In the JournalsPerspective

Pembrolizumab active in PD-L1–positive NSCLC, superior to ipilimumab in treatment-naive advanced melanoma

PHILADELPHIA — Patients with non–small cell lung cancer, as well as those with untreated advanced melanoma, may derive considerable benefit from pembrolizumab, according to results of two studies presented at the American Association for Cancer Research Annual Meeting.

Pembrolizumab (Keytruda, Merck) — an anti-programmed cell death-1 (PD-1) monoclonal antibody — is approved for second-line therapy of patients with metastatic melanoma whose disease progressed during treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) or BRAF inhibitors. However, the agent is currently under investigation in a variety of other indications, including lung, gastric, bladder, and head and neck cancers.

Edward B. Garon, MD, associate professor of medicine at the David Geffen School of Medicine at UCLA, presented data that showed pembrolizumab induced durable response rates and appeared tolerable in previously treated and treatment-naive patients with NSCLC.

Preliminary data from a training cohort (n = 182) indicated the objective response rate with pembrolizumab was higher in patients who had membranous programmed death ligand-1 (PD-L1) expression in at least 50% of their tumor cells (proportion score ≥ 50%). Garon and colleagues sought to confirm these results in an independent validation cohort composed of 313 patients who received pembrolizumab in one of three doses: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg doses every 2 weeks.

An analysis of both cohorts (n = 495) revealed an ORR of 19.4%, and the median duration of response was 12.4 months. Researchers reported median PFS of 3.7 months and median OS of 12 months.

Garon and colleagues assessed PD-L1 status in tumor samples through an immunohistochemistry clinical trial assay using the 22C3 antibody clone (Merck). That analysis included 204 evaluable patients in the validation cohort.

Researchers reported the highest ORR among patients with a proportion score of at least 50% (n = 73; ORR = 45.2%), followed by those with a proportion score between 1% and 49% (n = 103; ORR = 16.5%), and those with a proportion score less than 1% (n = 28; ORR = 10.7%).

The association between ORR and PD-L1 expression persisted in patients whether they were previously treated (proportion score ≥ 50%, ORR = 43.9%) or treatment naive (ORR = 50%).

Median PFS was 6.3 months (95% CI, 2.9-12.5) among patients with the highest proportion score compared with 2.3 months (95% CI, 2.1-4) among patients with the lowest proportion score.

Median follow-up for OS analyses was 10.9 months. Median OS was not yet reached (95% CI, 13.7-not reached) among patients with the highest proportion score, whereas patients with the lowest proportion score achieved a median OS of 8.8 months (95% CI, 5.5-12).

“The drug was particularly beneficial in patients who had high-staining for PD-L1,” Garon told HemOnc Today. “In that group of patients, the response rate was nearly 50%, median PFS exceeded 6 months and median OS was not reached after 10.9 months. So, with this data, there is now an indication that patients with this high level of expression are likely to derive benefit from pembrolizumab.”

Antoni Ribas

Antoni Ribas

In the second study, Antoni Ribas, MD, PhD, professor of hematology and oncology and director of the Tumor Immunology Program Area at UCLA Jonsson Comprehensive Cancer Center, and colleagues compared pembrolizumab vs. ipilimumab as first-line treatment for patients with advanced melanoma.

The results of this trial represent the first randomized comparison of two FDA-approved immune checkpoint inhibitors for the first-line treatment of advanced melanoma.

“Not that long ago, when we were in front of our patients with melanoma and discussing treatments, one in 10 would benefit at most, and most of these were temporary effects,” Ribas said during a press conference. “This has changed in the last few years with the development of new agents that turn on the immune system.”

The analysis included 834 patients with metastatic melanoma who had not previously received ipilimumab. Eighty percent of patients were PD-L1 positive — defined as staining in 1% or more of tumor cells — and 36% harbored BRAF V600 mutations.

Researchers randomly assigned patients 1:1:1 to 10 mg/kg pembrolizumab every other week, 10 mg/kg pembrolizumab every 3 weeks, or four 3-mg/kg doses of ipilimumab every 3 weeks.

PFS and OS served as the study’s primary endpoints. Secondary endpoints included ORR and safety.

Median follow-up for interim PFS analysis was 8 months. After 502 PFS events, pembrolizumab at both doses was associated with a 42% reduction in risk for progression compared with ipilimumab (HR = 0.58; P .00001).

More patients assigned pembrolizumab achieved 6-month PFS (every 2 weeks, 47.3%; every 3 weeks, 46.4%) compared with patients in the ipilimumab arm (26.5%).

Median follow-up for OS was 14 months. After 202 deaths occurred, both doses of pembrolizumab were associated with a significant OS benefit vs. ipilimumab (every-other-week schedule, HR = 0.6; 95% CI, 0.43-0.84; every-3-weeks schedule, HR = 0.56; 95% CI, 0.4-0.78).

Median survival had not yet been reached for either of the pembrolizumab cohorts. Median survival for the ipilimumab arm also had not yet been reached, but the lower bound of the 95% CI was 12.7 months.

“This study is outperforming all of our expectations,” Ribas said. “Even the ipilimumab arm is doing much better than expected.”

