Approvals Open Up New Potential Checkpoint Strategies in Metastatic Melanoma

Michael A. Postow, MD

Since the 2011 US Food and Drug Administration (FDA) approval of ipilimumab, an antibody inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4),¹there has been considerable interest in the potential for other immune system checkpoints, such as the programmed death ligand (PD-L1) and its receptor, programmed cell death receptor 1 (PD-1), to serve as therapeutic targets in metastatic melanoma. This September, 2014 that research was brought from concept to clinic as pembrolizumab (Keytruda) became the first PD-1 inhibitor to gain approval in the United States. Another PD-1 inhibitor, nivolumab, was approved in Japan in July 2014 for patients with unresectable melanoma under the trade name Opdivo.

PD-L1 is frequently expressed on tumor cells, and its engagement of the PD-1 receptor expressed on T-cells causes T-cell death and suppression, thereby allowing for a locally immunosuppressive environment around the tumor.²Inhibition of the PD-L1/PD-1 axis with antibody-based therapeutics, whether as monotherapies or in combination with anti-CTLA-4 therapy (ie, ipilimumab), is therefore being investigated as a next step in immunotherapy for advanced melanoma and other cancers.

Mario Sznol, MD, on Immunotherapy Combinations for Melanoma

Sznol is a professor at Yale Cancer Center.

Michael A. Postow, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, noted 2 main questions about the next steps for immunotherapy in advanced melanoma.

“One, is the combination of ipilimumab and a PD-1 approach better in a combination up front, or is it better to do one drug, and then the other in a sequence?” A second question, Postow noted, was: “What is the overall survival benefit of [a PD-1 inhibitor] in the randomized context? All we know about PD-1 really thus far is from large, early-phase studies, which suggest very high response rates with really wonderfully low toxicities.”

This article reviews some of the recent developments with immunotherapy in advanced melanoma.

Anti-PD-L1 Inhibitors

BMS 936559 is a fully human monoclonal antibody that inhibits binding of PD-L1 to both PD-1 and another receptor, CD80.³In a phase I study of patients with advanced cancers that included melanoma (n = 55), response rates of 6%, 29%, and 19% were documented among patients receiving 1 mg/kg, 3 mg/kg, or 10 mg/kg doses, respectively, and 14 of 52 patients (27%) had stable disease (SD) lasting >24 weeks.³

Results of the study also provided important proof-of-concept data for the inhibition of PD-L1 in melanoma and other cancers. Notably, while toxicities were also (as expected) immune-related, a distinct spectrum of adverse events (AEs) was observed with inhibition of the PD-L1/PD-1 axis when compared to the CTLA-4 pathway with ipilimumab; an example is severe colitis, which was infrequently observed with BMS 936559. Predominantly low-grade fatigue, infusion reactions, diarrhea, arthralgia, rash, nausea, pruritus, and headache were the most common drug-related AEs in the study, but grade 3 or 4 events were infrequent, observed in 19 of 207 patients (9%).³

Anti PD-1 Inhibitors

The safety and antitumor activity of nivolumab (also called BMS-936558), an anti-PD-1 monoclonal antibody, were assessed in a phase I study of patients with advanced solid tumors, including 104 patients with melanoma.⁴Fatigue, rash, diarrhea, pruritus, decreased appetite, and nausea were the most common treatment-related AEs observed during the study; grade 3/4 treatment-related AEs occurred in 14% and drug-related, serious AEs in 11%. Immune-related AEs of special interest included pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis, and the methods used to manage these AEs included treatment interruption, glucocorticoids, and replacement therapy (ie; for endocrine disorders)^.4

Objective responses were seen in 41% (7 of 17) patients given the 3.0 mg/kg dose of nivolumab, and, in the overall melanoma group, SD for >24 weeks was seen in 6% of patients, and the overall response rate (ORR) was 28%.⁴In a separate report focusing only on those patients with advanced melanoma in this trial, estimated median overall survival (OS) was 16.8 months, and 1-year and 2-year rates were 62% and 43%, respectively. The corresponding median and rates for progression-free survival (PFS) were, respectively, 3.7 months, 36%, and 27%.⁵

The ORR rate was 31%, with an additional 7% experiencing SD for >24 weeks. The most common AEs among melanoma patients were fatigue (32%), rash (23%), and diarrhea (18%), with grade 3/4 treatment-related AEs observed in 24 of 107 patients (22%).⁵

Pembrolizumab (previously called lambrolizumab), another antibody against PD-1, was approved by the FDA in September 2014 for the treatment of metastatic melanoma.6 The safety and antitumor activity of pembrolizumab were examined in a phase I expansion study of 135 patients with advanced melanoma, both with and without prior ipilimumab exposure. Safety results from this study showed predominantly low-grade (>95%) AEs that included generalized symptoms of fatigue and asthenia, fever and chills, myalgias, and headache. An ORR of 38% across doses (centrally confirmed by Response Evaluation Criteria in Solid Tumors [RECIST]) was observed in the study (44 of 117 patients).⁶Notably, there was no apparent impact of prior ipilimumab therapy observed, and 77% had a reduction in tumor burden during the study; the median PFS was >7 months.

