Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma

Abstract

Background: Talimogene laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB-IVM1c melanoma.

Methods: Patients were randomized 2:1 to receive intratumoral talimogene laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators.

Results: Of 436 patients in the intent-to-treat population, 295 were allocated to talimogene laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (95% confidence interval [CI], 19.5-29.6) and 18.9 months (95% CI, 16.0-23.7) in the talimogene laherparepvec and GM-CSF arms, respectively (unstratified hazard ratio, 0.79; 95% CI, 0.62-1.00; p = 0.0494 [descriptive]). DRR was 19.0 and 1.4% (unadjusted odds ratio, 16.6; 95% CI, 4.0-69.2; p < 0.0001); ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the talimogene laherparepvec and GM-CSF arms, respectively, achieved CR. In talimogene laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene laherparepvec efficacy was more pronounced in stage IIIB-IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis.

Conclusions: In this final planned OPTiM analysis, talimogene laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that talimogene laherparepvec was associated with durable CRs that were associated with prolonged survival.

Trial registration: ClinicalTrials.gov identifier: NCT00769704 .

Keywords: Efficacy; Final analysis; Melanoma; Overall survival; Talimogene laherparepvec.

Fig. 1

Duration of response for all patients with response per investigator assessment. Duration of response is defined as the longest individual period from entering response (PR or CR) to the first documented evidence of the patient no longer meeting the criteria for being in response or death, whichever is earlier. CR, complete response; GM-CSF, granulocyte-macrophage colony-stimulating factor; PR, partial response

Fig. 2

Analyses of CR in stage IIIB–IVM1c melanoma. a Time to achieve CR in patients treated with talimogene laherparepvec; b Duration of CR in patients treated with talimogene laherparepvec; c Kaplan-Meier plot of OS in patients who achieved a CR versus patients who did not achieve a CR prior to a landmark time of 9 months; d Kaplan-Meier plot of TFI in patients who achieved a CR versus patients who did not achieve a CR prior to a landmark time of 9 months; e RFS after achieving a CR with talimogene laherparepvec; f Factors associated with achieving CR with talimogene laherparepvec^f. ^aCR duration was defined as the interval from the initial date of CR to the first response of non-CR. Ongoing CRs were censored at the date with a CR. The longest interval was utilized due to multiple CR intervals. Median follow-up for CR duration = 7 months (range < 1 to 20 months). ^bFor landmark analyses, OS was calculated from the landmark time of 9 months after randomization to death. Unadjusted hazard ratios and log-rank P-values are shown. ^cTFI was defined as the interval from the last dose of study therapy and the first dose of systemic therapy categorized as chemotherapy/targeted agent or immunotherapy. The TFI analysis was limited to treated patients with tumor assessments ≥9 months. Unadjusted hazard ratios (HR) and log-rank P-values are shown. ^dRFS after achieving a CR was calculated from date of CR to date of recurrence, death due to disease progression, or start of new anti-melanoma therapy. Median follow-up for RFS = 31 months (range 1 to 53 months). ^e14.5 cm² was the median tumor burden. ^fPatients treated with talimogene laherparepvec who achieved CR (n = 50) versus those who did not (n = 245) using logistic regression models. AJCC, American Joint Committee on Cancer; CI, confidence interval; CR, complete response; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; ITT, intent-to-treat; NE, not evaluable; OR, odds ratio; OS, overall survival; RFS, recurrence-free survival; TFI, treatment-free interval

Fig. 3

Final planned analyses of OS. a Final OS in the intent-to-treat population; b Final OS in patients with stage IIIB/C melanoma; c Final OS in patients with stage IIIB-IVM1a melanoma; d Final OS in patients with stage IVM1b/c melanoma; e Exploratory subgroup analyses of final OS (intent-to-treat population); and f Final OS in the treatment-received population (all randomized patients excluding those who did not receive allocated treatment; n = 4 in the talimogene laherparepvec arm; n = 14 in the GM-CSF arm). ^aP-values are descriptive and represent the statistical significance of the treatment difference within the subgroup from log-rank test unless otherwise stated (*P < 0.05). CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; GM-CSF, granulocyte-macrophage colony-stimulating factor; HR, hazard ratio; NE, not estimable; OS, overall survival; T-VEC, talimogene laherparepvec