Top Takeaways from ASCO: Melanoma

Ipilimumab struggles to hold its place in (first) line; dramatic possibilities for future of CLND.

CHICAGO — The results of a phase 3 trial presented during the Plenary Session at the ASCO Annual Meeting comparing combination nivolumab-ipilimumab treatment to nivolumab alone and ipilimumab alone was one of the most pivotal presentations on melanoma at the 2015 ASCO Annual Meeting.

A second key melanoma study examined survival of patients undergoing SLNB who did or did not receive CLND. Several physicians shared their insights on the Top Takeaways from these findings with Healio.com.

Checkmate O67

Jedd D. Wolchok, MD, PhD, chief of melanoma and immunotherapeutics service and the Lloyd J. Old Chair for Clinical Investigation at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, presented the results of the CheckMate 067 study during the Plenary Session that compared the use of nivolumab alone to ipilimumab alone as well as to nivolumab plus ipilimumab. Nivolumab is a programmed death 1 (PD-1) checkpoint inhibitor and ipilimumab is a cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) checkpoint inhibitor.

Sanjiv S. Agarwala

“The most important data that came out — which is very clear — is that there’s no doubt now in anyone’s mind that anti-PD-1 beats anti-CTLA-4. Whether its nivolumab or pembrolizumab, it’s better than giving ipilimumab front-line,” Sanjiv S. Agarwala, MD, chief of oncology and hematology at St. Luke’s Cancer Center, professor at Temple University School of Medicine and a HemOnc Today Editorial Board member, told Healio.com. Pembrolizumab is another anti-PD-1 immunotherapy indicated for melanoma.

The study’s primary endpoints were PFS and OS, although OS results were not yet mature at the time of this analysis. Secondary endpoints included objective response rate (ORR) and safety. At a minimum follow-up of 9 months, the median PFS for ipilimumab alone was 2.9 months (95% CI, 2.8-3.4), whereas nivolumab alone conferred a 6.9-month median PFS (95% CI, 4.3-9.5). The combination of the two agents yielded the highest median PFS 11.5 months (95% CI, 8.9-16.7).

“The results of this trial are preliminary,” said Ryan J. Sullivan, MD, a medical oncologist at the Massachusetts General Hospital Cancer Center. “However, what we certainly saw was a higher response rate with patients receiving the combination of ipilimumab plus nivolumab vs. ipilimumab and a clear, [PFS] advantage for patients receiving the combination vs. those receiving ipilimumab. In addition, although the trial was not designed to specifically show the difference between the combination and single agent nivolumab, there was improvement in response rate with the combination vs. single agent nivolumab as well as an improvement in [PFS].”

The practice implications of this research may be significant, Ari VanderWalde, MD, MPH, a medical oncologist and Director of Research at West Cancer Center in Memphis and Associate Vice-Chancellor of Clinical Research at University of Tennessee Health Science Center, told Healio.com.

Ari VanderWalde

“It was very clear in this [plenary] presentation that the combination is superior to ipilimumab alone, which further cements the role of ipilimumab to no longer be in the first line,” Vanderwalde said. “I think that’s a really practice-changing or practice-affirming belief that we have — that ipilimumab should no longer be used in the first-line setting of metastatic melanoma.”

However, additional research is needed before this practice becomes commonplace, according to Sullivan.

“To summarize, I would say the data looks amazing – very high response rates and very high progression-free survival rates [for the combination],” Sullivan said. “[OS] data will hopefully be forthcoming and will really be illuminating whether or not [an] upfront combination of anti-PD-1 ipilimumab therapy will be the new standard, but I would say at this point it is not. We look forward to more data from this trial and other trials that have looked at this combination.”

Benefits of complete, incomplete LND

Complete lymph node dissection (CLND) after a positive sentinel lymph node biopsy (SLNB) did not improve survival for patients with melanoma, according to findings from a randomized phase 3 trial presented at the ASCO Annual Meeting.

Researchers randomly assigned patients 1:1 to observation (n = 241), which included a lymph node ultrasound exam every 3 months and CT/MRI or PET scans every 6 months, or CLND (n = 242). The groups were comparable with regard to age, gender, localization, ulceration, tumor thickness (median, 2.4 mm in each cohort), number of positive nodes and tumor burden in the sentinel node. Primary endpoints included RFS, distant metastases-free survival and melanoma-specific survival. Three-year follow-up was conducted in both groups.

“This is an important study,” Sullivan told Healio.com. “One of the major issues that our patients have with regards to surgical management of stage 3 disease is the morbidity of a completion lymph node dissection, so the trial was really looking to see whether or not it was worth doing that.”

Mean follow-up was 35 months. More patients in the observation cohort developed lymph node regional metastases compared with patients in the CLND cohort (14.6% vs. 8.3%). However, there was no significant treatment-related difference in 5-year RFS, distant metastases-free survival and melanoma-specific survival.

Ryan J. Sullivan

“The data is quite compelling,” Sullivan said. “It essentially showed that there was no difference if you underwent observation as opposed to underwent a completion lymph node dissection with respect to a metastasis-free survival as well as overall survival. This is very important, though there will need to be confirmation of this data. In fact, there’s this trial called the MSLT-2 study which is specifically designed to answer this question with 2,000 enrolled patients. Enrollment completed about a year and a half ago. We’ll hopefully have data emerging over the next few years.”

If the MSLT-2 study results in similar outcomes as the multicenter, randomized DECOG trial, the implications for practice — and patients — will be significant, Sullivan told Healio.com.

“If indeed that study confirms this result, then it will dramatically change the way we treat patients with a positive sentinel lymph node. Specifically, we may be able to avoid morbidity of [CLND] in the majority of our patients.” – by Julia Ernst, MS

References:

Wolchok JD, et al. Abstract LBA1.

Leiter U, et al. Abstract LBA9002.

Both presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Disclosures: Agarwala, Sullivan and VanderWalde report no relevant financial disclosures.