Melanoma peeps with durable benefit from anti-PD-1 even after stopping due to adverse events ~

In June, I posted:  Anti-PD-1 results in melanoma patients: outcomes plus responses to retreatment which includes links to multiple reports addressing how melanoma patients treated with anti-PD-1 have fared.  My synopsis of an ASCO 2018 report on outcomes for melanoma peeps after stopping anti-PD-1 follows ~  41 of them stopping after completing 2 years and 34 stopping due to side effects.  I noted: 

So - 580 melanoma patients were given anti-PD-1.  41 patients stopped after 2 years or at doc's discretion (characterized as MCB in study [maximal clinical benefit]).  34 stopped due to side effects.  I presume the rest of the peeps are still on treatment.  Overall, 56% of patients had a complete response, 35% had a partial response, and 9% had stable disease.  These responses were similar across the 2 groups with a response rate of 93% in the MCB group and 88% in the toxicity group.  Complete responses were higher in the MCB group (76% vs 32%).  Median time on drug = 19.5 months for MBC and 6.5 months for the toxicity group.  Median time to response was about 3 months (this has been demonstrated repeatedly in studies looking at anti-PD-1).  Median time to complete response was 7.3 months.  At f/u 16 months after stopping anti-PD-1, 89% were disease free, 93% were alive, 6 had died (NONE due to disease progression), but three deaths were due to complications from anti-PD-1.  8 patients progressed (3 in the MCB group and 5 in the toxicity group).  2 of the MCB group were rechallenged and 1 gained a complete response and the other a partial.

Now, researchers who examined how melanoma peeps forced to stop anti-PD-1 as a single agent due to adverse events have fared, with a median f/u of 30.3 months, found:

Durable Clinical Benefit in Patients with Advanced Cutaneous Melanoma after Discontinuation of Anti-PD-1 Therapies Due to Immune-Related Adverse Events.  Swami, Monga, Bossler, et al. J Oncol. 2019 Jul 25.

Anti-PD-1 therapies, pembrolizumab and nivolumab, are currently the standard of care for treatment of patients with metastatic melanoma. Treatment is usually continued until toxicity or disease progression. Though these therapies are well tolerated, some patients discontinue them due to immune-related adverse events (irAE). Discontinuation of therapy brings challenges to their management due to limited treatment options and lack of long-term prognostic information for these patients. Herein, we reviewed patients at our institution to analyze their clinical outcomes.

Charts of 1264 consecutive patients enrolled between 8/1/2012 and 7/31/2017 at Melanoma Skin and Ocular Tissue Repositories at Holden Comprehensive Cancer Center at the University of Iowa Hospitals and Clinic were reviewed. Eligible patients were those who received single-agent anti-PD-1 therapy and subsequently discontinued it due to irAE. Reviewed data included patient demographics, prior medical history, baseline disease parameters, and outcomes. Kaplan-Meier survival analysis was done to determine progression-free survival (PFS) and overall survival (OS).

Overall 169 patients with advanced, unresectable, or metastatic cutaneous melanoma received anti-PD-1 therapy of which 16 (9.5%) white, non-Hispanic patients with median age of 64.5 (range 35 to 81 years) discontinued treatment due to irAE. Fifteen patients received pembrolizumab and one received nivolumab. The median duration of treatment was 4.7 (range 0.7 to 11.5) months. Median follow-up was 30.3 (range 4.6 to 49.4) months. Median PFS was 24.6 months and median OS was not reached. Durable clinical benefit (time to progression or next treatment of more than 6 months from last treatment) was observed in 13 (81.2%) patients. At the time of analysis, 8 patients had progressed and 4 patients died (all-cause).

Our results suggest that advanced melanoma patients discontinuing anti-PD-1 therapy due to irAE usually experience durable clinical benefit. However, caution is needed with these agents in patients with underlying autoimmune diseases.

So ~ when the researchers drilled down on this, we are dealing with a rather small sample set of 16 patients who had to stop nivo (1) or pembro (15) as single agents due to side effects.  Average length of treatment was about 5 months (6.5 in the study above).  Median f/u was just over 30 months (16 in the study above).  Median PFS = 24.6 months.  Median OS was not reached. At the time of the report, about 30 months in, 8 (of 16) patients had progressed and 4 had died, though apparently that number includes causes in addition to melanoma. (In the study above, 5 (of 34) patients had progressed at 16 months in.)

As ever, studies annoy me by not looking at results in the same way!  But, it looks as though, much like what we have learned in folks who have to stop the ipi/nivo combo due to side effects, yet still gain a response and have a PFS that is not that much different from those who complete the recommended duration off therapy, melanoma peeps who have to stop anti-PD-1 as a single agent can still attain durable benefits.

For what it's worth ~ c