What's Next After Anti-PD-1 Therapy for Melanoma Fails?

Jeffrey S. Weber, MD, PhD


July 29, 2021

This transcript has been edited for clarity.

Hello. I'm Dr Jeffrey Weber, a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health in New York City. Today I'll be reporting two interesting abstracts from the most recent American Society of Clinical Oncology (ASCO) virtual meeting. Both studies looked at what to do in patients with advanced melanoma for whom PD-1 or other immunotherapies have failed.

The first abstract was presented by Ana Arance. It was an update of the LEAP-004 study, a phase 2 trial of lenvatinib, the tyrosine kinase inhibitor (TKI), plus pembrolizumab given at the standard dose and schedule of 200 mg every 3 weeks. Ultimately, 103 patients were treated; about 55% of these had elevated LDH levels. Previous immunotherapy had failed in all participants and they had either not responded to adjuvant therapy or had primary resistance or so-called secondary resistance to PD-1 blockade. The overall response rate in this study was 21.4% and the disease control rate, if you included those who were stable, was 66%. A modest 2.9%, or three patients, had a complete response. [In these updated results], the duration of response also increased to 8.3 months, which in this scenario is not trivial.

The waterfall plot looks pretty good, with 66% of patients having some decrease. If you look at the responses in the different subgroups, the patients who did not respond to ipilimumab (IPI) plus nivolumab (NIVO) did quite well. As you would expect, the best responses overall came in those who had secondary resistance, meaning they were stable or progressed after a PD-1 inhibitor alone, IPI/NIVO, or anti-CTLA-4 plus a PD-1 inhibitor, and then eventually required the use of the next treatment.

Progression-free survival was a fairly modest 4.2 months, but median survival is pretty darn good at 14.3 months. There was no obvious plateau. The follow-up is still fairly short, in the realm of 20 months. In terms of toxicity, 45% experienced grade 3-4, toxicity, with the usual TKI hypertension added to the usual expected immune-related adverse events seen with pembrolizumab.

I have to agree with the presenter, who said that this is worth pursuing; this therapy led to a good duration of response with a 21% response rate in a fairly refractory population.

The second abstract about second-line therapy was presented by James Larkin from the Royal Marsden Hospital in London. This was an update on the Iovance TIL C 144-01 phase 2 study of 66 patients, with about 41% with elevated LDH levels. This was a fairly beat-up population who had received a median of at least two to three previous regimens. Toxicity was as you'd expect in patients who received tumor-infiltrating lymphocytes (TIL; lifileucel) preceded by 2 days of high-dose cyclophosphamide and 5 days of fludarabine, the infusion of lifileucel, and then up to six doses of IL-2. It's a fairly toxic regimen, but all the toxicities virtually abate by day 14, so it's smooth sailing thereafter.

If you look at the mean number of TIL infused, it's 2.7 x 10 to the 10th, which is a healthy number. And with a follow-up of 33 months, a 36.4% response rate was maintained but median duration of response was not reached. So we're now at a median of almost 3 years of follow-up, and if you look at the waterfall plot, about 80% of patients had some response. So, nice waterfall plot with, however, only a handful of complete responders. Again, most of the partial responders remain in remission.

Roughly 80% of the patients had received IPI and/or IPI/NIVO, and virtually everyone had not responded to a median of two to three PD-1 regimens. Thus, to see that response rate and that duration of response in this population is pretty darn impressive. Compared with other small TIL trials conducted at single institutions, this multi-institution trial found no obvious association with tumor site — subcutaneous, nodal, lung, liver, etc. — to how well the patients responded. There was no association of total cell dose either, which was in a modest, narrow range; and there was no relationship of CD-4:CD-8 ratios to how a patient was going to respond.

Considering other associations of response with different parameters, multivariate analysis showed a modest association of LDH, with a P of roughly .04. Also, the longer patients were on PD-1, the worse they did, almost suggesting that you might want to bail out of PD-1 early if you think a patient is progressing, and move on to TIL therapy.

Impressive data, with the median duration of response not reached at 33 months of follow-up and a solid, 36.4% investigator-called response rate. Again, I would have to agree with the presenter that early intervention with TIL/IL2 preceded by cyclophosphamide/fludarabine would have to be indicated after the failure of PD-1.

This is Dr Jeffrey Weber reporting. Please contact us with comments, concerns, and questions. Thank you very much for your attention.

Jeffrey Weber, MD, PhD, is deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center and co-director of its Melanoma Research Program. His research, which has been continuously funded by the NCI for more than 20 years, focuses on experimental therapeutics and drug development, particularly in immunotherapy.

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