Treating melanoma by COMBINING targeted therapy AND immunotherapy!!

As usual, I've written on this topic previously:

As long ago as 2015, there was this:  BRAFi better when combined with or after immunotherapy and surgery!!!

And this in 2016:  BRAF/MEK combined with immunotherapy!!!

This from 2017:  The whole she-bang - immunotherapy WITH BRAF/MEK for melanoma...

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

Now there are these reports (highlights = my own):

Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma.  Ribas, Lawrence, Atkinson, Agarwal, ..., Hodi, ..., Hamid.  Nat Med. 2019 Jun;25. Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%) had an objective response, and six (40%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.  Sullivan, Hamid, Gonzalez, et al.  Nat Med. 2019 Jun;25.

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF^V600 mutations. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAF^V600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4⁺ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8%. The estimated median duration of response was 17.4 months with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.

Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.  Hellmann, Kim, Lee, et al.  Ann Oncol. 2019 Mar 27.

Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a PD-L1 inhibitor, atezolizumab, in patients with solid tumors.

This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary endpoints included ORR, PFS and OS.

Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received greater than/= to 1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had mCRC (n = 84), melanoma (n = 22), NSCLC (n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%) and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.

Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.

So - small numbers.  Pretty significant toxicity.  Only effective in the roughly 1/2 of melanoma patients who are BRAF positive.  Looks like BRAF/MEK with anti-PD-1/PD-L1 is demonstrating a 70% objective response rate while anti-PD-L1 with a MEK inhibitor alone attained a 40% response rate (ie = no better than the ipi/nivo combo).  Again, no matter the result...small numbers treated (only 37 melanoma patients total were in the first and last studies reported here - and Hamid et al ain't sharing their #'s unless you buy the paper - FYI).  Still, throwing the "kitchen sink" at melanoma may be a worthwhile treatment for some.

Hang tough ratties!!! - c

Atezolizumab - Renamed Tecentriq - FDA approved for urothelial cancer

When first diagnosed, my oncologist, with tears in his eyes, told me that melanoma and renal cancers were the ones he most hated giving the diagnosis of and trying to treat.  Not the most appropriate thing to say to me at that moment in 2003...but...  He wasn't wrong.  No effective treatments were in the works at that time and both are vicious with a poor prognosis.  BUT....times they be a changing!!!  A dear one of mine with a urothelial cancer has been participating in a Nivo/Opdivo trial.  He and others with that disease have been gleaning responses.  And now....Atezolizumab (Tecentriq) a PD-1/PD-L1 inhibitor, has just been FDA approved for urothelial cancers.

FDA Press release re: Atezolizumab

Hopefully this will give folks dealing with bladder (and related) cancers some relief and cures!!!  It is being tested in melanoma world as well.  Remember this from Weber's update?

Immunology up-date/webinar by Weber 2016

There he said this: 

Vemurafenib Plus Atezolizumab in BRAF-Mutant Melanoma—Trial Design

Patients with untreated BRAFV600-mutant unresectable or metastatic melanoma (N = 17)  
Cohorts: 1- atezo and vemurafenib together   2- vemurafenib X 56 days followed by atezo
3- vemurafenib X 28 days  followed by Atezo.  Atezolizumab (an anti PD-L1 anti-body) was given IV q 3 wk at 20 or 15 mg/kg and Vemurafenib was BID at 960 mg during run in, then decreased to 720mg bid.
Confirmed overall response rate:  Cohort 1 - 33%, Cohort 2 - 75 %, Cohort 3 - 100%.  Overall 76% response rate.  Median of 12.2 months.  AE's were manageable with no grade 4.  Additive activity with excellent level of response.  You will hear much more about this combo in the future.

Hang in there, ratties of all stripes!!!  Working together we help each other....and...times they be a changing!!! - c 

New trials for NRAS and Mucosal Melanoma patients - ASCO 2021

Melanoma sucks great big green hairy stinky wizard balls for everyone!  Still, it remains even more challenging for NRAS positive and mucosal melanoma patients.  Here are prior posts on Mucosal Melanoma. Now, there's this neoadjuvant trial:

A phase 2 clinical trial of neoadjuvant anti-PD-1 ab (toripalimab) plus axitinib in resectable mucosal melanoma.  Cui, Wang, Lian, et al.  ASCO 2021.

