ASCO 2016 - Other therapies after failing Pembro...and...trial with OX40 - alone and with Pembro...still enrolling....

The Mayo Clinic experience in patients with metastatic melanoma who have failed previous pembrolizumab treatment.  ASCO 2016. # e21014.  J Clin Oncol 34, 2016.  Yan, Failing, Leontovich, et al.

Background: Blockade of programmed death (PD-1) receptor has shown unprecedented rates of durable clinical responses in patients with metastatic melanoma. However, the majority of patients eventually progress on anti-PD-1 therapy. Currently, there is no standard strategy guiding the treatment in this setting, partly due to the lack of knowledge of the clinical course after PD-1 blockade failure. Methods: We retrospectively reviewed 140 patients with metastatic melanoma treated with pembrolizumab at Mayo Clinic, Rochester, between January 1, 2012 and November 1, 2015, identifying 70 patients who failed pembrolizumab treatment (due to disease progression or toxicity). The clinical outcomes and RECIST objective response rates (ORR) to treatments received after pembrolizumab were assessed. Results: Of the 70 patients who failed pembrolizumab therapy, 48 received further systemic therapies. Of these, 43 had complete follow-up data and were included in our analysis. Thirty patients received 1 line of subsequent therapy; while 13 patients received multiple subsequent treatments (average 2.5). Eighteen patients with a BRAF mutation received targeted therapy, 9 of whom received targeted therapy alone, with an ORR of 55.6% and 0% stable disease (SD). Nine of these 18 BRAF mutant patients received targeted therapy combined with chemotherapy and/or immunotherapy, with an ORR of 22.2% and 33.3% SD. Twenty two of the 43 patients received immunotherapy (nivolumab and/or ipilimumab or pembrolizumab)-based treatment (alone or in combination with chemotherapy), with an ORR of 31.8%, and 13.6% SD. Nineteen of the 43 patients received chemotherapy alone with an ORR of 26.3% and 0% SD. Conclusions: Patients with metastatic melanoma who failed previous pembrolizumab therapy appear to benefit from further systemic treatments, including additional immunotherapy. Combination therapies show favorable clinical outcomes. The biological mechanism of combining PD-1 blockade with other therapy modalities is currently being studied and will further improve patient outcomes.

Additional links along these lines:  
Response to ipi after being treated with anti-PD1 
Hope after standard melanoma immunotherapies fail 

As was mentioned in the last link....here is a report on OX40 alone and with pembro....still enrolling...

ENGAGE-1: A first in human study of the OX40 agonist GSK3174998 alone and in combination with pembrolizumab in patients with advanced solid tumors.  ASCO 2016.  # TPS3107.  J Clin Oncol 34, 2016.  Infante, Ahlers, Hodi, et al.

Background: OX40 (CD134) is a potent costimulatory tumor necrosis factor receptor expressed on activated CD4+ and CD8+ T cells. OX40 agonism promotes T-cell division and survival, resulting in stimulation of both immune effector and memory functions, while also blocking the suppressive function of regulatory T cells. This holds potential to overcome immune resistance and enhance immune mediated anti-tumor activity with OX40 agonism, particularly in combination with checkpoint inhibition. GSK3174998 is a humanized IgG1 anti-OX40 agonistic monoclonal antibody identified through collaboration with MD Anderson Cancer Center and is currently in phase I development. Methods: This is an open-label, non-randomized, multicenter study of GSK3174998 administered alone and in combination with pembrolizumab in patients (pts) with selected advanced or recurrent solid tumors: non-small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma, bladder, soft tissue sarcoma, triple-negative breast cancer, and colorectal carcinoma displaying microsatellite instability. The study will be conducted in 2 parts in approximately 180 pts. Primary objectives are to determine safety, tolerability, and maximum tolerated or administered dose of GSK3174998 as a single agent (Part 1) and when administered in combination with 200 mg pembrolizumab (Part 2). Secondary objectives include evaluation of antitumor activity, response rate and duration, progression-free survival, and overall survival, pharmacokinetics, pharmacodynamic activity in the blood and tumor microenvironment, and immunogenicity. Adverse events will be monitored using NCI CTCAE v. 4.0. Radiographic imaging will be obtained every 12 weeks to assess clinical response defined by immune-related RECIST. Tumor biopsies and blood samples will be collected before and during treatment to allow investigation of candidate biomarkers which may predict clinical response. As of Feb 1, 2016, Cohorts 1 and 2 have completed without DLT and enrollment to Cohort 3 is ongoing. Clinical trial information: NCT02528357

