ASCO 2017: Nivo or Ipi/Nivo combo in melanoma after progression on ipi or anti-PD-1

Despite a heavy heart, I begin my annual journey through the ASCO reports.  Great thanks to B for funneling the most pertinent of the entire meeting my way.  I will do my best to give you the unvarnished abstracts, any relevant history I have, and my take on what the expert's jargon is really saying.  As usual, my commentary will be in red.  However, there are many sources through which you can read them (as well as see videos) for yourself and I certainly encourage you to do so.  At any rate, in honor of Jamie and Josh - here we go....

Can you get a response to nivo (Opdivo) alone or the ipi/nivo combo after you've been treated with ipi or anti-PD-1 and progressed?????  Yes, you can!!!!!

Here patients who have poor prognostic factors as well as progression after ipi are treated with nivo alone:

Efficacy and safety of nivolumab (NIVO) in patients with advanced melanoma (MEL) and poor prognostic factors who progressed on or after ipilimumab (IPI): Results from a phase II study (CheckMate 172).

ASCO 2017. J Clin Oncol 35, 2017. Schadendorf, Ascierto, Haanen, et al.

Background: In the phase III CheckMate 037 study, NIVO improved the objective response rate and progression-free survival with less toxicity vs chemotherapy in patients (pts) with MEL who progressed after prior IPI treatment. We report the first efficacy and updated safety data from pts with MEL in CheckMate 172, including those with rare melanoma subtypes (uveal, mucosal), brain metastases, or an ECOG performance status (PS) of 2. Methods: In this ongoing phase II, single-arm, open-label, multicenter study, pts with MEL who progressed on or after IPI were treated with NIVO 3 mg/kg Q2W for up to 2 years until progression or unacceptable toxicity. We report efficacy and updated safety data from 734 treated pts with greater than/= to 1 year of follow-up. Results: Of 734 pts, 50% had LDH greater than ULN, 7% ECOG PS 2, 66% M1c disease, 15% a history of brain metastases, and 23% received greater than/= to 3 prior therapies. Overall, 593 pts (81%) received more than 4 doses of NIVO. Overall, response rate at 12 weeks was 32%, with a complete response in 1%. The 1-year overall survival (OS) rate was 63%. Any grade and grade 3/4 treatment-related adverse events (AEs) occurred in 66% and 17% of pts, respectively. Discontinuations due to treatment-related AEs occurred in 4% of pts. The most common treatment-related select (potentially immune-related) AEs were diarrhea (12%), hypothyroidism (9%), and pruritus (7%). Conclusions: CheckMate 172 is the largest study of NIVO efficacy and safety in pts with MEL who progressed on or after IPI. NIVO demonstrated a safety profile consistent with that of prior clinical trials. Efficacy outcomes were encouraging in some difficult-to-treat subgroups of pts with poor prognostic factors, such as mucosal melanoma and brain metastases. 

	Total pt (n=734)	ECOG PS 2 (n=48)	Uveal (n=75)	Mucosal (n=52)	CNS (n=112)
response rate at 12 weeks, % (n)	32 (123/386)	15 (2/13)	6 (2/34)	21 (5/24)	43 (20/47)
Med OS (mo)	19 (17-NR)	2 (1-4)	11 (7-15)	13 (6-NR)	13 (9-NR)
1-yr OS rate, %	63 (60-67)	14 (2-26)	47 (34-59)	53 (38-67)	51 (40-60)

* assessed in evaluable pts on tx for greater than/= to 12 weeks; NR = not reached.

Here patients who advanced after a variety of immunotherapy were treated with the ipi/nivo combo:

Salvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma.

ASCO 2017. J Clin Onco 35, 2017. Gaughn, Petroni, Grosh, et al.

Background: The combination of Ipilimumab and Nivolumab is standard initial therapy in patients with advanced melanoma based on trials involving treatment-naïve patients. The benefit in those previously managed with checkpoint monotherapy is not well defined. Methods: We identified metastatic melanoma patients from our Immunotherapy database managed with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. Baseline clinical factors, treatment history, combination therapy outcome by RECIST v1.1 and toxicity data were collected. Descriptive statistics were used to summarize the data. Given the small sample size and limited numbers of deaths, it is too early to look for preliminary associations between outcomes and clinicopathologic factors. Results: We identified 19 patients treated with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. The cohort included 15 men and 4 women with an average age of 63 years. Thirteen patients had M1c disease, and 7 had a BRAF mutation. Patients had received up to four lines of prior immunotherapy including 9 treated with both prior anti-PD1 and anti-CTLA4 monotherapy. Seven patients completed all four doses of combination therapy with 6 proceeding onto maintenance nivolumab. Eight patients stopped treatment due to toxicity and 4 due to progressive disease. Thirteen patients had clinically significant toxicity, with rash, colitis, hepatitis, and hypophysitis reported most frequently. There were no treatment-related deaths. Overall, 2/19 patients (10.5%,) had an objective response (CR+PR) and 9/19 patients (47.4%) had disease control (CR+PR+SD). Four of the patients had stable disease for over 6 months. Six of the 19 patients went on to receive subsequent treatment. Median follow-up for patients still alive was 7 months (range 1 to 20 months) and median survival was not reached. Six-month survival was 68.5%. Conclusions: The combination of Ipilimumab and Nivolumab can result in melanoma control in patients with progression on prior checkpoint monotherapy with an expected toxicity profile.

While response rates were not nearly what we'd like them to be, patients DID respond to both nivo after ipi and the Ipi/Nivo combo after prior treatments of ipi and anti-PD-1 alone.  Side effects were no worse than what we already know them to be on the respective immunotherapies. Hang tough ratties.  Much love and hope to each of you.  - c