Lynne Lederman, PhD

Patients with advanced melanoma saw evidence of clinical benefit with the combination of the oncolytic virus Imlygic (talimogene laherparepvec; T-VEC) and Keytruda (pembrolizumab). The combination also demonstrated an acceptable safety profile when the treatment regimen was administered at full doses, according to the results of a phase 1b study.

The findings of the MASTERKEY-265 (NCT02263508) trial were reported by Georgina V. Long, Melanoma Institute Australia and The University of Sydney, North Sydney, Australia, at a poster session during the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, a gathering of more than 30,000 oncology professionals in Chicago.

“This is a phase 1b trial, and it's only in 21 patients, ” Long said. “Like all phase 1 trials, it’s interesting—but it’s not going to change practice. We need to wait for randomized [trial] results. There’s a trial now ongoing looking at [Keytruda] combined with [Imlygic] versus [Keytruda] combined with a placebo by intralesional injection and that will tell us whether there is truly an additive effect with [Imlygic and Keytruda].”

Imlygicis a genetically modified herpes simplex virus-1 that selectively replicates in tumor cells after intralesional injection. The oncolytic virus also causes tumor cell lysis and the release of tumor-derived antigens, and stimulates the production of granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF enhances antigen presentation and stimulates antitumor immune responses in patients with melanoma.

Combining Imlygic with Yervoy (ipilimumab), which targets different cancer immune response pathways, has improved antitumor responses in patients with unresectable stage 3b/4 melanoma. Keytruda, an anti-programmed death receptor-1 (PD-1) antibody, is associated with greater progression-free survival (PFS) and overall survival (OS) than Yervoy, suggesting the combination of Imlygic with Keytruda might be more effective than the combination of Imlygic with Yervoy.

The MASTERKEY-265 trial was designed to determine safety, efficacy and biomarker data in patients with stage 3/4 unresectable melanoma receiving the combination of Imlygic with Keytruda. The primary endpoint of this study was the incidence of dose-limiting toxicities (DLTs), evaluated by a dose level review team. Secondary endpoints included the incidence of adverse events (AEs), objective response rate (ORR) by immune-related response criteria, duration of response (DOR) and PFS.

Key inclusion criteria for the 21 patients who were enrolled included presence of unresectable stage 3b/4 melanoma with injectable lesions, no prior systemic therapy and no active herpetic skin lesions or prior complications from a prior herpetic infection.

Patients received up to four mL Imlygic by injection into cutaneous/nodal lesions. The first dose contained 106 plaque-forming units (PFU) per mL; the second dose at day 22 contained 108 PFU per mL; subsequent doses at 108 PFU/mL were given every two weeks until progressive disease, intolerance, disappearance of all injectable tumors, or at two years of treatment. Keytruda 200 mg was given intravenously every two weeks after the first two Imlygic injections. DLTs were assessed for six weeks from the first Keytruda treatment.

No DLTs were observed. The safety profile of the combination of full doses of Imlygic and Keytruda was as expected for the agents as monotherapies. One patient died of progressive disease. AEs resulted in interruption of Imlygic in six patients and of Keytruda in seven patients. Two patients discontinued therapy because of Keytruda-related AEs.

The confirmed ORR was 57.1 percent, with 23.8 percent confirmed complete responses (CR). The unconfirmed ORR was 66.7 percent, and the unconfirmed CR rate was 28.8 percent. The median follow-up time was not indicated. The disease control rate (including stable disease, partial response and complete response) was 71.4 percent. Median PFS was not reached.

Biomarker analysis included characterization of T-cell subsets, expression of markers of proliferation, activation and checkpoint. Circulating cytotoxic T cells (CD3+/CD8+) increased, and PD-1 and TIM-3 on these cells were upregulated following initiation of Imlygic monotherapy. After the start of combination therapy, the proliferation marker Ki-67 increased in circulating cytotoxic T cells; however, TIM-3 and BTLA were not upregulated after initiation of combination therapy.

The phase 3 part of MASTERKEY-265 is a randomized, double-blind, placebo-controlled trial that will recruit 660 patient with unresectable state 3b/4 melanoma. The primary endpoints will be PFS and OS. This trial will assess long-term safety in a follow-up period lasting five years from the date of the last patient randomly assigned to treatment.

Long described the results of the phase 1b portion of MASTERKEY-265 as interesting, calling the combination of Imlygic and Keytruda “a very well-tolerated combination with no unusual adverse events.” Noting that these are “exciting early data,” she cautioned, “but let’s wait for the randomized data.”