Gotta love ratties!! - c

ASCO 2016 - Oral panRAF inhibitor (CCT3833) prelim results...with ??? more enrolling?

A Phase 1 first-in-human trial to evaluate the safety and tolerability of CCT3833, an oral panRAF inhibitor, in patients with advanced solid tumours, including metastatic melanoma.  ASCO 2016. # TPS9597.  J Clin Oncol 34, 2016.  Dean, Baneji, Girotti, et al.

Background: Over 70,000 patients are diagnosed with malignant melanoma in the USA every year with a high proportion occurring in young people. Although treatments targeting the mitogen activated protein kinase signal transduction pathway including BRAF inhibitors have improved survival for patients with BRAF mutated melanoma, their utility is limited by intrinsic and acquired resistance of diverse mechanisms. Patients with a RAS mutated melanoma also represent a current unmet need. CCT3833 is a potent inhibitor of mutant BRAF, CRAF and SRC kinases. Preclinical data using CCT3833 in a range of mutant RAF or RAS cell lines in vitro and human tumour xenograft models in vivo demonstrated activity, including melanoma patient-derived xenografts with intrinsic or acquired resistance to selective BRAF inhibitors. These data support clinical development of CCT3833 in humans. Methods: This ongoing open-label, multi-centre Phase I trial of CCT3833 is in two parts; an initial dose escalation stage (Part A) in a rolling six design, followed by a dose expansion (Part B). The primary objectives are to evaluate the safety and tolerability profile of CCT3833 and establish the Recommended Phase 2 Dose (RP2D). CCT3833 is administered orally once daily on a continuous basis over a 28-day cycle. In Part A, a single dose is administered for safety and pharmacokinetic (PK) purposes prior to commencing continuous dosing. Secondary objectives include characterization of the PK profile and correlation with tolerability / efficacy of CCT3833 in humans and assessment of response (radiological or clinical), supported by PD analyses. Eligible subjects include patients with advanced solid malignancies with performance status 0 to 1, fit for entry into a Phase 1 clinical trial. Part B will enroll patients with BRAF- or RAS- mutated metastatic melanoma into 3 cohorts i) treatment naïve V600E BRAF mutant melanoma ii) V600E BRAF mutant melanoma with progression on BRAF inhibitor therapy or iii) RAS mutant melanoma. Three cohorts of the dose escalation have been completed without DLT. Enrollment to cohort 4 began in January 2016. Clinical trial information: NCT02437227

Perhaps this will provide hope for those with RAS mutations.  Keep on rolling, ratties!!! - c

ASCO 2016 - Three anti-PD1 reports

A little surprisingly...not much has been said about anti-PD1 in the ASCO abstracts this year.  Perhaps more will be presented at the meeting, or perhaps it is all old news at the moment.  I certainly covered these reports already.  But, here are three anti-PD1 stories out of ASCO this year.

1.  When I started my nivo trial in 2010....you weren't even allowed to take anti-PD1 if you had already taken ipi....then you could, but you couldn't have had an immune related side effect.  All this was based on the thought that if you reacted badly to one...you were bound to have a worse reaction to the other...and you certainly couldn't take it if you already had an autoimmune condition.  Well, wonderful brave ratties have proven that that is NOT TRUE!!!  Here is a post covering some of that:  Anti-PD1 success in melanoma despite preexisting autoimmune disease with links to other reports about previous side effects, yet tolerating treatment and gleaning a response

Here's what came out of ASCO:

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders (AD) or major toxicity with ipilimumab (IPI).  ASCO 2016. #9515.  J Clin Oncol 2016.  Menzies, Johnson, Ramanujam, et al.

