Wednesday, April 26, 2017

Features of resistance to anti-PD-1

Clinical features of acquired resistance to anti-PD-1 therapy in advanced melanoma. Wang, Eroglu, Ozgun, et al. Cancer Immunol Res. 2017 Apr 10.

Anti-PD-1 therapy has improved clinical outcomes in advanced melanoma, but most patients experience intrinsic resistance. Responding patients can develop acquired resistance to anti-PD-1. We retrospectively reviewed 488 patients treated with anti-PD-1 from three academic centers and identified 36 patients with acquired resistance, defined as disease progression following objective response. The incidence, timing, disease sites, post-progression survival (PPS), and outcomes were evaluated descriptively. The acquired-resistance cohort consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial and complete responses were achieved in 89% (n = 32) and 11% (n = 4) of patients, respectively, and median time to resistance (progression-free survival; PFS) was 11.1 months (range 4.3-32.8 months). Most progression was isolated (78% of patients, n = 28) and occurred while receiving therapy (78%, n = 28). The median PPS was 12.8 months (range 0.1-51.8 months), and the median overall survival was 33.7 months. Among isolated progressors, 15 received localized therapy (12 with surgery, 3 with radiation). Patients with isolated vs. systemic progression exhibited a trend for improved PPS, and patients with an initial PFS greater or =to 15 months showed significant PPS improvement. Two patients experienced subsequent responses to anti-PD-1 resumption. In conclusion, acquired resistance to anti-PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption.

This report is mostly confirmation of what we already know ~

1.  Anti-PD-1 (both nivo/Opdivo and pembro/Keytruda) have roughly a 40% response rate.
2.  Folks with increased LDH, brain mets, and worse staging do less well.
3.  Folks respond less well to anti-PD-1 if it is taken after ipi (See this post:  Sequential nivo then ipi = ORR of 41%. Ipi followed by nivo = ORR of 20%!!!! FDA! Are you listening??????? )

On the good side.....even WITH progression on anti-PD-1 there is hope ~
1.  Localized therapy with surgery or radiation improved survival.
2.  Some folks experienced subsequent responses to anti-PD-1 with resumption of treatment.

Wishing you all my best. - c


  1. Yikes. Doesn't sound good for me. I am waiting to see what my next step is. I did 4 high dose ipi treatments. It attacked my liver and I have been on Prednisone since February 1st. A lung met appeared and then almost disappeared. At one time Keytruda was an option but this doesn't sound promising.Especially because my LDH keep rising. I guess I will find out what the next step is in June when I go for scans. Thanks again for all you do --- Vicki

  2. Don't forget that some folks DO respond to anti-PD-1 AFTER ipi....and AFTER anti-PD-1!!! Often with fewer side effects than they experienced on ipi....I've got lots of reports to that effect as well. Hang in there!!

  3. The response rate for anti-PD1-1 is disconcerting, but still a improvement over what was available just a few years ago. Just started Pembro following resection and SRS of my first brain met. So far, so good. Thanks for your blog Les ... Marty

  4. As someone dx'd as Stage IV in 2010...when there were NO valid FDA approved treatments...I am well aware. However, I took nivo for 2 1/2 years...and remain NED 7 years later. When it works it works. I wish you well. Hang in there.