IPI Ousted as First-Line Immunotherapy in Melanoma?

Editor's Note:
The melanoma presentations at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO) represent yet another high watermark for immunotherapy. To recap the highlights of the melanoma studies and put them into clinical perspective, Medscape spoke with Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center and professor of oncology and medicine at Georgetown University School of Medicine, in Washington, DC.

Nivolumab Packs a One-Two Punch

Medscape: What were the most important immunotherapy studies presented at the 2015 annual meeting of ASCO?

Dr Atkins: The first, and by far the most important, was the plenary session study CheckMate 067, presented by Jedd Wolchok^[1] [and simultaneously published in the New England Journal of Medicine^[2]]. That study compared nivolumab (Opdivo®)alone or combined with ipilimumab (Yervoy®) vs ipilimumab alone in treatment-naive patients with advanced melanoma. Nivolumab alone or in combination with ipilimumab was significantly more effective compared with ipilimumab alone. Nivolumab alone more than doubled the time to disease progression: a median of 6.9 months vs 2.9 months for ipilimumab alone (P < .0001); and the benefit in progression-free survival (PFS) was much greater for the combination of nivolumab and ipilimumab: 11.5 months (P < .001).

These were the first phase 3 data to show that nivolumab is superior to ipilimumab.

Medscape: Can you elaborate on the implications of this study?

Dr Atkins: These were the first phase 3 data to show that nivolumab is superior to ipilimumab and that the combination of nivolumab plus ipilimumab is superior to ipilimumab. On the basis of this study and the pembrolizumab (Keytruda®) vs ipilimumab KEYNOTE-006 study presented at the annual meeting of the American Association for Cancer Research,^[3] we can now say that monotherapy with either pembrolizumab or nivolumab has convincingly better efficacy and toxicity than monotherapy with ipilimumab. Ipilimumab should no longer be used as the standard of care for first-line immunotherapy of melanoma.

It also appears that the combination of nivolumab plus ipilimumab is superior to nivolumab alone but has greater toxicity. Therefore, we probably need to wait for survival data before we say definitively that nivolumab plus ipilimumab should be the preferred combination over anti-PD-1 alone.

Medscape: What about the toxicity of the combination? More than 50% had grade 3 and 4 adverse events on nivolumab plus ipilimumab compared with 16% on nivolumab alone and 27% on ipilimumab alone.

Dr Atkins: Although the toxicity was greater with the nivolumab plus ipilimumab combination, in this large phase 3 trial where many of the investigators were not experienced in using this combination, there were no deaths, and the toxicity could be controlled by immunomodulatory therapy (ie, steroids). This margin of safety allows the combination to be used by people experienced in delivering immunotherapy.

Furthermore, use of immunomodulatory therapy alleviates toxicity but does not affect efficacy.

Medscape: How do you interpret the biomarker data on PD-L1?

Dr Atkins: Patients who expressed PD-L1 > 5% did as well on single-agent nivolumab as with the combination in regard to PFS. Independent validation is needed using more relevant endpoints for immunotherapy, such as overall survival, landmark survival, duration of response, and treatment-free survival. These data are provocative and hypothesis-generating, but they need independent, prospective validation to be considered for clinical decision-making.

To me, PD-L1 is not a robust biomarker. For example, almost two thirds of the responders to nivolumab monotherapy had < 5% PD-L1 expression on their tumors. We need better biomarkers. Fortunately, there are several promising leads.

We need to know not only which patients respond to single-agent anti-PD-1 therapy as well as they do to the combination, but also which patients require combination therapy and which patients won't benefit from the combination and therefore might need a different approach.

Taking the Toxic Sting Out of Combo Immunotherapy

Medscape: Does this study suggest the direction for future studies?

Concurrent administration of pembrolizumab plus low-dose ipilimumab may be less toxic than the combination of nivolumab and full-dose ipilimumab.

Dr Atkins: The study by Wolchok and colleagues shows that combination immunotherapy can produce more potent effects than single-agent immune blockade. This establishes a platform on which to explore future combination approaches with a possibly improved therapeutic index—not just for patients with melanoma but for patients with tumors that respond to PD-L1 blockade.