Background: Anti-PD1-antibodies (PD1) have activity in many cancers, and are standard care for melanoma, lung and renal cancer. All trials excluded patients (pts) with significant preexisting AD or major immune-related adverse events (irAEs) with IPI. We sought to explore the safety and efficacy of PD1 in such pts. Methods: Pts with advanced melanoma and preexisting AD and/or major irAEs with prior IPI (requiring systemic immunosuppression, [IS]) treated with PD1 were retrospectively identified. Data regarding AD, IPI and PD1 treatments, toxicity and outcome were examined. Results: 119 pts were included, 95 with prior IPI. 109 received pembrolizumab, 10 nivolumab. 86 (72%) had greater or = to, 3 months follow-up, median (med) 4.6 mo, with med PFS 6.8 mo. 31 (26%) had died. Of 52 pts with preexisting AD, 15 (29%) had active symptoms at PD1 start and 16 (31%) were on IS. The ORR was 33%. 20 (38%) flared with PD1 after a med 1.3 mo, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 1/2 with scleroderma, 2/2 with immune thrombocytopaenic purpura, 3/8 with psoriasis, 1/4 with Graves’ disease, 0/6 with gastrointestinal (GI) (including 3 Crohn’s disease) and 0/5 with neurological disorders. 3 (6%) had grade (G) 3 flare, and 2 (4%) discontinued PD1 for flare. 15 (29%) developed other irAEs (5 G3), 3 (6%) discontinued PD1. 67 pts had irAEs requiring IS with prior IPI (9 G2, 51 G3, 7 G4), including 47 with greater than or = to, G3 colitis (15 had infliximab), 2 with G4 hepatitis (1 had antithymocyte globulin), and 9 with hypophysitis. All irAEs except hypophysitis had resolved at PD1 start except in 1 pt (arthritis), 5 were on IS at PD1 start. The ORR was 40%. 2 (3%) had recurrence of IPI irAEs with PD1 (arthritis, colitis), but 23 (34%) developed new irAEs (13, 19% greater than or = to, G3), and 11 (16%) discontinued PD1. There were no treatment related deaths. Conclusions: PD1 have efficacy in pts with preexisting AD and/or major irAEs with IPI. PD1 may flare preexisting AD, particularly rheumatologic, but GI and neurological disorders may flare less. In pts with prior major irAEs with IPI recurrence of the same irAE is rare, but new irAEs occur. The rate of irAEs in these pts appears higher than in clinical trial pts.

Not bad, not at all bad....

2.  Last year I posted this:  Folks with melanoma liver mets show less response to Pembro. Why?

On the other hand, President Jimmy Carter did well on Pembro (with very limited dosing compared to many...he's already off treatment) for brain met (radiated) and liver mets (though it was resected to some extent).   This from ASCO:

Correlation between metastatic site and response to anti-Programmed Death-1 (PD-1) agents in melanoma.  ASCO 2016. #9549.  J Clin Oncol 2016. Goldinger, tsai, Tume, Hamid, et al.

Background: Antibodies against PD-1 have shown remarkable activity in the treatment of advanced melanoma. Clinical characteristics correlated with response have not yet been fully characterized. Previous work has shown that site of metastasis can correlate with treatment outcome. We sought to confirm these findings in a larger cohort of metastatic melanoma patients (pts). Methods: We conducted a multicenter retrospective study in a cohort of metastatic melanoma pts treated with anti-PD-1 agents. Relevant clinical data were retrieved from electronic medical records. Tumor responses were evaluated by RECIST v1.1. A multivariate regression model was used to investigate demographic and clinical variables associated with response. Results: We identified 337 pts who received pembrolizumab (2mg/kg or 10mg/kg Q3W) (N = 326) or nivolumab (3mg/kg Q2W) (N = 11) on clinical trials (N = 273) and early access programs (N = 64) at UCSF and USZ. In the multivariate model, pts who had liver metastasis and prior ipilimumab were less likely to respond to treatment. Data for subgroup variables are shown. Pts with lung metastasis were more likely to respond. Conclusions: This multivariate model supports a significant correlation between liver metastasis and prior ipilimumab with poor response to anti-PD-1 therapy in melanoma pts. Presence of lung metastasis was correlated with improved response, though this just approached statistical significance. Efforts are ongoing to better identify clinical characteristics and biomarkers of response, and to further investigate the tumor microenvironment.

