New Crop of Combination Strategies Growing for Melanoma

Jeffrey A. Sosman, MD

The first combination therapy for advanced melanoma received approval from the Food and Drug Administration (FDA) January 2014. The oral, targeted combination of a MEK inhibitor, trametinib (Mekinist) and a BRAF inhibitor, dabrafenib (Tafinlar) was approved for patients with metastatic melanoma whose tumors harbor aBRAF^-V600Eor^-V600Kmutation. Both drugs were approved for the same indication as single agents in 2013.

Combinations of next-generation targeted agents for advanced melanoma are also currently in phase III trials. A phase III, randomized 3-arm open-label study of MEK162 plus LGX818 and LGX818 monotherapy compared with vemurafenib in patients with unresectable or metastaticBRAF^V600-mutant melanoma is currently enrolling patients.¹

As a way to attempt to overcome resistance that tumors develop to targeted agents and to boost the responses to immunotherapy agents, researchers are not only testing novel combinations of targeted agents, but also testing these targeted treatments in combination with immunotherapies. “Combinations of therapies are really where the field is currently putting much of the effort,” said Jeffrey A. Sosman, MD, professor of medicine at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Jedd D. Wolchok, MD, PhD, Explains Immune Checkpoint Blockade

Wolchok is the chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center.

The first combination of a targeted agent with an immunotherapy tested in the clinic was the phase I trial of concurrent treatment with vemurafenib plus ipilimumab in patients withBRAF-mutated melanoma at the approved, full doses of each agent. Unfortunately, this combination resulted in grade 2 and 3 liver toxicity in the form of elevations of aminotransferase (ALT) in 7 of the 10 patients enrolled on the trial.²Two of the patients also had grade 2 or 3 elevations in bilirubin along with ALT elevations. Although these cases of hepatotoxicity were not symptomatic and resolved after drug discontinuation, the study researchers closed the trial.²Both agents on their own were known to cause liver enzyme elevations. What is not clear from these results is whether these toxicities are specific to the combination of vemurafenib and ipilimumab or whether this could be a class effect of BRAF inhibitors or checkpoint blockade inhibitors.

Still, preclinical studies suggest that adding a BRAF inhibitor to an immunotherapy regimen could increase antigen presentation and potentially boost the efficacy of the patient’s immune cells.^3,4According to Patrick Hwu, MD, immunologist and chair of the department of melanoma medical oncology at the MD Anderson Cancer Center, research from his laboratory also suggests that BRAF inhibitors inhibit VEGF which generally keeps T cells from infiltrating tumors. Inhibiting the BRAF pathway may allow more T cells to infiltrate the tumor.

Other trials combining a targeted with an immunotherapy agent are ongoing. Triple combinations are also beginning to be explored: two clinical trials combining dabrafenib, trametinib, and ipilimumab in patients withBRAF-mutated melanoma as well as the double combination of trametinib plus ipilimumab for BRAF wild-type patients are currently being tested.^5,6

The newer immunotherapy antibodies, anti-PD1 and anti-PD-L1, which are in late-stage clinical trials, are also beginning to be tested in combination with targeted, oral agents. One example is the combination of the anti-PD-L1 antibody, MEDI4736, with dabrafenib and trametinib.⁷“Combining anti-PD1 and anti-PD-L1 agents with targeted therapies may be a way around the toxicity seen in the initial [ipilimumab plus vemurafenib] trial,” said Margaret K. Callahan, MD, PhD medical oncologist and immunotherapy specialist at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City. Other approaches being designed and entering the clinic are sequential rather than concomitant combinations, such as the phase II trial testing the efficacy and safety of vemurafenib, given for an initial 6 weeks, followed by ipilimumab for 4 doses every 3 weeks.⁸

Researchers, including Callahan and Hwu are looking toin vivoandin vitromodels to test the efficacy of potential of combination therapies. “There are so many possibilities of combinations, which is a wonderful issue and challenge,” said Hwu. “But we can’t afford to run too many trials in the era of diminishing research resources. We have to be smarter and isolate those combinations that are most likely to work.”

According to Callahan, so far the data are useful, but do not provide a substantial blueprint for designing rational clinical trials. “We are in situation where the field has been moving so fast that the pre-clinical data is scrambling to catch up,” said Callahan who believes that the next few years will see an uptick in valuable preclinical and clinical data that will allow clinicians to make better therapy decisions.