Background:  The outcome of patients (pts) with resectable mucosal melanoma (MM) is still poor. Toripalimab combined with axitinib has shown impressive results in metastatic MM with an ORR of 48.3% and a median PFS of 7.5 months in a phase 1b trial. It was hypothesized that this combination therapy might cause pathologic response in neoadjuvant setting for resectable MM, so we conducted this single arm phase 2 trial.

Methods:  Eligible pts were adults (aged 18 to 75) with histologically confirmed resectable (localized or regional lymph node metastasis) MM disease. Exclusion criteria included ocular or unknown primary melanoma, distant metastatic disease or previous use of anti PD-1 ab. Pts received toripalimab 3 mg/kg Q2W plus axitinib 5 mg BID for 8 weeks as neoadjuvant therapy, then surgery and the adjuvant toripalimab 3 mg/kg Q2W starting 2±1week after surgery for totally 52 weeks. The primary end point is pathologic response rate according to the International Neoadjuvant Melanoma Consortium (pCR+pPR, pCR is defined as the complete absence of residual viable tumor and pPR less than/= to 50% of viable tumor cells). The secondary end point is RFS in the ITT population.

Results:  From Aug 2019 to Dec 2020, 21 pts have been eligible and enrolled. Basic characteristics: median age 62 years; M: F 28.6% : 71.4%; primary sites 8 female genital(1urethra, 7vagina), 5 esophagus, 4 ano-rectal, 4 head and neck(3 nasal,1 oral), in which 47.6% localized disease (T3/4 60%), 52.4% regional lymphatic disease; Gene mutation: 4 cKit (1 amplification), 2 Nras,1 Braf (N581), 1mTOR. This therapy was tolerable with grade 3-4 treatment related AEs of 23.8% (liver dysfunction 14.3%, hyperglycemia 9.5% and hypertension 4.8%). 13 pts had received surgeries (local excision 30.8%, wide excision ± CLND72.7%)and 5 pts still in neoadjuvant treatment. One patient was inoperable for bone metastasis, and 2 pts withdrew for covid 19 epidemic. At a median follow up time of 59 weeks, the pathologic response rate was 28.6% (4/14, 2 pCR, 2pPR). Of the post-surgical specimens, 61.5% (8/13) showed significant TIL infiltration, with 38.5% Brisk and 23.1% Nonbrisk according to the definition of AJCC 8th edition. Plenty of plasma cells, histiocyte and pigment with hyaline fibrosis were also found in responders. No recurrence or metastasis was observed in responders until now, with a RFS reaching more than 58weeks. 5 pts with pNR (greater than 50% viable tumor cells) got disease progression, with 1 local recurrence, 1 regional lymphatic metastasis, and 3 distant metastases. The median RFS has not been reached.

Conclusions:  Neoadjuvant toripalimab plus axitinib in resectable MM has shown promising pathologic responses with good tolerance, which supports further investigation of neoadjuvant therapies in MM. Survival is still in follow-up. Clinical trial information: NCT04180995.

And this report on patients with unresectable disease:

Atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma: Interim analysis of an open-label phase II trial.  Si, Fang, Chen, et al.  ASCO 2021.

Background:  Mucosal melanoma is a rare malignant melanoma in Caucasians but ranks the second most common subtype in the Asian population. It is more often diagnosed at an advanced stage and responds poorly to current PD-1/PD-L1 inhibitors. Here we report the interim analysis results of ML41186, an open-label, multicenter, single-arm phase II study, aiming to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients (pts) with advanced mucosal melanoma.

Methods:  Eligible pts aged 18 to 75 years with histologically confirmed unresectable locally advanced or metastatic mucosal melanoma had at least one measurable lesion per RECIST version 1.1 at baseline, with an ECOG PS 0 or 1 and adequate hematologic and organ function. ML41186 is a Simon two-stage design study, if 22 pts completed ORR evaluation and more than 3 pts respond in stage I, the study then continue to Stage II. Atezolizumab and bevacizumab were administered at a fixed dose of 1200 mg and 7.5 mg/kg Q3W respectively (on day 1 of each 21-day cycle) until unacceptable toxicity or loss of clinical benefit. The primary endpoint is the objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), duration of objective response (DoR), disease control rate (DCR), and safety.