A phase 1/2 study, of which I was principal investigator, suggests a way to manipulate combination therapy to reduce toxicities.^[4] This study indicates that concurrent administration of pembrolizumab plus low-dose ipilimumab may be less toxic than the combination of nivolumab and full-dose ipilimumab used in the CheckMate 067^[1] and CheckMate 069^[5] trials. This regimen may have the potential for similar efficacy in melanoma and other tumors, with less toxicity.

Medscape: Were there other notable studies looking at a combination of immunotherapies?

Dr Atkins: A study presented by Antoni Ribas suggested a different strategy for building on the backbone of anti-PD-1 immunotherapy in patients with BRAF-mutant melanoma.^[6] Keep in mind that around 50% of all melanoma patients have BRAF mutations. This phase 1b, international, multicenter, open-label study evaluated MEDI4736, an investigational PD-L1 antibody, in combination with dabrafenib plus trametinib in 50 patients with BRAF mutation-positive or BRAF wild-type metastatic or unresectable melanoma. The results in the population with BRAF-mutant melanoma were particularly interesting.

This is the first study of triple-combination therapy involving a BRAF inhibitor and immunotherapy. Previous efforts to combine BRAF-targeted therapy with immunotherapy proved too toxic. It appears that this regimen could have palatable toxicity with considerable efficacy, but the efficacy could have been due to the molecularly targeted component of the regimen. We need further study and longer follow-up to determine the contribution of the anti-PD-L1 agent to this regimen.

Another interesting study was a retrospective, multicenter analysis of response to anti-PD-1/PD-L1 therapy in 23 patients with metastatic desmoplastic melanoma, an entity that comprises about 1% of melanomas.^[7] In this rare subset of patients treated with a median of nine cycles of immunotherapy using multiple anti-PD-1-based regimens, overall response rate by RECIST criteria was 70%, including nine complete responses and seven partial responses. These are the highest response rates we have ever seen with PD-1-based therapy in melanoma, suggesting that this variant is extremely sensitive to anti-PD-1-based immunotherapy. This observation takes on greater significance when we consider how very difficult it is to treat this type of melanoma, which is typically characterized by multiple local recurrences often requiring disfiguring surgery.

Medscape: What about the high cost of combination immunotherapy?

Dr Atkins: I have a different take on what Leonard Saltz presented during the ASCO Plenary Session.^[8] He computed the cost of combination therapy at about $300,000 per year and applied that to about 590,000 cancer deaths each year, coming up with a cost to society of $174 billion for 1 year of combination immunotherapy.

With single-agent anti-PD-1 therapy, patients are often treated for more than 1 year; but with combination therapy, most patients stop after 12 weeks, which means less therapy and less cost. Furthermore, if a patient is cured up-front, there is no further cost of subsequent therapy. I believe that the cost of the combination in patients with melanoma (9000 deaths per year) is likely to be viewed as trivial when compared with the costs of immunotherapy in other cancer types, such as lung cancer. Melanoma is unlikely to be the battleground for arguments about cost and value.

The Take-Home Message

Medscape: Among the melanoma presentations there were a number of studies evaluating the efficacy of intralesional immunotherapies, such as T-VEC.^[9,10,11] Where does this form of immunotherapy fit in treatment strategies?

Ipilimumab is no longer the preferred first-line immunotherapy for patients with advanced melanoma.

Dr Atkins: In my opinion, I do not see a major role for intralesional monotherapy with agents like talimogene laherparepvec (T-VEC). Most of these patients would be candidates for anti-PD-1 therapy and would probably do considerably better with that approach. The real future for T-VEC, or therapies like it, will be used in combination with other checkpoint inhibitors, such as PD-1 pathway blockers.

Medscape: What are the major take-home messages from ASCO 2015 regarding melanoma immunotherapies?

Dr Atkins: The first is that ipilimumab is no longer the preferred first-line immunotherapy for patients with advanced melanoma. The second is that combination immunotherapy with an anti-PD1 backbone offers efficacy advantages over single-agent anti-PD-1. This is the future: combination therapy with an anti-PD-1 backbone. The third is that a biomarker to select patients for anti-PD-1 treatment is not ready for prime time. The fourth is that there is still much work to be done to figure out how to use these new therapies and how to integrate them into other approaches for melanoma therapy. Finally, what we learn in melanoma will hopefully pave the way for use of immunotherapy in other cancers.

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