Three 'Game-Changers' in the Treatment of Melanoma 


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There have been three “game-changers” in the treatment of melanoma, Mark R. Albertini, MD, Associate Professor of Medicine at the University of Wisconsin in Madison, contended at the Best of ASCO Chicago meeting.

The first, he explained, was the recognition of different genetic driver mutations—most prominently BRAF mutations—and their pathways, and the development of targeted agents that interfere with these pathways.

“The second game-changer involved CTLA-4 blockade,” Dr. Albertini continued, and the CTLA‑4 blocking antibody, ipilimumab ­(Yervoy), which “basically disables the off switch resulting in T cells remaining active,” he said.

These two developments have provided “game-changing insights” over the past few years that have completely changed the landscape of melanoma treatment, Dr. Albertini said. “I would like to convince you that game-changer number 3 is the use of the PD-1/PD-L1 axis for immunomodulation,” he said, backing up that assertion with summaries of four studies presented at the ASCO Annual Meeting that addressed the hypothesis of PD-1/PD-L1 as an effective target in melanoma.

Distinct Differences

As pointed out in a review by Topalian et al,1 “PD-1 and CTLA-4 play distinct roles in regulating T-cell immunity. CTLA-4 modulates the early phases of activation of naive or memory T cells in response to T-cell receptor stimulation by MHC-peptide complexes displayed by antigen-presenting cells,” Dr. Albertini noted. “In contrast, PD-1 is expressed on antigen-experienced T cells in the periphery and serves to limit the activity of T cells at the time of an inflammatory response, thereby protecting normal tissues from collateral destruction.”

There are also distinct differences between anti-PD-1 and anti-PD-L1 blockade, Dr. Albertini pointed out. “They are not identical. They could behave differently because they block different distinct sets of inhibitory interactions.”

Four Studies

A study using the anti–PD-1 monoclonal antibody lambrolizumab (MK-3475) showed an overall response rate of 38% among patients with advanced melanoma who had or had not received prior treatment with ipilimumab.2 The highest response rate (52%) occurred among patients receiving lambrolizumab at 10 mg/kg every 2 weeks. While almost 80% of patients experienced some adverse event, the rate of grade 3/4 adverse events was 12.6%, and the treatment was well tolerated, Dr. Albertini said.

A study of MPDL3280A, an engineered PD-L1 antibody, looked at whether tumor expression of PD-L1 would predict which patients would respond.3 The objective response rate among patients with metastatic melanoma was 29% overall, 27% among patients who were PD-L1–positive and 20% among those who were PD-L1–negative. While the response among PD-L1–positive patients was greater, the investigators also saw responses in patients who were negative for PD-L1, Dr. Albertini said. “Importantly, if you include stable disease with responders, you actually see benefit in 58% of patients, 87% of patients who were PD-L1–positive,” he added.

A phase I/II trial of the anti–PD-1 antibody nivolumab with peptide vaccine included patients in whom ipilimumab had failed or had not yet been given.4 “Peptide vaccine was included as an immune-monitoring tool,” Dr. Albertini explained. “Importantly, you see similar activity both in the patients who are naive to ipilimumab and patients whose disease has been refractory to ipilimumab.” Although about 60% of patients experienced some toxicity, “the majority of adverse events were transient grade 1 or 2 and did not require intervention,” Dr. ­Albertini reported.

Introducing the final abstract,5 concerning the safety and clinical activity of the anti–PD-1 antibody nivolumab in combination with the anti-CTLA-4 antibody ipilimumab in patients with advanced melanoma, Dr. Albertini stated, “I will remind you of the difference in activity that is thought to occur with ipilimumab, with CTLA-4 blockade occurring earlier on, and with PD-1 blockade occurring in the tissue microenvironment—clearly setting up a model for potential combination immunotherapy.”

Rapid and deep tumor reductions > 80%, which Dr. Albertini termed “a striking response,” occurred among 13% of patients who received the two agents in sequence and among 31% who received the two agents concurrently. “In addition to magnitude of the reduction, what is also impressive is the rapidity of the reduction, these responses occurring quite quickly in contrast to what is more commonly seen with immunotherapeutic approaches,” Dr. Albertini commented.

Grade 3/4 related adverse events occurred in 53% receiving concurrent treatment and 18% of patients receiving sequenced treatment. The most common were asymptomatic lab abnormalities, including elevations of lipase. “It is important to note that the related adverse events were managed using standard protocol algorithms that have been well developed from the ipilimumab experience, and no deaths were reported,” Dr. Albertini stated.

Study Strengths and Limitations

Grouping these four abstracts together, Dr. Albertini listed the following strengths of this research:

  • The efficacy of the PD-1 pathway blockade is supported by high response rates that appear to be durable,” although more follow-up is needed.
  • PD-1 pathway blockade appears to have acceptable clinical toxicity and adverse events were readily managed using current algorithms.
  • Sequential therapy with anti–PD-1 after ipilimumab can result in clinical benefit.
  • Combination immunotherapy with ipilimumab and nivolumab induced rapid and deep responses that appear better than published monotherapy values.

Again grouping the four abstracts together, Dr. Albertini listed the following limitations:

We still need to determine the best pathway to inhibit. Should we inhibit PD-1 or PD-L1?

  • We clearly need biomarkers of response to anti-PD-1 therapy. There were many potential biomarkers of response presented. We need to identify those to figure out which patients will go on to have durable responses with these treatments.
  • We need to confirm the high response rate and anticipated durable benefit from combination immunotherapy with ipilimumab and nivolumab. A randomized study will evaluate the combination with the individual components.

Changing the Standard of Care

In conclusion, Dr. Albertini said that the anti–PD-1, anti–PD-L1 findings provided “exciting and impressive new data that I predict will change the standard of care for patients with melanoma…. [These new findings are] a confirmation of the ability of immunotherapy to produce durable responses in patients with metastatic melanoma,” he added.

“There is high anticipation that PD-1 blockade will result in improved survival for patients with metastatic melanoma,” although further follow-up is needed. “There is enthusiasm for looking at combination immunotherapy with PD-1 blockade, specifically combinations with other forms of treatment, including vaccines.” ■

Disclosure: Dr. Albertini reported that he has received or is discussing clinical trial research funding support from the following sources: EMD Serono, Eisai, MedImmune LLC, Merck Serono, Genentech, and Bristol-Myers Squibb.

References

1. Topalian SL, Drake CG, Pardoll DM, et al: Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24:207-212, 2012.

2. Ribas A, Robert C, Daud A, et al: Clinical efficacy and safety of lambrolizumab (MK-3475, anti-PD-1 monoclonal antibody) in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9009. Presented June 2, 2013.

3. Hamid O, Sosman A, Lawrence DP, et al: Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). 2013 ASCO Annual Meeting. Abstract 9010. Presented June 2, 2013.

4. Weber JS, Kudchadkar RR, Gibney GT, et al: Phase I/II trial of PD-1 antibody nivolumab with peptide vaccine in patients naive to or that failed ipilimumab. 2013 ASCO Annual Meeting. Abstract 9011. Presented June 2, 2013.

5. Wolchok JD, Kluger HM, Callahan MK, et al: Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). 2013 ASCO Annual Meeting. Abstract 9012. Presented June 2, 2013.



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