Results:  By the cut-off date of 9th September 2020, 35 pts has been enrolled, among whom 22 pts in the stage I analysis set has completed two efficacy evaluation, while 28 pts (full analysis set) has completed at least one efficacy evaluation. In ITT populations (n=35), mean age was 58.9 years with 10 (28%) pts had ECOG PS of 1. LDH level elevated in 9 (25.7%) pts. More than half pts (19, 54.3%) had metastatic mucosal melanoma, of whom 3 (15.8%) pts had more than 3 metastasis sites and 4 (21.1%) pts had liver metastasis. In stage I analysis set (n=22), the best confirmed ORR was 36.4% (17.0%-59.3%). Median progression-free survival was 5.32 months (1.58-not reached), and the best confirmed DCR was 59.1% (36.4%-79.3%). The median confirmed DoR was not reached ( 2.76-NR). In the full analysis set (n=28), the unconfirmed ORR was 42.9% (24.5%-62.8%). In ITT populations (n=35), 28 pts (80%) experienced at least one adverse event (AE) and 5 pts (14.3%) experienced at least one grade 3-4 AEs. Only one patient experienced AE leading to treatment discontinuation. One patient died of autoimmune lung disease.

Conclusions:  The combination of atezolizumab plus bevacizumab showed promising benefit and was tolerable in pts with advanced mucosal melanoma. At the time of this interim analysis, the primary endpoint did not cross the futility boundary, thus the study will run into Stage II. Clinical trial information: NCT04091217.

The NRAS mutation has it's own challenges.  Here are prior NRAS Reports.  Now, there are these:

A phase Ib trial of belvarafenib in combination with cobimetinib in patients with advanced solid tumors: Interim results of dose-escalation and patients with NRAS-mutant melanoma of dose-expansion. Shin, Lee, Kim, et al.  ASCO 2021.

Background:  Belvarafenib, a potent, selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant (NRASm) melanoma patients. The combination of belvarafenib and cobimetinib more potently and durably suppressed MAPK pathway output and tumor growth than currently approved BRAF/MEK inhibitors in RAS- or RAF-mutant tumor xenograft models. This interim results of phase 1b trial evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of belvarafenib in combination with cobimetinib in dose-escalation and NRASm melanoma patients among the 9 indication-specific expansion cohorts.

Methods: Patients with locally advanced or metastatic solid tumors harboring RAS or RAF mutation were enrolled in the dose-escalation stage, and the recommended doses were explored in the indication-specific expansion stage. Patients in the dose-escalation stage were given belvarafenib (100–300mg BID) in combination with cobimetinib (20–40mg QD) and the dose of subsequent cohorts was decided by a traditional 3+3 design and safety profile. Primary objectives were to evaluate the safety and tolerability, to estimate the maximum tolerable dose, and to identify the RP2D of the combination.

Results:  A total of 32 patients enrolled were evaluated for safety analysis; 19 were enrolled in 4 cohorts in the dose-escalation stage and 13 NRASm melanoma patients were enrolled in the indication-specific expansion stage (cut-off date: 2020-7-24). There were 3 DLTs (G3 colitis, G3 diarrhoea, G3 nausea) in 2 patients at the starting dose of belvarafenib 200mg BID continuously and cobimetinib 40mg QD 21/7 schedule. Belvarafenib dose was escalated to 300mg BID with cobimetinib 20mg QD, which did not result in DLTs. The most common treatment-emergent adverse events that occurred in ≥30% of 32 patients were dermatitis acneiform, diarrhoea, constipation, and increase in blood creatine phosphokinase. Two combination doses were explored in the indication-specific expansion stage. Out of the 9 indication-specific expansion cohorts, NRASm melanoma patients exhibited promising efficacy signal; 5 patients reached partial responses (PRs) out of 13, giving a response rate of 38.5%. Among them, 11 had been previously treated with checkpoint inhibitors (CPIs), including 5 (45.5%) who achieved PR. The median PFS was 7.3 months and 5 patients remained on the treatment at the cut-off date.

Conclusions: Belvarafenib in combination with cobimetinib showed acceptable tolerability and encouraging efficacy in NRASm melanoma, and in those with prior CPI treatment. Further research is ongoing in other cohorts (Clinicaltrial.gov, NCT03284502) and in NRASm melanoma (reference GO42273 by clinicaltrials.gov ID number). Clinical trial information: NCT03284502.