Researchers reported a higher rate of 12-month OS in the pembrolizumab cohorts (every other week, 74%; every 3 weeks, 68%) than the ipilimumab cohort (58%).

The ORR was 11.9% for patients assigned ipilimumab, whereas the ORR was 33.7% (P = .00013) for patients assigned pembrolizumab every 2 weeks and 32.9% (P = .00002) for patients assigned pembrolizumab every 3 weeks.

Researchers reported high rates of ongoing responses in all three cohorts (pembrolizumab every 2 weeks, 89%; pembrolizumab every 3 weeks, 97%; ipilimumab, 88%).

“These results meet and exceed the baseline assumptions of the benefit of pembrolizumab over ipilimumab,” Ribas said in a press release. “I hope the drug regulatory agencies around the world act fast on approving pembrolizumab for the front-line therapy of metastatic melanoma. I think we made a remarkable advance in the treatment of patients with melanoma. We had the biggest change in our thinking about how to use the immune system to treat cancer 2 decades ago, and now we have clear evidence that this approach helps patients.” – by Alexandra Todak

References:

The following were presented at the American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.

Garon EB, at al. Abstract CT104.

Ribas A, et al. Abstract CT101.

For more information:

Edward B. Garon, MD, can be reached at UCLA Hematology Oncology Santa Monica, 2020 Santa Monica Blvd., Suite 600, Santa Monica, CA 90404; email: egaron@mednet.ucla.edu.

Disclosure: Both studies were funded by Merck. Garon reports research funding paid to his institution from Merck. Ribas reports a consultant role with and honoraria paid to his institution from Merck.

PHILADELPHIA — Patients with non–small cell lung cancer, as well as those with untreated advanced melanoma, may derive considerable benefit from pembrolizumab, according to results of two studies presented at the American Association for Cancer Research Annual Meeting.

Pembrolizumab (Keytruda, Merck) — an anti-programmed cell death-1 (PD-1) monoclonal antibody — is approved for second-line therapy of patients with metastatic melanoma whose disease progressed during treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) or BRAF inhibitors. However, the agent is currently under investigation in a variety of other indications, including lung, gastric, bladder, and head and neck cancers.

Edward B. Garon, MD, associate professor of medicine at the David Geffen School of Medicine at UCLA, presented data that showed pembrolizumab induced durable response rates and appeared tolerable in previously treated and treatment-naive patients with NSCLC.

Preliminary data from a training cohort (n = 182) indicated the objective response rate with pembrolizumab was higher in patients who had membranous programmed death ligand-1 (PD-L1) expression in at least 50% of their tumor cells (proportion score ≥ 50%). Garon and colleagues sought to confirm these results in an independent validation cohort composed of 313 patients who received pembrolizumab in one of three doses: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg doses every 2 weeks.

An analysis of both cohorts (n = 495) revealed an ORR of 19.4%, and the median duration of response was 12.4 months. Researchers reported median PFS of 3.7 months and median OS of 12 months.

Garon and colleagues assessed PD-L1 status in tumor samples through an immunohistochemistry clinical trial assay using the 22C3 antibody clone (Merck). That analysis included 204 evaluable patients in the validation cohort.

Researchers reported the highest ORR among patients with a proportion score of at least 50% (n = 73; ORR = 45.2%), followed by those with a proportion score between 1% and 49% (n = 103; ORR = 16.5%), and those with a proportion score less than 1% (n = 28; ORR = 10.7%).

The association between ORR and PD-L1 expression persisted in patients whether they were previously treated (proportion score ≥ 50%, ORR = 43.9%) or treatment naive (ORR = 50%).

Median PFS was 6.3 months (95% CI, 2.9-12.5) among patients with the highest proportion score compared with 2.3 months (95% CI, 2.1-4) among patients with the lowest proportion score.

Median follow-up for OS analyses was 10.9 months. Median OS was not yet reached (95% CI, 13.7-not reached) among patients with the highest proportion score, whereas patients with the lowest proportion score achieved a median OS of 8.8 months (95% CI, 5.5-12).

“The drug was particularly beneficial in patients who had high-staining for PD-L1,” Garon told HemOnc Today. “In that group of patients, the response rate was nearly 50%, median PFS exceeded 6 months and median OS was not reached after 10.9 months. So, with this data, there is now an indication that patients with this high level of expression are likely to derive benefit from pembrolizumab.”

Antoni Ribas

Antoni Ribas

In the second study, Antoni Ribas, MD, PhD, professor of hematology and oncology and director of the Tumor Immunology Program Area at UCLA Jonsson Comprehensive Cancer Center, and colleagues compared pembrolizumab vs. ipilimumab as first-line treatment for patients with advanced melanoma.

The results of this trial represent the first randomized comparison of two FDA-approved immune checkpoint inhibitors for the first-line treatment of advanced melanoma.

“Not that long ago, when we were in front of our patients with melanoma and discussing treatments, one in 10 would benefit at most, and most of these were temporary effects,” Ribas said during a press conference. “This has changed in the last few years with the development of new agents that turn on the immune system.”

