaxel on days 1, 8 and 15 of every 3-week cycle for four cycles, followed by 200 mg pembrolizumab every 3 weeks.

The other 281 patients received placebo plus the same chemotherapy regimen.

Treatment continued for 24 months, or until disease progression or unacceptable toxicity. Patients assigned placebo were given the opportunity to switch to single-agent pembrolizumab at the time of disease progression.

OS, PFS and ORR served as the primary efficacy outcome measures.

Results showed the pembrolizumab regimen significantly improved OS (median, 15.9 months vs. 11.3 months; HR = 0.64; 95% CI, 0.49-0.85), PFS (median, 6.4 months vs. 4.8 months; HR = 0.56; 95% CI, 0.45-0.7) and ORR (58% vs. 35%; P = .0008).

Median duration of response was 7.2 months (range, 2.4-12.4+) with pembrolizumab vs. 4.9 months (range, 2-12.4+) with placebo.

Safety data from the first 101 patients assigned pembrolizumab plus carboplatin and either paclitaxel or nab-paclitaxel showed 15% discontinued treatment due to adverse reactions.

Also, 43% of patients required treatment interruption due to adverse events, the most common of which were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%) and diarrhea (2%).

The most frequent serious adverse reactions were febrile neutropenia (6%), pneumonia (6%) and urinary tract infection (3%).

“The results that support this approval from the KEYNOTE-407 trial demonstrate the potential of Keytruda in combination with chemotherapy [for] patients with squamous non-small cell lung cancer, regardless of PD-L1 expression,” Balazs Halmos, MD, MS, director of the multidisciplinary thoracic oncology program at Montefiore Einstein Center for Cancer Care and director of clinical cancer genomics at Albert Einstein College of Medicine, said in a press release. “With this important approval, more patients will have the opportunity to benefit from immunotherapy.”

Pembrolizumab now is approved for 14 indications as treatment for certain patients with melanoma, lung cancer, HCC, head and neck cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, gastric cancer, cervical cancer and microsatellite instability-high cancers.

The FDA approved pembrolizumab for two additional indications.

The agency granted accelerated approval to pembrolizumab (Keytruda, Merck) — an anti-PD-1 therapy — for treatment of patients with hepatocellular carcinoma who previously received sorafenib (Nexavar, Bayer).

The agent also now is approved for use in combination with carboplatin and either paclitaxel or nab-paclitaxel for first-line treatment of metastatic squamous non-small cell lung cancer.

HCC indication

The FDA based the HCC indication on results of the single-arm, open-label KEYNOTE-224 trial.

Balazs Halmos, MD, MS
Balazs Halmos

The trial included 104 patients (median age, 68 years; 83% men; 81% white; 14% Asian) with HCC who experienced disease progression during or after sorafenib treatment or who were intolerant to sorafenib.

All patients had ECOG performance status of 0 (61%) or 1 (39%), and all had Child-Pugh class A liver impairment (A5, 72%; A6, 22%; B7, 5%; and B8, 1%).

In addition, 21% were hepatitis B virus seropositive, 25% were hepatitis C virus seropositive and 9% were seropositive for both.

Sixty-four percent of patients had extrahepatic disease, 17% had vascular invasion and 9% had both.

Patients received pembrolizumab 200 mg every 3 weeks for up to 24 months, or until disease progression or unacceptable toxicity.

Objective response rate and duration of response served as the primary efficacy outcomes.

Median pembrolizumab exposure was 4.2 months (range, 1 day to 1.5 years).

Researchers reported an ORR of 17% (95% CI, 11-26), including a 1% complete response rate and 16% partial response rate.

Among the 18 patients who achieved a response, 16 (89%) remained in response for at least 6 months, and 10 (56%) remained in response for at least 12 months.

Adverse reactions among pembrolizumab-treated patients with HCC appeared similar to those observed in other studies of the agent for treatment of melanoma or NSCLC, with the exception of increased incidence of ascites (grade 3/grade 4, 8%) and immune-mediated hepatitis (2.9%).

Grade 3 or grade 4 laboratory abnormalities that occurred more frequently in the KEYNOTE-224 trial included elevated alanine transaminase (20%), elevated aspartate transaminase (9%) and hyperbilirubinemia (10%).

“Hepatocellular carcinoma is the most common type of liver cancer in adults and, [although] we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease,” Andrew X. Zhu, MD, PhD, lead investigator of KEYNOTE-224, director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, said in a Merck-issued press release. “[This] approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib.”

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NSCLC indication

The lung cancer approval makes pembrolizumab the first anti-PD-1 therapy approved for first-line treatment of squamous NSCLC regardless of tumor PD-L1 expression.

“[This] approval expands our current lung cancer indications to include combination treatment in patients with squamous cell carcinoma, a type of lung cancer that is particularly difficult to treat,” Roger M. Perlmutter, MD, PhD, president of Merck Research Laboratories, said in a company-issued press release. “Approval by the FDA has the potential to mean that Keytruda can be used to improve survival for more patients with this debilitating disease.”

The FDA based the approval on results of the randomized phase 3 KEYNOTE-407 trial, which included 559 patients with metastatic squamous NSCLC who had received no prior systemic treatment for metastatic disease. Patients could participate regardless of tumor PD-L1 expression status.

Researchers randomly assigned 278 patients to receive 200 mg pembrolizumab and carboplatin every 3 weeks for four cycles, plus paclitaxel every 3 weeks for four cycles or nab-paclitaxel on days 1, 8 and 15 of every 3-week cycle for four cycles, followed by 200 mg pembrolizumab every 3 weeks.

The other 281 patients received placebo plus the same chemotherapy regimen.

Treatment continued for 24 months, or until disease progression or unacceptable toxicity. Patients assigned placebo were given the opportunity to switch to single-agent pembrolizumab at the time of disease progression.

OS, PFS and ORR served as the primary efficacy outcome measures.

Results showed the pembrolizumab regimen significantly improved OS (median, 15.9 months vs. 11.3 months; HR = 0.64; 95% CI, 0.49-0.85), PFS (median, 6.4 months vs. 4.8 months; HR = 0.56; 95% CI, 0.45-0.7) and ORR (58% vs. 35%; P = .0008).

Median duration of response was 7.2 months (range, 2.4-12.4+) with pembrolizumab vs. 4.9 months (range, 2-12.4+) with placebo.

Safety data from the first 101 patients assigned pembrolizumab plus carboplatin and either paclitaxel or nab-paclitaxel showed 15% discontinued treatment due to adverse reactions.

Also, 43% of patients required treatment interruption due to adverse events, the most common of which were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%) and diarrhea (2%).

The most frequent serious adverse reactions were febrile neutropenia (6%), pneumonia (6%) and urinary tract infection (3%).

“The results that support this approval from the KEYNOTE-407 trial demonstrate the potential of Keytruda in combination with chemotherapy [for] patients with squamous non-small cell lung cancer, regardless of PD-L1 expression,” Balazs Halmos, MD, MS, director of the multidisciplinary thoracic oncology program at Montefiore Einstein Center for Cancer Care and director of clinical cancer genomics at Albert Einstein College of Medicine, said in a press release. “With this important approval, more patients will have the opportunity to benefit from immunotherapy.”

Pembrolizumab now is approved for 14 indications as treatment for certain patients with melanoma, lung cancer, HCC, head and neck cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, gastric cancer, cervical cancer and microsatellite instability-high cancers.