From the recent Boston meeting of the Society for Melanoma Research:
Preventing resistance by combining BRAF with hydroxychloroquine (HCQ).
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!!!
Treatment with
neoadjuvant + adjuvant dabrafenib and trametinib (D+T) is associated with improved relapse-free survival (RFS) versus standard of care (SOC) therapy in patients with high-risk resectable BRAF-mutant melanoma. Amaria, et al.
The treatment of stage IV melanoma has been revolutionized by targeted therapy and immune
checkpoint blockade, and there is a strong rationale to evaluate these agents
in earlier stages of disease. The current SOC in patients (pts) with
high-risk resectable melanoma (stage IIIB/IIIC) is upfront surgery +/- adjuvant
therapy, but relapse rates are high. We hypothesized that treatment with
neoadjuvant + adjuvant D+T in this population would result in lower relapse
rates compared to SOC. Methods: We conducted a prospective randomized clinical trial (NCT02231775) in pts with resectable
Stage IIIB/C or oligometastatic stage IV BRAF-mutant melanoma. Pts were randomized in a 1:2 fashion to SOC (Arm A)
or neo + adjuvant D+T (Arm B, 8 wks neoadjuvant + 44 wks adjuvant). Planned
enrollment was 84 pts. Primary endpoint was RFS. Results: Randomization was halted after 21 pts were enrolled (arm A=7, arm
B=14). Arms were well matched for gender
and stage of disease, though pts in arm A were younger. Perioperative complication
rates were similar and toxicity in arm B was manageable. At week 8 the RECIST response rate with D+T was 77% and the pathologic complete
response (pCR) rate was 58%. Early analysis revealed a significantly higher RFS
in the D+T arm over SOC, with 6-month survival estimated at 100% in Arm B and
28.6% in Arm A, leading to trial closure. Conclusions: Treatment with
neoadjuvant + adjuvant D+T is well tolerated, results in high clinical response
and pCR rates, and markedly improves RFS in pts with high-risk resectable
metastatic melanoma. Correlative analyses are underway to characterize
mechanisms of response and resistance to neo + adjuvant D+T.
T-VEC plus ipi = OOR of 50% vs 27.5% for ipi alone.
T is a herpes simplex virus 1-based oncolytic immunotherapy designed to selectively replicate in tumors,
produce GM-CSF and stimulate antitumor immune responses. I (anti-CTLA-4 Ab) blocks inhibition of antitumor T-cells. Both T
and I monotherapy are approved in the US and EU for the treatment of advanced
melanoma. The primary endpoint for the phase 2 part was ORR by immune-related
response criteria. Key secondary endpoints are safety, progression-free
survival, time to response, duration of response, and survival. Key entry
criteria are unresectable stage IIIB-IV melanoma, with 2 or fewer prior tx, measurable/injectable
tumor(s), and no symptomatic autoimmunity or clinically significant
immunosuppression. T was given on d1 w1; w4, then q2w in arm 1 until no
injectable tumors, disease progression, or intolerance. I started with the 3rd dose of T in arm 1 or alone in arm 2 at 3
mg/kg IV q3w x 4. An interim analysis (IA) for efficacy was performed when 82 patients (pts) had ≥48 w of follow
up. 173 pts were randomized: 88 T+I; 85 I. Characteristics for all pts were
similar: 54% stage IIIB-IVM1a, 45% IVM1b/c. Median follow up time for 82 pts in
the efficacy set was 61.2 w. Confirmed
ORR was 35.7% (T+I) and 17.5% (I); unconfirmed
ORR was 50% (T+I) and 27.5% (I). Of 165 pts in the safety set (85 T+I, 80
I), most common adverse events (AEs) for T+I, I (%) were fatigue (52, 39),
chills (51, 3), diarrhea (39, 34), pyrexia (39, 8), rash (39, 31) and pruritus
(38, 35). 20% T+I and 18% I pts had grade 3/4 tx-related AE. A grade 5 autoimmune
hepatitis occurred in the T+I arm (investigator attributed to I). ORR was higher for T+I vs I alone at this
IA. AEs were comparable between arms except for increased fatigue, chills, and pyrexia in the T+I arm.
Intra tumoral HF10 plus ipi = good!
