Menzies and Long, Ther Adv Med Oncol. 2013;5(5):278-285.
Despite being a little over a year old, and most of the studies referenced - I've already posted, this article still presents a very good overview of the combination therapies with some clear explanations. Here are the highlights:
Combination BRAF and MEK Inhibitors
Several trials have combined BRAFi and MEKi for patients with V600 BRAF-mutant melanoma.
1. Dabrafenib with trametinib (CombiDT)
2. Vemurafenib with cobimetinib
3. LGX818 with MEK 162
The reason for the combinations is twofold: to prolong the progression-free survival by delaying or preventing the development of MAPK-dependent resistance and to reduce BRAFi related toxicities as a result of the paradoxical activation of the MAPK pathway in non-melanoma BRAF wild-type cells.
In normal cells, growth factors bind to the cell surface receptor tyrosinekinases (RTKs). There they trigger signals down various pathways: RAS-RAF-MEK-ERK(MAPK) and P13K-AKT-mammalian target of rapamycin (mTOR). This [normal] signaling creates regulated cell proliferation, growth and survival. Melanoma causes abnormal activation of the MAPK pathway, and include activation of mutations in BRAF (40-50%), NRAS (20%), and KIT (less than 5%).
1. Dabrafenib with trametinib (CombiDT)
Initial data showed that response rates were higher with CombiDT than with dabrafenib alone, BUT, only 19% of patients who had failed prior BRAFi therapy got a response. The randomized section of the trial showed a higher response rate (76% vs 54%), longer median progression free survival (9.4 vs 5.8 months), and fewer toxicities in MAPK inhibitor naive patients compared with dabrafenib monotherapy. All BRAFi toxicities: hyperkeratosis, alopecia, arthralgia and rash were less frequent. Cutaneous squamous cell carcinoma with CombiDT was 1/3 of that with dabrafenib alone (7% vs 19%). Fever was the most common AE and occurred in 70% of patients on CombiDT, but was found in only 26% of dabrafenib only patients. Mechanism is not understood. Fevers occur early, are often repetitive, can be managed with brief dose interruption, or if recurrent...with corticosteroid prophylaxis.
2. Vemurafenib with cobimetinib
In the phase 1 trial, 70 patients with Cobas-positive metastatic melanoma, of which 38 (54%) had failed to respond to prior vemurafenib. {The Cobas 4800 BRAF V600 mutation test by Roche, is a polymerase chain reaction based test that is very sensitive and specific for V600E BRAF mutation, but only detects 40-70% of V600K and no other V600 mutations.} All 25 BRAFi naive patients had a reduction in tumor size. In 32 patients previously treated with BRAFi, the response was only 19%. Squamous cell carcinoma, rashes, arthralgia, and fatigue were decreased with the combo compared to vemurafenib alone. MEK inhibitor AE's: creatine kinase elevation, diarrhea and chorioretinopathy were reported in 4-6% of patients.
3. LGX818 with MEK 162
The phase 1 trial of the BRAFi, LGX818 and the phase 1/11 trial of the combo, LGX818 and the MEKi, MEK162 allowed any V600 BRAF mutation, including rare variants like V600R. The phase 1 trial of the BRAFi LGX818 monotherapy enrolled 26 BRAFi naive and 28 BRAFi pretreated patients. Results showed a confirmed response rate of 58% in BRAFi naive and 11% in BRAFi pretreated patients. Unlike vemurafenib and dabrafenib - photosensitivity, liver enzyme elevations, and fever were rare. In the combo trial - 9 BRAFi naive and 14 BRAFi pretreated patients were studied. There was a confirmed response rate of 88% in naive patients and an 18% response in pretreated patients. No fever, photo-sensitivity, nor squamous cell carcinoma reported thus far.
Anti-PD1 and Anti-PD-L1 Antibodies [immunotherapy] (Note: what follows is pretty old news but a good summation of data, especially from the early trials.)