Variable	Odds ratio	95% CI	p value
Liver metastasis	0.35	0.21-0.59	< 0.0001
Prior ipilimumab	0.39	0.24-0.64	0.0002
Elevated LDH	0.64	0.40-1.04	0.07
ECOG	0.71	0.43-1.16	0.17
WBC	0.99	0.92-1.07	0.86
Brain metastasis	1	0.56-1.8	1
Lung metastasis	1.56	0.99-2.51	0.06

For what it's worth....

3.  I've actually posted these results before.  In Weber's report here:  Immunology update webinar for melanoma...  where this was presented (red in this case are HIS words):

   CheckMate 064: Study Design:  Cohort A - nivo 3mg/kg q2wk X6, then ipi 3mg/kg 1 3wk X4.  Cohort B - ipi 3mg/kg 1 3wk X4, then nivo 3mg/kg q2wk X6. Both cohorts were followed with nivo, 3mg/kg q2wk until progression, toxicity, or withdrawal of consent. Toxicities were no different between arms.  Significant difference in response rates due to sequence of drugs.  Nivo followed by ipi gave better results. "A real surprise."
I already had a rant on this one:  Sequential nivo then ipi orr of 41%!

Efficacy Summary Week 13				Week 25
NIVOàIPI (n = 68)		IPIàNIVO (n = 770)		NIVOàIPI (n = 68)		IPIàNIVO (n = 70)
Confirmed ORR, %	--		--		41.2		20.0
Complete response, n	0		0		0		0
Partial response, n	24		7		28		14
Conventional ORR, %	35.3		10.0		47.7		22.6
Progression rate, %	38.2 (26.7–50.8)		61.4 (49.0–72.8)		38.2 (26.7–50.8)		60.0 (47.6–71.5)

And you can see the link to my earlier rant above as well!!  At any rate...here it is...out of ASCO:  

Survival outcomes of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064).  ASCO 2016. # 9517.  J Clin Oncol 34, 2016.  Weber, Gibney, Sullivan, Sosman, Slinghuff, Hodi, et al.

Background: Combining or sequencing immune checkpoint inhibitors that target distinct pathways has the potential to improve survival outcomes compared to either agent alone. This randomized phase II trial (CheckMate 064) previously demonstrated improved response rates with NIVO followed by IPI vs. IPI followed by NIVO in patients (pts) with advanced melanoma. Here, we report the first overall survival (OS) data from this study. Methods: Pts (N = 140) were randomized 1:1 to receive sequential induction treatment with NIVO 3 mg/kg Q2W x 6 doses followed by IPI 3 mg/kg Q3W x 4 doses (cohort A; N = 68 treated) or IPI 3 mg/kg Q3W x 4 doses followed by NIVO 3 mg/kg Q2W x 6 doses (cohort B; N = 70 treated). Following induction, both cohorts received NIVO 3 mg/kg Q2W until progression or unacceptable toxicity. The primary endpoint was to evaluate treatment-related grade 3–5 adverse events (AEs) during the induction periods until week 25. Secondary and exploratory endpoints included objective response rate (ORR) by modified RECIST v1.1, progression-free survival rate, and OS. Results: As previously reported, baseline patient characteristics were mostly balanced between cohorts, although a higher percentage of pts in cohort A had an ECOG performance status of 0, PD-L1 tumor expression ≥ 5%, and brain metastases. Similar rates of treatment-related grade 3/4 AEs occurred during both induction periods to week 25 in cohort A (50%) and cohort B (43%). In the updated analysis (minimum follow-up of 14 months), grade 3/4 AEs were 63% in cohort A and 50% in cohort B across all study periods, which led to discontinuation in 25% and 27% of pts, respectively. ORR was higher in cohort A than in cohort B (54% vs. 31%), with more complete responses (11% vs. 6%). A significant difference in OS was observed between cohorts A and B, with the median not reached vs. 16.9 months, and 1-year OS rates of 76% and 54%, respectively. Conclusions: NIVO followed by IPI continues to show improved efficacy outcomes vs. IPI followed by NIVO, with longer OS. A higher frequency of AEs was observed in cohort A, with the types and rates of AEs similar to that reported for NIVO given concurrently with IPI. 