A Phase 2
multicenter trial to evaluate efficacy and safety of HF10, oncolytic virus
immunotherapy and ipilimumab in patients with unresectable or metastatic
melanoma. Andtbacka, Ross, ...Agarwala,... Daud, et al.
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 for Stage 3 mel.
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.
Brain mets post SRS/crani: nivo vs pembro.
Control of brain
metastases with anti-PD-1 therapy in patients with melanoma post-SRS/craniotomy. Ozgun, et al.
While anti-PD-1 antibodies have shown significant clinical
benefit in patients (pts) with advanced melanoma, a majority of these pts
develop brain metastases for which standard treatments remain radiation therapy and/or surgery. We examined outcomes in pts who were diagnosed with melanoma brain
metastases (MBM) and received upfront locoregional therapy, to determine how
well their subsequent anti-PD-1 therapy could control their MBM. We
retrospectively reviewed 146 pts with advanced melanoma who were treated with
anti-PD-1 therapy, to identify 23 pts
who had received prior stereotactic radioasurgery (SRS) or craniotomy for MBM.
There were 13 men and 10 women, with median age 56 (27-85). Most common site of
metastases was in the frontal lobe (n=13, 57%). Primary treatment for the MBM
was SRS in 17 (74%), and craniotomy in 6 (26%) pts. Median follow-up was 2 years post-locoregional therapy. Eleven pts
subsequently received pembrolizumab and 12 pts received nivolumab; median
duration of therapy was 5 months. Eight pts received these drugs as their
first-line systemic therapy post-SRS/craniotomy, 13 as second line therapy, and
2 as third-line; other first-line therapies included ipilimumab, chemotherapy
or BRAF-targeted therapies. While receiving their anti-PD-1 therapy, five (22%)
pts had no recurrence of any brain metastases (n=2 with pembro, n=3 with nivo)
and eight (35%) pts had stable MRI brain imaging with no new or growing
lesions. However, ten pts (44%) had progession of their brain metastases while
on anti-PD-1 therapy (n=3 with nivo, n=7 with pembro). Median overall survival from time of SRS or craniotomy was 24 months
(5.6-32) for pts treated with pembro
and 36 months (1.7-84) with nivo. While there may be a suggestion of
improved outcome with nivolumab in MBM after locoregional therapy, larger
analyses are needed for definitive conclusions.
Acetylsalicylic acid governs the effect of Sorafenib in mutant NRAS melanoma. Hammerlindl, et al.
To date no therapies directly targeting mutant
NRAS melanoma have been approved, leaving chemotherapy with very low response
rates or immunotherapy for the treatment of mutant NRAS melanoma patients. Here
we report a novel strategy to target mutant NRAS melanoma by combining the
multi kinase inhibitor Sorafenib and the nonsteroidal anti-inflammatory drug
acetylsalicylic acid (Aspirin), both of which are clinically tested and
approved. The addition of Aspirin, but not isobutylphenylpropanoic acid
(Ibruprofen) or Celecoxib significantly increased the invitro cytotoxicity of
Sorafenib resulting in a fivefold reduced effective Sorafenib dose in WM1366,
WM832, and WM1361 mutant NRAS melanoma cells. Mechanistically, combined
exposure resulted in the simultaneous hyperactivation of AMPK and ERK pathways.
Combining Sorafenib with other AMPK activators like Metformin or A769662 was not sufficient
to induce cell death due to sole activation of the AMPK pathway. Accordingly,
cytotoxicity of Sorafenib and Aspirin was blocked by concurrent inhibition of
AMPK or ERK pathways using pharmacological inhibitors of RAF (LY3009120), MEK
(Trametinib) and AMPK (Compound C) or shRNA targeting BRAF or AMPKα1/2. The
combination was found to be specific for mutant NRAS and had no significant
effect in wild type RAS keratinocytes or melanoma cells. In-vivo the treatment
of SCID mouse xenografts with Sorafenib and Aspirin significantly reduced
tumour volume compared to single treatment alone. Combined Sorafenib and Aspirin
selectively target mutant NRAS melanoma cells by simultaneously affecting two
independent pathways. The combination represents a novel treatment strategy for
mutant NRAS melanoma by repurposing clinically approved drugs with the
potential to reduce Sorafenib induced adverse effects while maintaining clinical efficiency.
Ok. I'm tired now. But...some pretty interesting stuff. For what it's worth - c
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