Unlike CTLA-4 antibodies, the PD-1 and PD-L1 antibodies aim to potentiate the antitumor T-cell response at a tumor-specific level, by impairing the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumor cells. T cells interact with tumor cells in peripheral tissues. Tumor cells can present antigen to the T-cell receptor, resulting in a stimulatory signal to the T cell. Tumor cells may also express PD-L1, which interacts with PD-1 on activated T cells, and results in inhibition of the antitumor T-cell response. (See below)
Nivolumab (BMS-936558, MDX-1106, ONO-4538, Opdivo) Anti-PD1
A fully human immunoglobulin monoclonal PD-1 antibody and was first of its class to be tested in a phase 1 trial with 107 patients with metastatic melanoma with no exclusions. Approximately 25% of patients had received 3 or more lines of systemic therapy, responses were seen throught the range of doses given every 2 weeks, with an overall response rate of 31% (41% in the 3mg/kg group). Median duration of response was over 2 years. Well tolerated generally. Toxicities were immune related and were less frequent and less severe than with ipi. Common toxicities were: fatigue, rash, diarrhea, and itching. Grade 3/4 AE's occurred in 21% of patients = lymphopenia, fatigue, diarrhea, nausea and anemia. Pneumonitis was a rare but significant side effect, resulting in the death of three patients. There was no association between drug dose and efficacy or toxicity.
Lambrolizumab (MK-3475, Pembrolizumab) Anti-PD1
A humanized monoclonal PD-1 antibody, studied in phase 1 trial that included 132 patients with metastatic melanoma. 67% of patients had BRAF wild type, 9% had brain mets. Overall response rate was 51% in the 85 patients dosed at 10mg/kg. Ipi naive patients had a response rate of 55%. Patients who had progressed on ipi had a 41% response rate. 15.9% of entire cohort had immune related AE, only 5.3% of those were grade 3/4. All grade 3/4 toxicities were at the 10mg/kg dose and included: nephritis, pleuritic pain, pancytopenia, pneumonia, v/d, thyroiditis. Pneumonitis occurred in 3% of patients, all grade 1/2 and was managed with dose interruption, and in once case, steroids.
BMS-936559 - PD-L1
A fully human PD-L1 antibody, was tested in 55 patients with metastatic melanoma. 56% of the patients had received prior immunotherapy and 9% had had BRAFi. Overall response rate was 17%. Highest response rate was in the 3 mg/kg dosage. Of the 9 who responded, 5 had an ongoing response for over a year, and overall, 27% of patients had stable disease for over 6 months. Toxicity was mild. 9% of patients had grade 3 AE's, 39% had immune adverse event of any grade - rash, hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, DM, and myasthenia gravis.
Future Implications
- MAPK inhibitors in combination result in response in almost every patient and are more durable than single agent responses, but acquired resistance is still an obstacle, and most patients relapse within a year. However, there is a subgroup of patients that may benefit for a prolonged period.
- PD-1 and PD-L1 immunotherapies provide faster and more frequent responses than ipi, but durability remains unknown {though we are gaining more info daily!!}.
- Combining MAPK inhibitors and immunotherapy seems to have a real possibility of greater success. However, the first combo trial tried (vemurafenib and ipi) had to be terminated due to liver toxicity, a known side effect of both drugs. Trials with dabrafenib and ipi with/without trametinib are underway.
- IPI and nivo combined, and ipi combined with radiation, are producing good results.
- Though not compared head-to-head, anti-PD1 and anti-PDL1 are probably more active and have fewer toxicities than ipi. Also, the possibility that tumor PD-L1 expression may be a biomarker to predict response is appealing. In one nivo trial, no responses were seen in 17 patients with tumors that did not express PD-L1, while 9 of 25 patients with PD-L1 expression had a response. Pretreatment biopsies have been collected for all patients on the lambrolizumab trial and results are awaited.
- The greatest role for systemic treatments may be in the adjuvant setting. The risk of distant relapse and death in patients with high-risk early stage melanoma (11C/111) is approximately 50%. The only approved adjuvant, interferon, is toxic and has little impact on survival. Several drugs ipi, MAGE-A3, vermurafenib, and CombiDT are in ongoing trials as adjuvants vs placebo....so.....
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