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A small, early trial demonstrated that a combination of Imlygic and Keytruda can have clinical benefit for patients with advanced melanoma.

Immunotherapy Combination Demonstrates Benefit in Small, Early Trial of Melanoma

It is unclear which strategy is optimal for determining the prevalence of germline cancer susceptibility gene mutations in patients with colorectal cancer (CRC), according to an analysis presented at 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of over 30,000 oncology professionals in Chicago.

Inherited factors are important determinants of the risk for CRC. However, current estimates of the prevalence of inherited CRC syndromes have been determined by testing for syndrome-specific genes in patients with high-risk features, such as a personal or family history of CRC or the known presence of CRC-associated genes.

The aim of this study, presented by Matthew B. Yurgelun, physician, instructor in Medicine, Harvard Medical School, Dana-Farber Cancer Institute, was to determine the prevalence of pathogenic germline mutations in cancer risk genes in patients with CRC who were not selected for the presence of high-risk indications. Individuals seen at Dana-Farber Cancer Institute for a CRC diagnosis from December 2008 through March 2014 were eligible for the study. Of 1,100 patients screened, 1,059 participated in the study.

Testing was done on blood samples at a CLIA-approved commercial laboratory using a 25-gene hereditary cancer panel that included high-penetrance susceptibility genes (e.g., those associated with Lynch syndrome, adenomatous polyposis syndromes and hereditary breast and ovarian cancer [

]), as well as genes of moderate penetrance both linked and not linked to CRC risk.

Data collected from study participants included results of microsatellite instability (MSI) and mismatch-repair protein immunohistochemistry (MMR IHC), which is used to screen for Lynch syndrome. PREMM1,2,6 scores were used to generate a numerical estimate of the likelihood of an underlying Lynch syndrome mutation.

Patients were 56 percent male, with a mean age of 55.7 years at diagnosis. The median PREMM1,2,6 score was 3.93 percent; 39 percent of patients had a PREMM1,2,6 score of at least 5 percent, which is the cut-off value for recommended testing for Lynch syndrome.

Germline testing results revealed 106 patients (10 percent) with at least one pathogenic mutation. Of the 5.2 percent of patients with high-penetrance gene mutations, 3.1 percent had Lynch syndrome. The most common non-Lynch, high-penetrance mutation was 

, which occurred in 1 percent of the patient population, which is higher than the 0.2 percent to 0.3 percent estimated prevalence in the general population.

Although this study included a large group of patients who were not selected for high-risk features, it was clinic-based; personal and family history were extensive, but were not verified beyond a review of the medical record. Tumor testing data were incomplete for some patients, and enrollment of many occurred before universal MMR IHC testing. Additional limitations were a lack of data on Ashkenazi ancestry, polyp number and histology.

Multigene germline genetic testing in this study revealed an additional 7 percent inherited non-Lynch genes associated with CRC risk that were not predicted by personal or family history. Many of the high- and moderate-penetrance genes, whether linked to CRC risk or not, have National Comprehensive Cancer Network—recommended screening or risk-reduction interventions. Early identification of these genes would be required to implement these interventions.

Although MSI/MMR IHC and PREMM1,2,6 reliably identify the presence of Lynch syndrome in patients with CRC, Yurgelun concluded that the spectrum of genetic factors in CRC is more diverse than has been appreciated; personal and family history are not reliable predictors for these factors.

A participant at the session mentioned observing an excess of CRC in women below the age of 50 who have 

mutations, and wondered if men with those mutations might also have a higher risk of CRC. He asked whether these individuals should be screened for CRC, and if so, how often and at what age.

Yurgelun answered, “It is not a question that I have an obvious or a direct answer to. I agree that data such as ours today and those you mentioned are certainly provocative for how much of an overlap there is between 

For what to do for patients with these mutations, he said, “I don’t know that our study necessarily is able to tell us when we should start colonoscopies in individuals with 

 mutations, and should it be different for men versus women. Is there an actual benefit to screening them earlier with regards to reducing their colorectal cancer risk? I think those are the types of questions that naturally come out of these sorts of data.”

While inherited factors do play a role in many people getting colorectal cancer, researchers are still unsure how to identify these mutations. 

Lynne Lederman, PhD

Immunotherapy Combination Demonstrates Benefit in Small, Early Trial of Melanoma

Questions Remain in Identifying Mutations in Non-Lynch Syndrome Patients With Colorectal Cancer

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