Fingers crossed that there will soon be viable treatments for all melanoma ratties.  For what it's worth - c

The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -

This interview/report is pretty cool and clear.  I'll just let the Wizard break it down - 

Novel Immunotherapy Combinations May Be the Future of Melanoma Treatment

By Caroline Helwick December 10, 2016  The ASCO Post

Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies. — Jeffrey Weber, MD, PhD

The future treatment of melanoma may rely on combinations of immunotherapy agents beyond the current checkpoint inhibitors, and they are entering clinical trials, according to Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, who has spearheaded clinical trials in melanoma. At the 2016 European Society for Medical Oncology (ESMO) Congress, Dr. Weber gave attendees a taste of what’s to come in this tumor type.

“It’s become obvious that multiple checkpoints exist that are both antagonistic and agonistic molecules controlling adaptive immunity and innate immunity,” Dr. Weber said. He counted more than 50 members of the immunoglobulin or tumor necrosis factor (TNF) receptor superfamilies that could act as controlling or regulatory molecules.

In other words, the pipeline is rife with drugs that will target far more than cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). T cells also express TIM-3, LAG-3, GITR, and other factors, which, if agonized or antagonized, could boost an immune response and yield potential clinical benefit. They include many receptor agonists, “which press on the gas pedal,” he added, and receptor antagonists, such as CTLA-4 and PD-1, which “release the brakes.” In addition to antibodies in development, up to 15 new indications could be approved for the current CTLA-4 and PD-1/programmed cell death ligand 1 (PD-L1) inhibitors, Dr. Weber predicted.

A High Bar to Surpass
The best results so far in advanced melanoma have been achieved by the combination of the anti–PD-1 agent nivolumab (Opdivo) and the anti–CTLA-4 agent ipilimumab (Yervoy). Nivolumab/ipilimumab yielded a 2-year survival rate of 63.8%, vs 53.6% for ipilimumab alone, in the CheckMate-069 trial.²

“In developing new checkpoint inhibitors, that’s the number we will have to be beat. If you want to add an inhibitory or agonistic molecule, you must at least match this, with less toxicity, and that’s a daunting challenge,” admitted Dr. Weber. “The fact that anti–PD-1 was developed early on sets a very high bar, which ironically could be a significant barrier to the successful development of other checkpoint inhibitors.”

Dr. Weber expects all new checkpoint agents to be tested in combination. Although 64% survival at 2 years is “fantastic,” he said, “at the end of the day, at least half the patients will need other therapy.” In all the tumor types for which these agents are important, “there is space for improvement,” he added.

Rationale for Novel Combinations
Immunotherapy combinations, with anti–PD-1/PD-L1 agents as backbones, will be driven by four key aims:

1. To bring T cells into tumors and overcome suppression of the immune system: For this, anti–PD-1/PD-L1 agents can be combined with anti–CTLA-4, immune-activating antibodies of cytokines, Toll-like receptor agonists, oncolytic viruses, indoleamine 2,3-dioxygenase (IDO) inhibitors, macrophage inhibitors, and targeted therapies.
2. To generate de novo T cells: This might be accomplished by vaccines, T-cell receptor–engineered adoptive-cell transfer, and chimeric antigen receptor–engineered adoptive-cell transfer.
3. To increase immune recognition: Stimulators of interferon genes (STING) agonists and interferons may help here.
4. To facilitate T-cell infiltration: This will be especially important for “cold” tumors that are deficient in T cells; the aim is to turn these “cold” tumors into “hot” ones. T-cell suppression, which occurs via multiple active and passive processes, must also be overcome.
These aims will be the mission of novel agonists, including anti-ICOS, anti-GITR, anti-OX40, anti-41BB, and anti-CD27, and novel antagonists, including anti–LAG-3, anti–TIM-3, anti-VISTA, anti-A2AR, anti-TIGIT, and IDO inhibitors.
“With T-regulatory cells, M2 macrophages, myeloid-derived suppressor cells—each a different lineage that requires a different maneuver to overcome—it’s amazing that any of this works at all,” he commented.

