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