Phase Ib study of talimogene laherparepvec in combination with atezolizumab in patients with triple negative breast cancer and colorectal cancer with liver metastases

Abstract

Background: Talimogene laherparepvec (T-VEC), a first-in-class oncolytic viral immunotherapy, enhances tumor-specific immune activation. T-VEC combined with atezolizumab, which blocks inhibitor T-cell checkpoints, could provide greater benefit than either agent alone. Safety/efficacy of the combination was explored in patients with triple negative breast cancer (TNBC) or colorectal cancer (CRC) with liver metastases.

Methods: In this phase Ib, multicenter, open-label, parallel cohort study of adults with TNBC or CRC with liver metastases, T-VEC (10⁶ then 10⁸ PFU/ml; ≤4 ml) was administered into hepatic lesions via image-guided injection every 21 (±3) days. Atezolizumab 1200 mg was given on day 1 and every 21 (±3) days thereafter. Treatment continued until patients experienced dose-limiting toxicity (DLT), had complete response, progressive disease, needed alternative anticancer treatment, or withdrew due to an adverse event (AE). The primary endpoint was DLT incidence, and secondary endpoints included efficacy and AEs.

Results: Between 19 March 2018 and 6 November 2020, 11 patients with TNBC were enrolled (safety analysis set: n = 10); between 19 March 2018 and 16 October 2019, 25 patients with CRC were enrolled (safety analysis set: n = 24). For the 5 patients in the TNBC DLT analysis set, no patient had DLT; for the 18 patients in the CRC DLT analysis set, 3 (17%) had DLT, all serious AEs. AEs were reported by 9 (90%) TNBC and 23 (96%) CRC patients, the majority with grade ≥3 [TNBC, 7 (70%); CRC, 13 (54%)], and 1 was fatal [CRC, 1 (4%)]. Evidence of efficacy was limited. Overall response rate was 10% (95% confidence interval 0.3-44.5) for TNBC; one (10%) patient had a partial response. For CRC, no patients had a response; 14 (58%) were unassessable.

Conclusions: The safety profile reflected known risks with T-VEC including risks of intrahepatic injection; no unexpected safety findings from addition of atezolizumab to T-VEC were observed. Limited evidence of antitumor activity was observed.

Keywords: breast neoplasms; drug therapy combination; gastrointestinal neoplasms; viral immunotherapy; virotherapy.

Figure 1

CONSORT diagram (A) TNBC and (B) CRC. CRC, colorectal cancer; T-VEC, talimogene laherparepvec; TNBC, triple negative breast cancer.

Figure 2

Kaplan–Meier plot for PFS^a in (A) TNBC and (B) CRC, and OS^b in (C) TNBC and (D) CRC for all patients who have received ≥1 dose of T-VEC or atezolizumab. CI, confidence interval; CRC, colorectal cancer; irRC-RECIST, immune-related response criteria simulating Response Evaluation Criteria in Solid Tumors; NE, non-estimable; OS, overall survival; PFS, progression-free survival; TNBC, triple negative breast cancer; T-VEC, talimogene laherparepvec. ^aPFS per modified irRC-RECIST is the interval from the first dose to the earlier of patient overall response of progressive disease or death from any cause; PFS is censored at the later of their last assessable tumor assessment or date of first dose. ^bOS is the interval from the first dose to death from any cause; OS is censored at the date the patient was last known to be alive.