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Expert Critique

FROM THE ASCO Reading Room

Meghan Mooradian, MD Clinical & Research Fellow Massachusetts General Hospital

There has been a rapid emergence of efficacious agents approved for the treatment of advanced melanoma in the last 5 years. Since 2011, six agents, (ipilimumab, vemurafenib, dabrafenib, trametinib, pembrolizumab, and nivolumab) have gained FDA approval for the treatment of this disease. Though more effective treatment options have improved patient outcomes, the growing therapeutic options have led to questions surrounding how and when to use these new approaches options.

In BRAF-WT patients, immunotherapy is the primary systemic treatment modality for metastatic melanoma. Treatment with ipilimumab, a CTLA-4 antagonist, has been associated with overall response rates (ORR) of 10-15% with durable treatment-free responses in approximately 20% of patients. The anti-PD1 antibodies, pembrolizumab and nivolumab, are associated with ORR of 30-40% with the majority of those responses being durable. PD1 inhibitors have each demonstrated superiority in comparison with chemotherapy and in KEYNOTE-006, pembrolizumab showed impressive activity when compared with ipilumamab in both BRAF-WT and BRAF-mutant patients, with improved progression-free survival (PFS), improved overall survival (OS) and less toxicity than anti-CTLA4 agent.

An excited prospect in the field is the realization that blocking CTLA4 and PD1simultaneously is not a redundant approach. This combination was studied CheckMate 067 and demonstrated that patients treated with nivolumab alone, and in combination with ipilimumab, had significantly improved PFS and the ORR, as compared with use of ipilimumab alone. Though OS data is pending the improvement in PFS has lead many clinicians to question if combination strategy is the upfront treatment of choice. Giving pause is the additive toxicity of the combination with high-grade adverse events seen in over 60% of patients. The authors point out that a key issue is determining which patients are appropriate candidates for combination anti鈥揅TLA-4, PD-1 therapy and which are more suitable for either up-front single-agent anti-PD1 therapy or ipilimumab.

Future work going forward includes the identification of the patients who will benefit from combination immunotherapy and ultimately determining the optimal treatment sequence for all active treatments, especially in patients with BRAF-positive melanoma. Notably, the EA6134 study, currently underway in the U.S., is evaluating whether initial treatment with either combination ipilimumab-nivolumab (with subsequent dabrafenib-trametinib) or dabrafenib in combination with trametinib (with subsequent ipilimumab-nivolumab) significantly improves 2 year overall survival. Final results from CheckMate 067 and EA6134, will hopefully shed light on the optimal treatment sequencing patients for both BRAK-mutant and WT metastatic melanoma.

Full Critique

The recent expanded FDA approval for the programmed death (PD)-1 inhibitor nivolumab (Opdivo) approximately doubled the number of advanced melanoma patients eligible for frontline immunotherapy. The expanded approval includes use of nivolumab alone and in combination with the cytotoxic T-lymphocyte–associated antigen 4 (CTL4) inhibitor ipilimumab (Yervoy) in patients with or without BRAF mutations.

Several immunotherapies are now available for patients with metastatic melanoma harboring a BRAF V600 mutation. These include the nivolumab-ipilimumab combination, monotherapy with each agent, and monotherapy with another PD1 inhibitor, pembrolizumab (Keytruda). In addition, two different combinations of targeted therapies with BRAF and MEK inhibitors are also indicated.

The , based on the results of the trial, "makes sense since the study shows that the combination offers superior outcomes over monotherapy with ipilimumab," said , of Memorial Sloan Kettering Cancer Center, a co-author of the study.

That phase III trial, which included 945 patients with previously untreated melanoma, found that nivolumab alone, and in combination with ipilimumab, significantly improved progression-free survival (PFS) and the overall response rate (ORR), as compared with use of ipilimumab alone. However, the combination was associated with more grade 3-4 adverse events. About 30% of patients discontinued the combination due to treatment-related adverse events, compared with 5% with nivolumab and 13% for ipilimumab.

Other published data have also shown no differences in patient outcomes on the basis of BRAF mutational status. In an , researchers found no association between BRAF-V600E mutation status of melanoma tumors and durable disease control after treatment with ipilimumab. A of four trials, led by , of the Institute of Cancer Research and Royal Marsden Hospital in London, who is also the lead author of CheckMate-067, found that nivolumab has similar efficacy and safety outcomes in patients with wild-type or mutant BRAF, regardless of prior BRAF inhibitor or ipilimumab treatment.

"All studies show that BRAF-mutant response seems to be the same as BRAF wild-type response," said Postow.

He noted that the CheckMate-067 study does not yet have overall survival data. Moreover, the trial did not directly compare the combination against nivolumab monotherapy.

"We don't have an overall survival benefit in this trial. We need that to unanimously endorse this immunotherapy combination for all patients," Postow said.

A of pembrolizumab showed prolonged PFS and overall survival, with less high-grade toxicity, as compared with ipilimumab in patients with advanced melanoma.

"We now have two randomized Phase III trials that demonstrated that PD1 inhibition is superior to CTLA4 inhibition. I would question using a CTLA4 inhibitor alone for advanced melanoma," Postow said, adding that he believes CTLA4 inhibition should be either second-line therapy after a PD1 inhibitor or used in combination with a PD1 inhibitor as frontline therapy.

With more patients now to consider for treatment, tolerance to therapy becomes a more important factor. "A PD1 combination has replaced monotherapy in the frontline setting of melanoma," he continued. "But I think we have to take into consideration the clinical gestalt -- how well will the patient tolerate side effects of the combination, how severe is the disease, and how quickly does the patient need a response? We have to incorporate the answers into the decision to start with a combination immunotherapy or start with single therapy."

One potential way to better select patients may be to test for expression of programmed death-ligand 1 (PD-L1). In a subset of the CheckMate-067 trial, those patients whose tumors expressed lower levels of PD-L1 appeared to respond better to the combination.

One of the nuances in selecting treatment for melanoma patients with a BRAF mutation is that they can start with either immunotherapy or a combination of targeted therapies, Postow noted.

"There are many exciting drugs now available for melanoma. We need to figure when to combine immunotherapies or whether to them give sequentially. For targeted therapy, a combination is clearly best."

He noted that clinical trials are currently exploring PD-1 blockade with nivolumab or pembrolizumab in the postsurgical adjuvant setting.