A Novel Immunotherapy Demonstrates Durable Responses in Metastatic Melanoma

Howard Kaufman, MD

Talimogene laherparepvec (T-VEC), a novel oncolytic immunotherapy derived from the herpes simplex virus type 1, demonstrated a significant improvement in durable response rate (DRR), the primary endpoint in a pivotal phase III trial in patients with stage IIIB-IV melanoma.¹The data were presented at the European Cancer Congress (ECCO-ESMOESTRO), held September 27-October 1, 2013, in Amsterdam, The Netherlands. Interim overall survival (OS) subset results from the trial, presented at the 2013 Society for Melanoma Research (SMR) Congress, in Philadelphia (November 18, 2013), seem to complement the DRR data reported at ESMO.

At the predefined interim analysis of this phase III study, median OS was 23.3 months in the T-VEC arm over 19.0 months in the granulocyte-macrophage colony-stimulating factor (GM-CSF) arm (HR = 0.79, 95 percent CI 0.61-1.02;P= 0.0746).

The immunotherapy, which is delivered directly to tumors, produced a DRR of 19% versus 1% with the comparator. To satisfy the primary endpoint of a DRR, patients must have experienced a complete or partial response lasting continuously for at least 6 months. In a news release, Amgen, the manufacturer, announced additional results, highlighting an objective response rate (ORR) of 31% for T-VEC, compared with 6% for GM-CSF.²There was a high degree of correlation between the independent and investigator assessments.

Median time to response was 4.1 months (range, 1.2-16.7 months). The duration of response favored patients randomized to talimogene laherparepvec versus GM-CSF. An estimated 68% of patients taking talimogene laherparepvec had responses lasting at least 9 months. A total of 47% of patients who received GM-CSF had responses lasting at least 9 months.

The phase III trial involved more than 400 patients with unresected stage IIIB, IIIC, or IV melanoma who were randomized 2:1 to receive T-VEC intralesionally every 2 weeks or GMCSF subcutaneously for the first 14 days of each 28-day cycle. Treatment could last for up to 18 months.

“These results further support the primary analysis reported at ASCO [2013 Annual Meeting], which demonstrated a statistically significant durable response rate,” commented Sean E. Harper, MD, executive vice president of Research and Development at Amgen, in comments from the company. “We look forward to the mature overall survival data expected next year.”

“The fact that this study met the primary endpoint shows the value of continuing to explore the potential of talimogene laherparepvec in regional and distant metastatic melanoma, said Howard Kaufman, MD, professor and director of Surgical Oncology in the Department of General Surgery at Rush University Medical Center in Chicago.

At the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31-June 4 in Chicago, investigators reported a trend in support of T-VEC.³Median OS was 23.3 months in the T-VEC arm versus 19.0 months in the GM-CSF arm (hazard ratio = 0.79;P<.07). The most frequent adverse events (AEs) observed were fatigue, chills, and pyrexia. The most common serious AEs included pyrexia as well as disease progression and cellulitis.

&ldquo;[Talimogene laherparepvec] is the first oncolytic immunotherapy to demonstrate a therapeutic benefit against melanoma in a phase III trial,&rdquo; said investigator Robert Hans Ingemar Andtbacka, MD, from the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

T-VEC is designed to replicate within tumors and to increase the production of GM-CSF to enhance systemic antitumor immune responses without harming healthy cells. GM-CSF, a nonstandard treatment for melanoma, was chosen as a comparator because of this mechanism of action of T-VEC. According to Amgen, T-VEC represents a new class of therapy against melanoma, combining both local and systemic effects against tumors. This effect is thought to occur through the functional deletion of two key genes (ICP34.5 and ICP47) from HSV-1, depriving [tumors] of the proteins normally used to circumvent the body&rsquo;s response to infections, followed by the addition of the human GM-CSF gene.

References

T-VEC is injected directly into tumors, where it selectively replicates, causing lysis of the membrane of the cancer cells, destruction of the cells, and release of viruses that have been replicated. The released [therapeutic] viruses in turn invade other tumor cells in a repeating cycle that continues until the weakened virus encounters healthy cells. T-VEC also induces tumors to produce GM-CSF, a white blood cell growth factor that is involved in the body&rsquo;s systemic immune response.

1. Kaufman H, Andtbacka RHI, Harrington K, et al. Secondary endpoints from OPTiM: A multicenter, randomized, phase 3 trial of talimogene laherparepvec GM-CSF for the treatment of unresected stage IIIB/C and IV melanoma. Presented at: European Cancer Congress 2013. September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 3733.
2. Amgen Presents New Data From Phase 3 Study of Talimogene Laherparepvec in Patients With Metastatic Melanoma [news release]. September 30, 2013. Available at: http://www. amgen.com/media/media_pr_detail.jsp?year= 2013&releaseID=1859577. Accessed October 28, 2013.
3. Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.J Clin Oncol. 2013;31(suppl; abstr LBA9008).