ASCO 2017: Atezo (anti-PDL1) with Cobimetinib (MEKi) and Vemurafenib (BRAFi) for BRAF V-600 melanoma

In 2016 several reports came out and studies started looking at combining immunotherapy with BRAF/MEK.  Here's one report with a link within:  The whole she bang - immunotherapy with BRAF/MEK for melanoma

Per the researchers, the theoretical benefit of the triple whammy is this:
"Immunotherapy of advanced melanoma with CTLA-4 or PD-1/PD-L1 checkpoint blockade induces in a proportion of patients long durable responses. In contrast, targeting the MAPK-pathway by selective BRAF and MEK inhibitors induces high response rates, but most patients relapse. Combining targeted therapy with immunotherapy is proposed to improve the long-term outcomes of patients."

Here is a post from ASCO of last year:  Anti-PD1/PDL1 combined with BRAFi in BRAF+ patients

Part of that post notes a trial in which atezolizumab (an anti-PD-L1 monoclonal antibody, also called Tecentriq) was dosed with vemurafenib (a BRAF inhibitor) like this:
1.  atezo and vemurafenib together = ORR of 33%
2.  Vemurafenib X 56 days followed by atezo = ORR of 75%
3.  Vemurafenib X 28 days followed by atezo = ORR 100%

Here atezo is combined with cobimetinib (a MEKi) and vemurafenib:   

Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAF^V600-mutant metastatic melanoma (mel): Updated safety and clinical activity.

ASCO 2017. J Clin Oncol 35, 2017. Sullivan, Gonzalez, Lewis, Hamid, Infante, ...Hodi, ...et al.
Background: Targeted inhibition of MEK with C and BRAF with V in BRAF^V600-mutant mel can lead to both anticancer immune activation and direct tumor cell death. A, an anti–PD-L1 monoclonal antibody, inhibits PD-L1/PD-1 signaling. Combining C + V with A may enhance antitumor activity, potentially leading to improved clinical responses and durability. Preliminary data from this phase Ib study showed that A + C + V had a manageable safety profile and promising antitumor activity in patients (pts) with untreated BRAF^V600-mutant unresectable/metastatic mel, with increases in CD8-positive T-cell infiltration observed after C + V. We present updated safety and efficacy data. Methods: Pts received A + C + V after a 28-day run-in with C + V. A was given at 800 mg q2w, C at 60 mg qd for the first 21 days of each 28-day cycle, and V at 960 mg bid during day 1–21 of run-in and 720 mg thereafter. Safety was evaluated in pts who had ≥1 dose of A; efficacy, in pts who had greater than/= to1 dose of A by the data cutoff date and received greater than/= to 1 dose of A, C, or V by the dosed-by date. Results: Thirty-four patients were treated and evaluated for both safety and efficacy. Median survival follow-up was 7.1 months (range 2.5–19.9). Elevated AST/ALT, diarrhea, arthralgia, fatigue, photosensitivity, pyrexia, nausea, flu-like symptoms, maculopapular rash, and pruritus were reported as A- and/or C- and/or V-related in and 20% of pts at any grade (G). A/C/V-related G3–4 adverse events (AEs) were seen in 15 pts (44.1%) with the triple combination (none G5). Three serious AEs were A-related. All AEs were manageable and reversible. Elevated ALT/AST (three pts each) and rash (one pt) led to discontinuation of any drug. Unconfirmed RECIST V1.1 responses were observed in 29 pts (85.3%; six complete, 23 partial). Three pts with confirmed partial responses had resolution of target lesions. Twenty of the 29 responding patients continue to respond at the time of the data cutoff. Conclusions: Updated results confirm preliminary findings that A + C + V has a manageable safety profile and promising antitumor activity in pts with BRAF^V600-mutant metastatic mel. Continued exploration of A + C + V is warranted. Clinical trial information: NCT01656642  

This trial was really just to assess dosage and safety.  However - 34 patients with BRAF V600 mutated melanoma were treated with the BRAF/MEK combo for 28 days and then atezo was added q 2 wks while the MEKi was continued once daily for the first 21 days of each 28 d cycle and BRAFi was given in the same way, though twice a day and at a decreased dose than had been given in the initial treatment cycle.  Side effects were as expected for these drugs and all reversible, though 4 patients had to discontinue their use.  Unconfirmed (????  don't know why they were unconfirmed!!!) responses were found in 29 patients. 6 patiens had a complete response and 23 had a partial.  Three of those with partial responses had resolution of their target lesions.  20 of the 29 responders were still responding at data cutoff...though how long that was is not clearly delineated in the abstract.

So...one more bit of hope for ratties.  Granted 1/2 of melanoma patients (those who are not BRAF+) remain unaddressed with this approach.  But - step by step. - c