Monday, February 24, 2020

Response after discontinuation of anti-PD-1 in melanoma patients whether due to disease progression, side effects or choice

The length of time melanoma patients should remain on immunotherapy and what happens to them after they come off has been a huge point of interest for researchers and patients since these drugs were first determined to be an effective treatment for melanoma.  In my Phase 1 nivolumab trial, begun in 2010, unless we progressed or developed untenable side effects, we were all allowed 2 1/2 years of therapy.  Period.  The end.  I was happy to be off it at the end.  However, that was certainly colored by the fact that I was NED.  Had I had lesions - stable or otherwise - I don't know that I would have been so at ease.  No matter, by the time I was reaching the end of my participation in 2013, Dr. Weber, lead investigator for the trial, was already postulating that we had been given the medication "too long".  His thinking ran along the lines that only a "certain amount" of the medication would do a patient any good and to give the medication longer would only increase the risk of side effects.  Still, determining the "certain amount" that does a body good has been hard to define.  In fact, I posted this in 2018:  Awesome news regarding how and when to stop immunotherapy in melanoma patients.  Now, seven years later, there is this...

When is it OK to Stop Anti-Programmed Death 1 Receptor (PD-1) Therapy in Metastatic Melanoma?  Banks and Sullivan.  Am J Clin Dermatol.  2020 Feb 5.

Systemic therapy for metastatic melanoma has been revolutionized over the past decade with the development of highly effective immune checkpoint inhibition, specifically anti-Programmed Death 1 receptor (PD-1) therapy. However, even though one-third of patients will have durable response to single-agent or combination therapy, the optimal duration of therapy is unknown. Identifying the optimal duration of therapy is important, as exposure to anti-PD-1 therapy increases the risk of developing immune-mediated toxicities that can have significant morbidity and are, at times, fatal. It has long been understood that patients with complete responses to high-dose interleukin-2 and ipilimumab typically maintain their responses after a brief treatment course; thus, it is important to better understand the data to help understand the optimal management of melanoma patients treated with anti-PD-1 therapy. The clinical data with anti-PD-1-based therapy and published data on the duration of therapy suggest that patients may not require a full 2 years of anti-PD-1 therapy and that the risk of toxicity may be mitigated by further understanding the mechanisms and kinetics of response to therapy. Although novel markers to help guide therapeutic decision making are under investigation, there is an ongoing need to improve our tools to monitor response to therapy and disease activity.

{Note:  Those "novel markers"  they mention refer to the various blood tests that allow us a peek into the body's response that melanoma peeps STILL aren't routinely allowed to avail ourselves of though researchers keep mentioning it and I keep YELLING about it!!!  As in the zillions of reports here on bio-markers generally:  Biomarkers  And these on circulating DNA in particular:  ctDNA }

Apart from not being very clear about how long melanoma patents really should continue immunotherapy for the best result, there is the issue of what happens to patients when they do stop.  Is the outcome different for those who must stop due to side effects as opposed to those who complete the current recommended doses?  Well...  I have reported this data over and over and over ~

This from 2016:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!

And again in 2017:  40% of melanoma patients stop ipi/nivo due to side effects...BUT...efficacy is about the same!!!

Per this data, the difference made in response in those who "completed" the proposed therapy vs those who do not due to side effects is - NOT MUCH!!!!

I've also written posts that cover what happens to folks who choose to end their immunotherapy for whatever reason.  This link to a post in 2019 includes links to many others:  Anti-PD-1 results in melanoma patients: outcomes plus responses to retreatment

Now, there's this:

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma.  Jansen, Rozeman, Mason, et al.  Ann Oncol.  2019 Jul 30.

Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established.  This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N=167) or nivolumab (N=18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia.

Median time on treatment was 12 months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18 months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12 months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response.

In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for greater of equal to 6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients.

For what it's worth - again. ~ c

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