Sampler of Novel Combinations
Novel immunotherapies are not expected to be particularly potent as single agents, but in combination with other checkpoint inhibitors or targeted drugs, they are showing promise. More than a dozen combinations (including some triplets) are in phase II and phase III trials, including the following agents:

• Ipilimumab plus IDO inhibitors, talimogene laherparepvec (also known as T-VEC), interferon, and nivolu­mab/histone deacetylase (HDAC) inhibitor
• Nivolumab plus anti-CD137, TRAIL-R2 antibody, and LAG-3 antibody
• Pembrolizumab (Keytruda) plus IDO inhibitor, talimogene laherparepvec, BRAF/MEK inhibitors, interferon, and JACK/STAT inhibitor
• Atezolizumab (Tecentriq; anti–PD-L1) plus BRAF/MEK inhibitors
• Durvalumab (anti–PD-L1) plus BRAF/MEK inhibitors.
  

“Looking at all the mouse data from almost every antibody, results are better with combinations than with single drugs alone,” he said. “Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies.”

Promising Early Data
Early data suggest that, for mutated patients, checkpoint inhibition plus BRAF and MEK inhibition is a powerful approach. In a study of the anti–PD-L1 antibody atezolizumab plus vemurafenib (Zelboraf) and cobimetinib (Cotellic), all patients in a 16-patient study had a reduction in target lesions; 3 patients had complete responses.³ The anti–PD-L1 antibody durvalumab plus a BRAF and MEK inhibitor produced a 69% response rate in another study, and all responses were ongoing at the time of analysis.⁴ In KEYNOTE 022, pembrolizumab in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) produced tumor regression in almost all patients.⁵

Novel Combinations in Melanoma

• The future treatment of advanced melanoma may involve combinations of agents, with anti–PD-1/PD-L1 and anti–CTLA-4 as backbones.
• The pipeline is replete with agonistic and antagonistic molecules that target new checkpoints.
  

Pembrolizumab plus the IDO inhibitor epacadostat produced responses in 56% of 61 patients (63% of treatment-naive patients), and a disease control rate of 78% (and 75% of treatment-naive patients).⁶ Hepatotoxicity can be an issue with epacadostat, but it was not concerning in this study, he said.

One of the “more innovative” compounds targets OX40, an agonistic molecule that is expressed on activating T cells. An antibody against OX40 has shown significant and long-lasting antitumor activity in a mouse model of ovarian cancer when paired with an anti–PD-1 antibody.⁷ “This combination looks very impressive,” Dr. Weber commented. “You see very long survival [mean of 80 days, vs < 40 days for either agent alone], and, in fact, many of these mice were resistant to re-challenge. It’s clear that an adaptive immune response is promoted by the combination.”

An OX40 antibody (MOXR0916) was also combined with the PD-L1 inhibitor atezolizumab in a phase Ib study in solid tumors, but only 2 responses were observed among 51 patients, which he considered “disappointing.” However, this regimen will be further tested in melanoma and in other histologies with demonstrated responses to atezolizumab.

Checkpoint Inhibition Plus Talimogene Laherparepvec
The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.⁸ “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.⁹ This regimen is now in phase III trials.

Wishing strength and peace to all my fellow melanoma ratties and fighters.  We've come a long way, baby!!!  And though there are miles to go...We Will GET THERE!!!! - love, c  

ASCO 2016 - Anti-PD1/PDL1 combined with BRAFi in BRAF+ patients

Combining BRAF inhibitors with other treatments can sometimes lead to very unfortunate side effects, but remember what Weber noted (The words in red in the next section are his.): Atezolizumab (Tecentriq) combined with Vemurafenib

Vemurafenib Plus Atezolizumab in BRAF-Mutant Melanoma—Trial Design

Patients with untreated BRAFV600-mutant unresectable or metastatic melanoma (N = 17)  
Cohorts: 1- atezo and vemurafenib together   2- vemurafenib X 56 days followed by atezo
3- vemurafenib X 28 days  followed by Atezo.  Atezolizumab (an anti PD-L1 anti-body) was given IV q 3 wk at 20 or 15 mg/kg and Vemurafenib was BID at 960 mg during run in, then decreased to 720mg bid.
Confirmed overall response rate:  Cohort 1 - 33%, Cohort 2 - 75 %, Cohort 3 - 100%.  Overall 76% response rate.  Median of 12.2 months.  AE's were manageable with no grade 4.  Additive activity with excellent level of response.  You will hear much more about this combo in the future.

