Wednesday, June 21, 2017

ASCO 2017: ipi plus pembro, ipi after pembro and identifying markers for outcome with pembro for advanced melanoma

It goes without saying that over the years I have posted a zillion reports about all things immunotherapy:  anti-PD-1 ~ Pembrolizumab (also referred to as Pembro and Keytruda) as well as Nivolumab (also called nivo and Opdivo) both of which have very similar side effect profiles and a roughly 40% response rate when used alone; anti-CTLA-4 ~ ipilimumab (also called ipi and Yervoy) which has similar side effects but with greater frequency and intensity than the anti-PD-1 products {though many tolerate it well} with about a 15% response rate when used alone; as well as the ipi/nivo combo which has a response rate of 50+%. (Here's a link:  ASCO 2016: Checkmate 069 - ipi/nivo combo in Stage IV melanoma demonstrated a 68% ORR)  Consistently, treatment naive patients have responded best to all of the above, responses are the most durable we have ever had in any melanoma treatments, many folks continue to respond even if they have to stop treatment due to side effects.  We have also learned that side effects need to be treated as soon as possible, often with steroids, so as to save lives and prevent greater damage than has already occurred, AND the use of steroids, if needed, DOES NOT IMPEDE RESPONSE!!!!  Feel free to use the blog's search bubble to find more info and data on all of this.  Now researchers are looking at:

Pembro plus ipi:

Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma.
ASCO 2017. J Clin Oncl, 35, 2017. Carlino, Atkinson, Cebon, et al.

Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAFV600mutant, and 13% received greater than/= to 1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61%; the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685

Here 153 Stage IV melanoma patients (no brain mets) but some with increased LDH were given Pembro 2mg/kg and ipi at only 1mg/kg, together every three weeks for 4 doses and then pembro alone q 2 wks.  There were no treatment related deaths, though ALL patients had side effects, but were grade 3/4 in only 45%.  The way the data was examined ~ with one near endpoint and another 7 months later...proved...AGAIN...that responses can occur late....and as per Weber and Agarwala, when it comes to immunotherapy, "Give the patient time!" ~ for an ultimate ORR of 61% and CR of 15%.  So....these responses are no better than those demonstrated in the ipi/nivo combo.  But...what is interesting is that ipi was dosed at only 1mg/kg whereas in the ipi/nivo combo it is used at 3mg/kg. (AGAIN!!!  Why can't researchers [and Big Pharma!!!!] construct trials so that you can REALLY compare results!!!) At any rate, this tidbit of data may prove important in decreased side effects and it would be important/interesting to see if nivo with ipi at only 1m/kg would continue to do as well as the combo does currently.  I'm betting it would....but that's just me.

While the next couple of articles did not come out of ASCO this year...they pertain to the topic at I've included them here.

Here, researchers looked at the response to ipi after patients have progressed on pembro:

Antitumor activity of ipilimumab after pembrolizumab in patients with advanced melanoma  KEYNOTE-006 Poster Spotlight: G. Long (Australia).  European Cancer Conference, Jan 2017.

Background: The efficacy and safety of PD-1 inhibition in patients with advanced melanoma previously treated with the CTLA-4 inhibitor ipilimumab has been established in several studies, including the KEYNOTE-001 and 002 trials of pembrolizumab. Conversely, the efficacy of CTLA-4 inhibition with ipilimumab following anti–PD-1 therapy is not clearly established. We assessed outcomes in patients enrolled in KEYNOTE-006 (NCT01866319) who received ipilimumab monotherapy after pembrolizumab.
Methods: Patients in KEYNOTE-006 were randomized 1:1:1 to 2 years of pembrolizumab 10 mg/kg Q2W (n = 279) 10 mg/kg Q3W (n = 277) or to 4 doses of ipilimumab 3 mg/kg Q3W (n = 278). Treatment was continued until disease progression, intolerable toxicity, or patient or physician decision. After study treatment discontinuation, subsequent anticancer therapy and outcomes were reported.
Results: As of December 3, 2015, ipilimumab was recorded as a subsequent therapy for 129 pembrolizumab-treated patients, including 97 for whom ipilimumab was the first post-study therapy. Of these 97 patients, 64% had M1c disease, 33% had elevated serum LDH at baseline, and 16% had BRAFV600-mutant tumors at baseline. Best response to pembrolizumab was PR in 16%, SD in 12%, nonCR/nonPD in 5%, PD in 62%, and nonevaluable/not assessed in 4%. Median duration of pembrolizumab before the start of ipilimumab was 18 weeks, and the median time between the last pembrolizumab dose and first ipilimumab dose was 5 weeks. Median duration of ipilimumab was 8 weeks. The reported ORR for ipilimumab was 14%, with a best overall response of CR in 3%, PR in 11%, SD in 33%, PD in 33%, and unknown in 23%; subsequent progression occurred in 40% of patients with PR and 48% with SD. Best response to pembrolizumab in the 13 patients who responded to ipilimumab was SD in 1, nonCR/nonPD in 2, PD in 8, and not assessed in 2. Best response to ipilimumab in the 16 responders to pembrolizumab who received greater/= to 1 ipilimumab dose was SD in 8, PD in 3, and unknown in 5. Fifty-seven of 97 patients had died, and median OS from randomization was 19.6 months.
Conclusions: Ipilimumab has antitumor activity following pembrolizumab in patients with advanced melanoma, including those whose best response to pembrolizumab was PD, with an ORR consistent with historical data.

So in 97 patients, most of whom had taken pembro for about 18 weeks with a PR in 16% and SD in 12%, PD in 62% (clearly, these were folks who were not responding to pembro as well as the usual data) were, in about 5 weeks placed on ipi at 3mg/kg, with most folks taking it for 8 weeks.  At that point, the ORR to ipi was 14% (which is what responses to ipi usually run at).  Additional data showed:  CR in 3%, PR in 11%, SD in 33%, PD in 33%.  While not great, this certainly shows that if you are not a responder to pembro....switching ASAP to ipi can gain a response of about 15%.  A similar response was attained in the last abstract noted in this post from ASCO 2015:  ASCO 2015: Nivo and Pembro after failing ipi. Ipi after failing anti-PD1.

Here researchers looked at how tumors, and subsequently the patients!!!, responded to pembro:

Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions. Nishino, Giobbie-Hurder, Manos, et al. Clin Cancer Res. 2017 June 7.

Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.

Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.
Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median, -18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained less than 20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with less than 20% tumor burden increase from baseline had longer OS than patients with greater than/= to 20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with less than 20% tumor burden increase during therapy had significantly reduced hazards of death.  Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.
Conclusions: Tumor burden increase of less than 20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention.

Here 96 patients with measureable disease were given pembro.  ORR was the expected 44%.  Folks whose tumor burden increased less than 20% from their baseline, once therapy was started, did best, and this was 55% of the peeps in the study.  They ended up with a longer OS than those whose known tumor burden increased more than 20% from baseline while on pembro.  Of course!  If your tumors mostly just shrink while on do better!!!   BUT!  The pseudoprogression thing is real for some...albeit in small numbers...3 patients had target lesions increase in size but went on to gain a response and 1 patient that didn't have measureable disease when they started treatment developed a new lesion that then regressed.

Well, there you have it.  Things remain about as clear as mud if you are a melanoma patient who is progressing on immunotherapy as to trying to decide what to do next!!! is clear...that there is hope.  Love and luck to all the ratties - c

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