1056 - Primary 2-year (yr) results of a phase 2, multicenter, randomized, open-label trial of efficacy and safety for talimogene laherparepvec (T-VEC) neoadjuvant (neo) treatment (tx) plus surgery (surg) vs surg in patients (pts) with resectable stage IIIB-IVM1a melanoma

Background

Risk of recurrence and death remain high for pts with advanced melanoma after resection. TVEC, an intralesional immunotherapy for advanced melanoma, selectively replicates in tumors and enhances systemic antitumor immune response. We examined the impact of neo T-VEC in resectable metastatic melanoma.

Methods

Pts with resectable stage IIIB-IVM1a melanoma and ≥ 1 injectable cutaneous, subcutaneous or nodal lesions were randomized 1:1 to 6 doses/12 wks of neo T-VEC then surg (Arm 1) vs surg alone (Arm 2). T-VEC was given until surg, no remaining injectable tumors or intolerance. The primary endpoint per protocol was recurrence-free survival (RFS) at 2-yrs, with events defined as first of local, regional or distant recurrence or death due to any cause after surg in the ITT set. Per protocol, pts who withdrew prior to surg or had a non-R0 resection were counted as an RFS event at randomization. An additional sensitivity analysis that did not count non-R0 events at baseline per conventional RFS calculation was also conducted.

Results

Demographics, tx status and safety for the 150 pts analyzed has been reported (Dummer et al., ASCO 2019). Median follow-up (range) was 31.2 (0.1, 49.9) mos. Per protocol, 29.5% of pts in Arm 1 and 16.5% of pts in Arm 2 remained recurrence free at 2 yrs (HR 0.75, P = 0.07). 50.5% of pts in Arm 1 and 30.2% of pts in Arm 2 (HR 0.66, P = 0.038) remained recurrence free at 2 yrs in the additional sensitivity analysis. 2-yr overall survival (OS) rates were 88.9% in Arm 1 and 77.4% in Arm 2 (overall HR 0.49, P = 0.050). In Arm 1, T-VEC resulted in a 3x increase in intratumoral CD8+ cell density (P < 0.001) and an increase in PD-L1 (P ≤ 0.05). CD8+ density and PD-L1 H-score were higher post-tx in Arm 1 vs Arm 2 (P < 0.001). Increased intratumoral CD8+ density post-tx correlated with longer RFS in the sensitivity analysis and OS.

Conclusions

In the largest randomized trial of neo tx in resectable stage IIIB-IVM1a melanoma, neo T-VEC improved 2-yr RFS and OS. T-cell influx and PD-L1 upregulation after T-VEC tx support a role for the adaptive immune system consistent with the mechanisms of action.

Clinical trial identification

NCT02211131, release date: August 7, 2014; EudraCT: 2014-001146-13.

Editorial acknowledgement

Medical writing support was provided by Sarah K Madsen (Amgen Inc.).

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

R. Dummer: Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Novartis; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Merck Sharp & Dohme (MSD); Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work.: BMS; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Roche; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Amgen Inc; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Takeda; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work.: Pierre Fabre; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Sun Pharma; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Sanofi; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship outside the submitted work: Catalym. D.E. Gyorki: Honoraria (self), Travel / Accommodation / Expenses: Amgen Inc.. J. Hyngstrom: Advisory / Consultancy, Reviews of general surgery research articles every 2 months for Practical Reviews of General Surgery: Ebix. A. Berger: Speaker Bureau / Expert testimony: Cardinal Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Castle Biosciences. R. Conry: Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Amgen Inc.; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Array; Speaker Bureau / Expert testimony: Regeneron-Sanofi. L. Demidov: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Roche. A. Sharma: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen Inc.. S.A. Treichel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen Inc.. K. Gorski: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen Inc.. A. Anderson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen Inc.. M. Faries: Advisory / Consultancy: Delcath Systems Inc.; Advisory / Consultancy: Pulse Bioscience; Advisory / Consultancy: Novartis. M.I. Ross: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Amgen Inc.; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Research grant / Funding (self), Travel / Accommodation / Expenses: Provectus; Travel / Accommodation / Expenses: Castle Biosciences; Travel / Accommodation / Expenses: Novartis.