Now there is this from ASCO:

Responses in patients with BRAF V600-mutant metastatic melanoma receiving anti-PD1/PDL1 therapy alone or combined with BRAF inhibitors.  ASCO 2016. # 9546.  J Clin Oncol 34, 2016.  Barcena, Trinh, McIntyre, et al.

Background: Whether anti-PD1/PDL1 (anti-PD) therapy alone, or anti-PD combined with BRAF inhibitors (BRAFi) represents the best treatment for patients (pts) with BRAF V600-mutant metastatic melanoma (BMMM) remains unclear. Combination therapy has been attempted in practice to improve disease control in BMMM pts. We report our single-institution experience using anti-PD therapy both alone and in combination with BRAFi in BMMM. Methods: At MD Anderson Cancer Center, 457 metastatic melanoma pts (excluding uveal melanomas) received anti-PD therapy between November 2009 and December 2015. Among the 113 pts (25%) with BMMM, 34 (30%) pts were BRAFi-naïve and 79 (70%) were previously treated with BRAFi. These pts were separated into 4 cohorts based on exposure to BRAFi prior to anti-PD therapy (BRAFi naïve vs. treated) and whether anti-PD therapy was administered alone or in combination with BRAFi. Data were collected and analyzed for rates and duration of responses (RECIST v1.1) or disease stabilization. Results: See table. Conclusions: Our retrospective study showed anti-PD therapy alone had robust antitumor activity in pts with BMMM, regardless of prior BRAFi exposure.BRAFi-naïve pts appeared to achieve higher response rates with the combination of BRAFi and anti-PD therapy than with anti-PD therapy alone; however, the number of pts was small. BRAFi-treated pts derived less benefit from combined BRAFi and anti-PD therapy than from anti-PD alone.

	N (pts)	CRs+PRs N (%)	Median Response Duration mos (range)	SDs N (%)	Median Disease Control Duration mos (range)
BRAFi-naïve/anti-PD alone	14	5 (36)	25 (3+-34+)	7 (50)	5 (2+-7+)
BRAFi-naïve/anti-PD+BRAFi	20	10 (50)	9 (3-29+)	8 (40)	5 (2-10+)
BRAFi-treated/anti-PD alone	38	12 (32)	15 (7+-34+)	18 (47)	8 (3-18+)
BRAFi-treated/anti-PD+BRAFi	41	5 (12)	8 (7+-15+)	26 (63)	7 (2-16+)

All my best - c

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

Immunology update/webinar for melanoma by Dr. Weber with a look forward...

Check out the link below for a webinar with slides presented by Jeffrey S. Weber, MD, PhD now of the Laura and Isaac Perlmutter Cancer Center at NYU.  Just click the 'view activity' button at the bottom.  I have included some info off the slides as well as my report of Dr. Weber's applicable comments in red below.  (Sorry for the strange lay out...best I could do without retyping everything!)

Immuno-Oncology 2016 update by Dr. Weber

What’s New in Melanoma 2016?

 Combination immunotherapies and targeted therapies

 Overcoming BRAF resistance

 New immune agonistic molecules

 Novel cytokines and fusion molecules

 Chemokine antibodies

 Bispecific T-cell engaging molecules

 Adoptive cell therapy

 Targeted therapy and immunotherapy

 Masked antibodies

Vemurafenib Plus Atezolizumab in BRAF-Mutant Melanoma—Trial Design

Patients with untreated BRAFV600-mutant unresectable or metastatic melanoma (N = 17)  
Cohorts: 1- atezo and vemurafenib together   2- vemurafenib X 56 days followed by atezo
3- vemurafenib X 28 days  followed by Atezo.  Atezolizumab (an anti PD-L1 anti-body) was given IV q 3 wk at 20 or 15 mg/kg and Vemurafenib was BID at 960 mg during run in, then decreased to 720mg bid.
Confirmed overall response rate:  Cohort 1 - 33%, Cohort 2 - 75 %, Cohort 3 - 100%.  Overall 76% response rate.  Median of 12.2 months.  AE's were manageable with no grade 4.  Additive activity with excellent level of response.  You will hear much more about this combo in the future.