Wishing you all my best.  - c

ASCO 2016 - Anti-PD1 for acral and mucosal melanoma

Acral and mucosal melanoma often fail to play by even the random rules that other melanoma tumors share and as such make treatment of them even more difficult.  But...there is this:

Clinical activity of anti-programmed death-1 (PD-1) agents in acral and mucosal melanoma.  ASCO 2016. #9516.  J Clin Oncol 2016.  Munhoz, Shoushtari, Kuk, et al.

Background: Antibodies against PD-1 resulted in a paradigm shift in the management of melanoma. Nevertheless, melanoma is a heterogeneous disease: compared to cutaneous melanoma, mucosal melanoma (MM) and acral melanoma (AM) have distinct genetic and clinical characteristics, lower somatic mutational burden, and poorer prognosis. We sought to investigate the efficacy of PD-1 blockade in patients (pts) with advanced mm and AM. Methods: We conducted a multicenter retrospective study of pts with advanced mm or AM treated with nivolumab or pembrolizumab. Clinical, pathologic, and treatment data were retrieved from electronic medical records. Response rates were assessed by RECIST v1.1 and survival intervals were calculated using the Kaplan-Meier method. Variables associated with response and survival were investigated. Results: Sixty pts were identified; 35 (58%) with mm and 25 (42%) with AM. Fifty-one (85%) pts had received prior therapy, including 77% with prior ipilimumab. Forty pts (67%) received pembrolizumab at 2mg/kg or 10mg/kg and 20 (33%) received nivolumab at 1mg/kg or 3mg/kg every 2-3 weeks. Objective response rate (ORR)  was 23% (10-40%) in mm and 32% (15-54%) in AM. ORR did not vary by age, primary site, or prior therapy outcomes. With a median follow-up of 10.6 months (mo) for mm and 20 mo for AM, the median progression-free survival was 3.9 mo and 4.1 mo, respectively. Median overall survival for the entire cohort was 16.8 mo; in mm it was 12.4 mo, and in AM 31.7 mo. Only two pts (3%) discontinued treatment due to toxicity. Conclusions: PD-1 blockade resulted in clinically meaningful activity in pts with mm and AM. Response rates and safety profile were comparable to published clinical trials which largely consisted of cutaneous melanoma and support the use of PD-1 blockade for mm and AM as well. The role of specific driver mutations, immunologic infiltrates and potential biomarkers of response and resistance in these melanoma subtypes needs further investigation.

Here, the roughly 40% response rates with anti-PD1 for treatment naive cutaneous melanoma patients were not achieved.  But, 85% of these patients had been previously treated....something many studies shows diminishes response rate and then there is the fact we are dealing with mucosal and acral melanoma.  Response rates of 23 and 32% are certainly something and definitely worth pursuing!!!  Interestingly, mucosal melanoma can often be NRAS positive.  Earlier I posted this: Good news for NRAS positive folks re: Anti-PD1 In that report, where NRAS positive patients were evaluated for response to IL2, ipi, vs anti-PD1 they found:  

"Within specific immune therapy types, patients with NRAS-mutant melanoma experienced the greatest benefit in CR/PR compared to patients with WT melanoma when treated with anti-PD1/PD-L1 agents (70% vs 20%)."   
 
Which got me thinking:  "A ray of light for folks with NRAS mutation. And maybe one more reason not to make them go through ipi before they get to take anti-PD1???!!!!!"  
Not all mucosal or acral melanoma are NRAS positive...but that info would probably be a good thing to find out!  Hang in there, dear ones!  Hang in there.   - c