One challenge in planning combination therapy trials is that thus far, mouse models have not been useful in predicting potential toxicities in humans. For example, neither colitis nor uveitis was documented in mice given anti-CTLA4 antibodies such as ipilimumab.

Combinations of immunotherapy antibodies with other oral, kinase inhibitors are also in the works. Unlike the boost in immune cell activity following exposure to a BRAF inhibitor, MEK inhibitors have been shown to interrupt T-cell activation, at leastin vitro.³But according to Callahan, analyses of patients’ tumor samples do not suggest this inhibitory effect. “We still have a lot to understand on how targeted agents effect immune responses. There are some data points but no substantial coherent story—yet” said Callahan.

Another approach is the combination of antibodies against immune checkpoint pathways. Combining ipilimumab with nivolumab, an anti-PD1 antibody, resulted in a 40% objective response in a phase I clinical trial of 53 patients.⁹At the maximum tolerated dose, 53% of patients had an objective response with tumor reductions of 80% or greater. High-grade adverse events were relatively high, occurring in 53% of patients, but similar to the types of toxicities experienced by patients receiving ipilimumab alone. The most common types of adverse events were increases in liver enzymes. Nivolumab is not yet approved by the FDA. It is currently being tested as a monotherapy in phase III clinical trials for melanoma and other tumor types. “This phase I combination study generated an exciting signal that is now being followed up in a phase III clinical trial,” said Callahan. A phase III trial is now ongoing, comparing ipilimumab or nivolumab with the combination of the two antibodies. This 3-arm study is especially well-designed, set up to answer the big question of whether the benefit of the combination is substantial or incremental and outweighs the toxicity, according to Callahan. “This trial has the potential to redefine what is first-line therapy for melanoma,” Callahan said.

Even newer antibodies against other immune checkpoint proteins are already in pre-clinical and early stage clinical trials. These include receptor targets such as LAG3 and TIM-3. “Our immune system can be very dangerous to us which is why there are many molecules that can inhibit the immune system and alleviating those brakes will be beneficial in cancer,” said Hwu.

Thus far, laboratory studies show that these immune inhibitory pathways are unique and nonredundant with the CTLA-4 and PD-1 pathways, suggesting that combining agents against two different pathways could be synergistic in stimulating the immune system against tumors. A phase I trial testing an anti-LAG3 antibody either as a monotherapy or in combination with nivolumab in patients with solid tumors is already underway.¹⁰For these newer antibodies, there is preclinical mouse model data of antitumor effects, but how well this will translate into human trials and which tumors are most likely to respond are outstanding questions. Before embarking on novel combinations with these newer antibodies, however, results of phase I monotherapy trials with these agents to demonstrate they safe in the clinic are first needed.

Another immunotherapy combination early stage trial that is currently being planned is the combination of the anti-PD1 antibody, MK-3475, with an oncolytic vaccine, talimogene laherparepvec (T-Vec). MK-3475 is currently under review by the FDA for approval as a monotherapy in patients with metastatic melanoma. T-Vec is a re-engineered herpes simplex virus, injected locally into tumors, that then divides inside the tumor cells, causing them to lyse and releasing GM-CSF, an immune cell growth factor. It’s not clear whether T-Vec can exert a distal effect on internal, metastasized tumors, but Sosman noted that injection of the vaccine into skin lesions can shrink both those tumors that are injected and adjacent lesions. “This combination is promising, particularly because both MK-3475 and T-Vec have generally mild side effects,” said Sosman.

Hwu agrees. T-Vec allows the release of many immunogenic antigens from the lysed tumor cells that can activate the immune system against the cancer. “Adding T-Vec to an anti PD-1, anti-PD-L1 or anti-CTLA4 antibody makes a lot of sense in theory,” said Hwu.

“I am hopeful that these combinations, both immunotherapy with another immunotherapy and immunotherapies with targeted agents will result in better responses and longer lives for patients with melanoma,” said Hwu. “Additionally, this research will enable approaches to move forward in other tumor types.”

References

1. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01909453.
2. Liu C, Peng W, Xu C, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice.Clin Cancer Res. 2013;19:393-403.
3. Ribas A, Hodi, FS, Callahan, M et al. Hepatotoxicity with combination of vemurafenib and ipilimumab.N Engl J Med. 2013; 368:1365-1366
4. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.Cancer Res. 2010;70:5213-5219
5. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01767454.
6. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01940809.
7. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT02027961.
8. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01673854.
9. Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013;369:122-133.
10. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01968109.