 MASTERKEY-265: A Phase Ib/III Study of T-VEC + Pembrolizumab (NCT02263508)

        Phase Ib:Enrollment from December 2014 to March 2015  (n = 21 ) N = 21 patients, Unresectable stage III or IV melanoma, treatment naive, injectable lesions, no clinically active brain mets, no active herpetic skin lesions or prior complications from herpetic infection.  TVEC intralesional 4ml/treatment was given with pembro 200 mg IV q2wk.  Mild side effects.

Complete response - 12.5%, Partial response - 43.8%. ORR - 56.3%.  Additive effects, may even be better.  Phase 3 study is ongoing.   
           

Epacadostat (an IDO inhibitor) + Pembrolizumab:Preliminary Results

                61 patients were enrolled by September 2, 2015  Safety data on 46 patients (19 melanoma, 7 RCC, 7 NSCLC, 5 transitional cell carcinoma, 4 endometrial adenocarcinoma). Most common all-grade treatment-related AEs were rash (22%), fatigue (17%), nausea (11%), and pruritus (11%).    Grade 3/4 treatment-related AEs occurred in 13% of patients (rash, 7%).   One patient discontinued for a treatment-related AE.  IDO inhibitor did not seem to increase side effects.  Melanoma patients only (n - 18) - 56% ORR.  Melanoma treatment naive patients (n - 16) - 63% ORR.  Weber found these results very promising and comparable to the ipi/nivo combo in regard to response rates but with much milder side effects!!!

 

KEYNOTE-029: Pembrolizumab + Low-Dose Ipilimumab for Advanced Melanoma
 Pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg.  72% received all 4 ipilimumab doses.  36% incidence of grade 3-4 treatment-related AEs.  54% incidence of immune-mediated AEs (17% grade 3/4).   Pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg provided an ORR of 56%, comparable to that previously reported for nivo 1 mg/kg + ipilimumab 3 mg/kg.   Efficacy, safety, and biomarkers to be further analyzed in the full expansion cohort of 153 patients.  So far, the side effects appear to be decreased by decreasing the ipi dose...while response rates remain good.

                 

                        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)

Intralesional Immunotherapy With Oncolytic Coxsackievirus A21 (CVA21) 
 Final response and safety data of the open-label, multicenter phaseII CALM (CAVATAK in Late-stageMelanoma) study of intratumoral CVA21 in 57 patients with unresectable stage IIIC/IV melanoma.    The study met its primary endpoint.  22 of 57 (38.6%) evaluable patients with PFS at 6 months.    Median PFS of 4.2 mos.   ORR 28.1%; median TTR 2.8 mos.  1-year survival rate 75.4%.  Median OS and median DOR not reached (16.5 mos follow-up).  Most common AEs were grade 1 fatigue, chills, fever, and injection site reactions; no grade 3/4 AEs observed.  Looks like another promising intralesional therapy.  Will soon have phase 3 study.

Radiotherapy in Combination With Anti-PD-1 Antibodies: Safety and Efficacy

    Retroactively evaluated all patients at Melanoma Institute Australia and Westmead Hospital who had received either pembrolizumab or nivolumab for unresectable stage III/IV melanoma who had sequential or concurrent radiotherapy.     In 32 evaluable patients, 9 (28%) PR and 5 (16%) stable disease.     In 25 patients who had progressed on PD-1 at the start of RT, 7 (28%) subsequent PRs and 3 (12%) CRs, while 5 (20%) continued progressing.    Survival Brain metastases: PFS 2.5 mos, OS 6.8 mos.  Which I think is excellent.   No brain metastases: PFS 4.1 mos, OS 16.4 mos.   

No excess RT toxicity observed except cerebral radionecrosis in 1 patient 3 months after SRS; potential delayed neurotoxicity in 1 patient with multiple small asymptomatic BMs; disproportionate cerebral edema in 1 patient with rapidly progressive BMs.  So, yes, you can deliver radiation to the brain, or elsewhere, safely...there is no excess toxicity if radiation is given with either nivo or pembro.

Clinical Activity To Date: BRAF + MEK + PD-L1 ab MEDI 4736

 Response-evaluable population includes all patients dosed ≥16 weeks prior to the cut-off date with measurable disease at baseline and ≥1 f/u scan (or discontinuation due to death or PD prior to 1st scan).  Dabrafenib (BRAFi) and Trametinib (MEKi) and MEDI 4736 (PD-L1 antibody) were given in various regimens.   Median duration of response has not yet been reached for Cohorts A and B.             *Shorter follow up in Cohort C, with 5 additional patients ongoing with best response of unconfirmed PR.