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The analysis included 834 patients with metastatic melanoma who had not previously received ipilimumab. Eighty percent of patients were PD-L1 positive — defined as staining in 1% or more of tumor cells — and 36% harbored BRAF V600 mutations.

Researchers randomly assigned patients 1:1:1 to 10 mg/kg pembrolizumab every other week, 10 mg/kg pembrolizumab every 3 weeks, or four 3-mg/kg doses of ipilimumab every 3 weeks.

PFS and OS served as the study’s primary endpoints. Secondary endpoints included ORR and safety.

Median follow-up for interim PFS analysis was 8 months. After 502 PFS events, pembrolizumab at both doses was associated with a 42% reduction in risk for progression compared with ipilimumab (HR = 0.58; P .00001).

More patients assigned pembrolizumab achieved 6-month PFS (every 2 weeks, 47.3%; every 3 weeks, 46.4%) compared with patients in the ipilimumab arm (26.5%).

Median follow-up for OS was 14 months. After 202 deaths occurred, both doses of pembrolizumab were associated with a significant OS benefit vs. ipilimumab (every-other-week schedule, HR = 0.6; 95% CI, 0.43-0.84; every-3-weeks schedule, HR = 0.56; 95% CI, 0.4-0.78).

Median survival had not yet been reached for either of the pembrolizumab cohorts. Median survival for the ipilimumab arm also had not yet been reached, but the lower bound of the 95% CI was 12.7 months.

“This study is outperforming all of our expectations,” Ribas said. “Even the ipilimumab arm is doing much better than expected.”

Researchers reported a higher rate of 12-month OS in the pembrolizumab cohorts (every other week, 74%; every 3 weeks, 68%) than the ipilimumab cohort (58%).

The ORR was 11.9% for patients assigned ipilimumab, whereas the ORR was 33.7% (P = .00013) for patients assigned pembrolizumab every 2 weeks and 32.9% (P = .00002) for patients assigned pembrolizumab every 3 weeks.

Researchers reported high rates of ongoing responses in all three cohorts (pembrolizumab every 2 weeks, 89%; pembrolizumab every 3 weeks, 97%; ipilimumab, 88%).

“These results meet and exceed the baseline assumptions of the benefit of pembrolizumab over ipilimumab,” Ribas said in a press release. “I hope the drug regulatory agencies around the world act fast on approving pembrolizumab for the front-line therapy of metastatic melanoma. I think we made a remarkable advance in the treatment of patients with melanoma. We had the biggest change in our thinking about how to use the immune system to treat cancer 2 decades ago, and now we have clear evidence that this approach helps patients.” – by Alexandra Todak

References:

The following were presented at the American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.

Garon EB, at al. Abstract CT104.

Ribas A, et al. Abstract CT101.

For more information:

Edward B. Garon, MD, can be reached at UCLA Hematology Oncology Santa Monica, 2020 Santa Monica Blvd., Suite 600, Santa Monica, CA 90404; email: egaron@mednet.ucla.edu.

Disclosure: Both studies were funded by Merck. Garon reports research funding paid to his institution from Merck. Ribas reports a consultant role with and honoraria paid to his institution from Merck.

    Perspective
    Suzanne L. Topalian

    Suzanne L. Topalian

    To put the results of Ribas and colleagues into context, ipilimumab was approved for first-line therapy for patients with advanced melanoma in 2011. That was a landmark moment not only for melanoma — because it was the first drug ever to show a survival advantage in a randomized trial in melanoma — but it was also a landmark moment for immunotherapy and checkpoint blockade. This was the first checkpoint-blocking drug to show an impact on survival. Ipilimumab then became the gold standard against which everything else had to be measured. This is the first demonstration in a prospectively randomized trial that another checkpoint-blocking drug, pembrolizumab, is superior to ipilimumab in terms of OS, response rate and PFS. This is now expected to change the treatment landscape for melanoma, and it is a very high-impact drug.
    The most exciting moment for me, personally, in the development of anti–PD-1 drugs was the realization that lung cancer could respond to this form of immunotherapy. In the past, we had tried many different forms of immunotherapy that did not have any impact on lung cancer.
    The study by Garon and colleagues is the largest study of any PD-1–blocking agent in lung cancer. More than three-quarters of the patients received a previous systemic treatment for their cancer and had progressive disease after that. This is a very-difficult-to-treat patient population, where the impact of second- and third-line agents is generally not expected to prolong survival. So, these results are especially impressive given this treatment setting.
    There is a big push to identify biomarkers for cancer therapy so that patients do not spend time on trials or on therapies that are not going to help them. Certainly, that situation is more clear-cut for the kinase inhibitor class of drugs, where the drug is not likely to work without a particular mutation. These data describe a potential biomarker to select patients with lung cancer for anti–PD-1 therapy. But, this kind of biomarker is a lot more blurry. Even patients with lower levels of expression of this marker still had notable response rates.

    • Suzanne L. Topalian, MD
    • Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medicine

    Disclosures: Topalian reports research funding from and consultant roles with Bristol-Myers Squibb, Five Prime Therapeutics, GlaxoSmithKline, Jounce Therapeutics and MedImmune.