Novel Targets

The second speaker of the session, Keith Flaherty, MD, of Massachusetts General Hospital, focused on novel targets for melanoma treatments.

According to Dr Flaherty, most patients with metastatic melanoma still experience disease relapse and progression despite the introduction of therapies targeting BRAF/MEK, PD-1, and CTLA-4.

“Since these therapies have been in the field several years now, we and others have had the chance to delve into the biology of therapeutic resistance to these agents,” Dr Flaherty told Cancer Therapy Advisor. “A few important themes have been reproducibility described regarding resistance to these therapies that point toward the types of therapies we should prioritize for clinical investigation in melanoma.”

Two categories of novel targets have emerged from recent work. The first category includes targets that can directly kill melanoma cells that have a transcriptional state reflecting a neural crest precursor cell (as opposed to a melanocyte). According to Dr Flaherty, screens are actively being conducted to identify such potential therapies. One that has been identified in clinical trials is JAK1 inhibitors.

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The other major category is drugs that target cancer cell metabolism.

“The same cells that resist the available therapies undergo a metabolic switch in which they utilize oxidative phosphorylation for energy production, as opposed to glycolysis,” Dr Flaherty said. “These drugs may come in many forms.”

Agents that have been nominated for this include phenformin, mTOR inhibitors, and mitochrondrial HSP90 inhibitors.

“These agents aren’t expected to have significant single-agent activity, but rather to complement BRAF/MEK or PD-1 antibody-based therapy,” Dr Flaherty said.

Dr Flaherty emphasized that these new drugs will have to be studied extensively to make sure that they are safe in combination with currently available treatments.

“Then we will need to document that they are doing their molecular job at achievable concentrations,” he said. “Lastly, we will need to see that efficacy is observed in patients whose cancers are expressing the markers of therapeutic resistance outlined above.”

Adoptive Cell Therapy

The final speaker of the session discussed the evolution of the use of adoptive cell therapy for the treatment of melanoma. According to Stephanie Goff, MD, FACS, a clinician in the surgery branch of the National Cancer Institute, adoptive cell therapy harnesses the power of tumor infiltrating lymphocytes (TILs) or immune cells that have been identified as cells that have successfully attacked the patient’s tumor.

Adoptive cell therapy is similar to chimeric antigen receptor T-cell (CAR-T) therapy in that patients get an infusion of white blood cells, but in the case of adoptive cell therapy, researchers harness the power of immune cells that can attack the tumor without necessarily knowing the target.

The first human study of adoptive cell therapy with TILs included 20 patients with metastatic melanoma.3 Patients were treated with a single dose of cyclophosphamide, intravenous autologous TILs, and high-dose IL-2. More than half of the patients had an objective response; however, responses were mostly short in duration.

Later studies changed the chemotherapy regimen to combined cyclophosphamide and fludarabine, and a greater rate of complete response was seen. One study of adoptive cell therapy included 194 patients with 46 experiencing complete response. With a median potential follow-up of 6 years, only 2 patients have experienced relapse.4

With the success of checkpoint inhibition, it remains to be seen where adoptive cell transfer would fit in with other treatment approaches for metastatic melanoma. According to Dr Goff, growing and maintaining TILs and the management of patients undergoing adoptive cell transfer can be complex.

“For those reasons, despite durable complete remissions of widespread melanoma, the use of TILs remains a research enterprise,” Dr Goff said. “The vast majority of patients with metastatic melanoma will be treated with other immunotherapy medications prior to seeking this more intense process, but we and others have demonstrated that TILs can still work for patients when those immune drugs fail.”

References

  1. Ugurel S, Rohmel J, Ascierto PA, et al. Survival of patients with advanced metastatic melanoma: The impact of novel therapies. Eur J Cancer. 2016;53:125-134.
  2. Merck. Incyte and Merck provide update on phase 3 study of epacadostat in combination with Keytruda (pembrolizumab) in patients with unresectable or metastatic melanoma. http://investors.merck.com/news/press-release-details/2018/Incyte-and-Merck-Provide-Update-on-Phase-3-Study-of-Epacadostat-in-Combination-with-KEYTRUDA-pembrolizumab-in-Patients-with-Unresectable-or-Metastatic-Melanoma/default.aspx. Published April 6, 2018. Accessed June 26, 2018.
  3. Rosenberg SA, Packard BS, Aebersold PM et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N Engl J Med. 1988;319:1676-1680.
  4. Ascierto PA, Flaherty K, Goff S. Emerging strategies in systemic therapy for the treatment of melanoma. Am Soc Clin Oncol Educ Book. doi: 10.1200/EDBK_199047