Clinical activity	Cohort A(n = 26)		Cohort B(n = 19)		Cohort C*(n = 15)
	D + T + M	T + M		T /M (sequential)
ORR, n (%)	18 (69)		4 (21)		2a(13)
DCR (CR + PR + SD), n (%)	26 (100)		15 (79)		12 (80)
SD ≥12 weeks, n (%)b	4 (15)		10 (53)		6 (40)
Ongoing responders, n/N (%)	16/18 (89%)		4/4 (100%)		1/2 (50%)
Range of duration of ongoing response, wks	7.7+ –50.6+		7.9+ –24.7+		7.0+

Very interesting study.  I like this a lot.  Large influx of T-cells with the trio, converting a cold tumor to a hot tumor, leading to an augmentation of T-cell function.  The trio with its 69% response rate, at least gave additive efficacy, if not synergistic, without increased side effects.

Innovative Ideas: Targeted Therapies 

                           Immunotherapy with targeted therapies:

 BRAF + MEK + pembro,  atezo, IPI + HDAC inhibitor, Ipi + nivo + HDAC inhibitor

              Overcoming BRAF resistance by combining with:
Hsp90 inhibitors,   HDAC inhibitors,   PI3 kinase/AKT inhibitors,   ERK inhibitors,   ERBb3 inhibitors
  

Innovative Ideas: Immunotherapy

 “Masked antibodies” have a peptide linker that “masks” the antigen-binding region of antibodies unless it is cleaved by proteases within the tumor (This is the same as the ADC's - antibody drug conjugates.  Post here:  Another antibody drug conjugate)

 IL-12 has been linked to a tumor-targeting antibody

 IL-15/IL-15 receptor alpha fusion proteins to augment binding to effector T cells but not T regulatory cells

 TGF-beta receptor antibody has been linked to a PD-L1 antibody

 Neoantigen-specific T cells can be expanded from tumor-infiltrating lymphocytes and adoptively transferred

 Bispecific T-cell engagers link CD3 and tumor-associated antigens

Prime Points:  Melanoma Immunotherapy

IDO plus pembro trial will have mature data at ASCO
Survival f/u from sequential BMS-064 trial of nivo then ipi vs nivo then ipi

Nivo + CD137 antibody phase I-II trial
LAG-3 antibody + nivo phase I-II trial
OX- 40 antibody phase I trial
IL-15/IL-15 receptor complex phase I trial
Coxsackievirus + pembro phase I-II trial
Ipi + high dose IL=2


Synopsis of final thoughts by Dr. Weber:

"I think we will all agree that it is a very bright era for immunotherapy in melanoma and immunotherapy for cancer in general.  Ipi is a very impressive drug that is more like a shotgun, while anti-PD1 is like a sniper rifle.  Ipi has the capacity to expand a lot of different antigen specific cells whether they are tumor specific or not, and therefore, combining anything with ipi will expand the side effects.  If you look at survival, the plateau on the curve, for melanoma over the last decade it's about 10%.  Long term results from the early ipi trials, 2010 - 2011, we got up to 20% and that was progress.  If you look at the plateau with the PD-1 trials, we're probably at about 30%, which could be construed as a cure...something we now tell our patients for the first time...but I am absolutely not satisfied with a 30% rate of plateau .  So, we may be looking at triple drug therapy or quadruple drug therapy...and tailoring the therapy to the individual patient.  In patients with slow growing, low burden disease with a normal LDH, it's ok to start with immunotherapy before targeted therapy, since the targeted therapy appears to work just as well whether it is given before or after the immunotherapy.  I think most of us agree that in a BRAF mutated patient with high disease burden, that's symptomatic, rapidly progressing with a high LDH, we would all go with BRAF plus MEK.   If BRAF mutated with low disease burden...that's a tough one.   Interestingly, you might argue that you could go either way because BRAF plus MEK drugs work best with a low LDH, with a low tumor burden, while ipi plus nivo works very well with a high LDH or not...so you might counter argue that you might go with the BRAF/MEK for a finite period of time and then come in with the immunotherapy."

More to come it seems!!!  Thanks, ratties. - c