From the recent Boston meeting of the Society for Melanoma Research:
Autophagy is a resistance mechanism to BRAF inhibitors that can be targeted with hydroxychloroquine (HCQ). We launched a Phase I trial of vemurafenib and HCQ in BRAFV600 melanoma patients. 7 patients in the 1st dose level (vemurafenib 960 po bid + HCQ 400 po bid) had 2 dose limiting toxicities ... preventing further dose escalation. 6/6 patients evaluable for response had PR or CR. Prolonged PFS was seen in 1 CR (30+ mo) and 1 PR (20 mo). Combined BRAF/MEK inhibition was adopted widely so this trial was closed, and a multi-institution phase I/II trial of dabrafenib (D), trametinib (T) and HCQ was opened. Phase I was completed with no DLT (n=7). Recommended phase II dose was HCQ 600 bid with D+T. Phase II enrollment continues. D+T+HCQ was well tolerated, with no evidence of visually significant ocular toxicity. Striking responses were observed: 6/7 patients responded and 5/6 patients had a CR. The only non-responder was found to have BRAFV600E amplification, and had pyrexia that required frequent dose interruptions. Only 1 of 6 responders has progressed (PFS for responders 7-19 months, ongoing, censored as of July 2016), with brain metastases harboring a BRAFV600E and PIK3CA mutation after 15 mo. A cell line created from this resected metastases showed continued sensitivity to D+T+HCQ in vitro. The patient developed progressive CNS disease despite brain radiation and restarted D+T+HCQ, benefiting from second response that continues to date. Patient derived xenografts were created from 4/4 pretreatment tumor biopsies from the 7 patients. A randomized PDX trial with all combinations of treatments is underway with PDX from responding and resistant patients to determine if the addition of HCQ to D+T is significantly contributing to the activity of this regimen.
Stage IIIB/C treated with adjuvant BRAFi = 100% 6 month survival vs 28.6% with standard care!!!
HF10 (intratumoral injection) shows activity in injected lesions and non-injected metastatic lesions presumably via an antitumor immune response elicited by viral destruction of injected lesions. An ongoing Phase 2 study of HF10 combined with ipilimumab (ipi) in melanoma pts is assessing whether the antitumor effect of HF10 is enhanced by concurrent ipi treatment. Efficacy and safety of HF10+ipi treatment are reported herein. An immunologic correlative data analysis is currently ongoing. Ipi naïve adults with stage IIIB, IIIC or IV unresectable melanoma with measurable non-visceral lesion(s) received HF10 injections into single or multiple tumors; 4 injections qwk; then up to 15 injections q3wk. Ipi (4X at 3 mg/kg, IV) was administered per SOC. Tumor responses were assessed at 12, 18, 24wks, and 36, 48wks for pts continuing HF10 monotherapy. Best Overall Response Rate (BORR) was determined at 24wks. Of 46 pts treated, 20% were stage IIIB, 43% stage IIIC, and 37% stage IV. Most HF10-related AEs were ≤G2, similar to HF10 monotherapy. No DLTs were reported; 3 G4 AEs reported, all not treatment related. 30.4% had G3 AEs. HF10-related G3 AEs (n=3) were left groin pain, thromboembolic event, lymphedema, hypoglycemia, and diarrhea. Of 43 efficacy evaluable pts, preliminary BORR at 24 wks per irRC was 41.8% (11.6% CR, 30.2% PR), disease stability rate 67.4% (25.6% SD). 8 responders (53%) were stage IV. Overall study BORR, including those after 24 weeks, by irRC was 48.8% (18.6% CR, 30.2% PR), disease stability was 67.4% (18.6% SD). In summary, HF10+ipi treatment does not appear to exacerbate ipi toxicity, is safe and well tolerated, has both local and systemic antitumor activity, with promising response rates when combined with ipi.
IPI+NIVO induces high response rates and improved overall survival in late stage melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering and therefore depends on the amount of antigen present, arguing for that adjuvant immunotherapy willwork most efficiently, when initiated prior to surgery. Two-arm Phase 1b feasibility trial consisting of 20 high risk AJCC stage 3B/C melanoma patients with palpable nodal disease receiving the combination of IPI 3mg/kg and NIVO 1mg/kg, either adjuvant four courses after surgery, or split neo-adjuvant and adjuvant. To date, 17 patients are evaluable (9 neoadjuvant; updated data and first analyses of melanoma specific T cell responses will be presented.). Neo-adjuvant application of IPI+NIVO was feasible and no surgery-associated adverse events were attributed to (neo-)adjuvant therapy. 15/17 patients (88%) had to stop earlier due to grade 3/4 toxicities. ORR in the neo-adjuvant IPI+NIVO arm was 78% (3 pCR, 3 near pCRs [minimal remaining micrometastasis], 1 pPR [remaining metastasis of 0.5mm], 1 SD and 1 PD). So far, post-surgery, none of the responders in the neoadjuvant arm has relapsed. Relapse was observed for 1 neoadjuvant SD patient and for 3 patients within the adjuvant arm. The combination of IPI+NIVO in the (neo-)adjuvant treatment setting for high risk stage 3 melanoma patients is feasible. However, severe grade 3/4 toxicity was more frequent than expected from stage 4 melanoma patient study data. In parallel, response rate and depth of response also may be higher than in stage 4 melanoma patients. These results indicate that IPI+NIVO is a promising combination for neo-adjuvant treatment in stage 3 melanoma, which will be tested in adjusted schemes in the upcoming phase 2 OpACIN-neo trial, with the aim of preserving efficacy, but reducing toxicity.
Acetylsalicylic acid governs the effect of Sorafenib in mutant NRAS melanoma. Hammerlindl, et al.