Combining Immunotherapies

Wolchok and coworkers in 2013 reported results from a phase I trial combining nivolumab and ipilimumab in patients with advanced melanoma.⁷The rationale for using these 2 agents in combination stems from their apparent complementary roles in regulating adaptive immunity, with CTLA-4 involved in early T-cell activation and PD-1 being more important for T-cell exhaustion in peripheral tissues.7 In the 53 patients receiving concurrent treatment with ipilimumab and nivolumab, rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%) were most commonly observed as treatment-related AEs, and 72% had grade 3/4 AEs. These events, however, were generally manageable with immunosuppressive or hormonal replacement treatments, and overall the results showed that these 2 therapies could be safely administered together. Objective responses (modified World Health Organization [WHO] criteria) were seen in 40% (21/52 patients), and 16 patients had tumor reductions of 80% or more by 12 weeks; overall evidence of clinical activity was seen in 65% of patients on this concurrent therapy.⁷

Clinical Pearls

• This September, 2014 research was brought from concept to clinic as pembrolizumab became the first PD-1 inhibitor to gain approval in the United States.
• Another PD-1 inhibitor, nivolumab, was approved in Japan for patients with unresectable melanoma under the trade name Opdivo in July 2014.
• PD-L1 is frequently expressed on tumor cells, and its engagement of the PD-1 receptor expressed on T-cells causes T-cell death and suppression, thereby allowing for a locally immunosuppressive environment around the tumor.
• Anti-PD-L1 inhibitor, BMS 936559, is a fully human monoclonal antibody that inhibits binding of PD-L1 to both PD-1 and another receptor, CD80.
• Inhibition of the PD-L1/PD-1 axis with antibody-based therapeutics, whether as monotherapies or in combination with anti-CTLA-4 therapy, is being investigated in immunotherapy for advanced melanoma and other cancers.

Looking Ahead

Commenting on the findings with PD-1-directed therapies when compared with earlier results with ipilimumab, Postow noted a tendency for less frequent and severe side effects with the PD-1 inhibitors, with more rash, fatigue, and arthralgias seen, while other toxicities such as diarrhea are more commonly observed with ipilimumab. He cautions however, that such findings are not directly comparative, and are limited to data from large, early phase trials.

As noted earlier, he also sees a major unanswered question about the use of these 2 types of immunotherapy in combination upfront as opposed to sequentially. Indeed, sequential use of these 2 immunotherapies, which differ in mechanism of action, might increase therapeutic options for patients with advanced disease. Asked about such a scenario, Postow said: “If a patient progressed on ipilimumab monotherapy, I would move to the next step of just giving the PD-1 monotherapy as a subsequent step alone.” Postow also expects many questions to be answered in the numerous clinical trials underway with these therapies, both alone and in combination with other approved agents for advanced melanoma.

Patient access to these groundbreaking therapies will also increase soon; an expanded access program (EAP) for pembrolizumab has recently been announced, whereby advanced melanoma patients who have received prior therapy with ipilimumab (or a BRAF inhibitor, if indicated) may be eligible for treatment at no cost.⁸

“I’m grateful for the opportunity to provide many patients with this drug—a truly life-saving drug—before it was FDA-approved,” said Postow, who is heading the pembrolizumab EAP at his own institution. He explained that, while slightly different from a logistical and operational standpoint compared to running a standard clinical protocol, “the bottom line is, it’s increased the ability for more patients to get [anti] PD-1 [therapy], and I think that’s a good thing.”

References

1. Postow MA, Callahan MK, Wolchok JD. The antitumor immunity of ipilimumab: (T-cell) memories to last a lifetime?Clin Cancer Res. 2012;18(7):1821-1823.
2. Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: releasing the restraints on anti-tumor immunity for patients with melanoma.Cancer J. 2012;18(2):153-159.
3. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N Engl J Med. 2012;366(26):2455-2465.
4. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012;366(26):2443-2454.
5. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.J Clin Oncol. 2014;32(10):1020-1030.
6. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.N Engl J Med. 2013;369(2):134-144.
7. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013;369(2):122-133.
8. Frequently Asked Questions About Pembrolizumab U.S. Expanded Access Program. Available at: http://www.merck.com/about/eap_faq.html Accessed: September 3, 2014