FDA Approves Tecentriq in Lung Cancer Subset

Tecentriq (atezolizumab) just gained FDA approval for the treatment of metastatic non-small cell lung cancer (NSCLC) who progressed after a platinum-containing regimen and an FDA-approved targeted therapy for patients with EGFR or ALK abnormalities.

The approval is based on multiple clinical trials, the largest being the phase 3 OAK trial, which was presented at the 2016 European Society for Medical Oncology (ESMO) Congress. In the study, Tecentriq reduced the risk of death by 26 percent compared with docetaxel in patients with advanced NSCLC following the failure of platinum-based chemotherapy. The median overall survival (OS) was improved by 4.2 months with the PD-L1 inhibitor versus chemotherapy. The survival benefit with Tecentriq was observed regardless of PD-L1 status or histology.

“Tecentriq is a new option to help people with this type of previously treated metastatic lung cancer, regardless of PD-L1 expression, live longer than chemotherapy,” Sandra Horning, M.D., chief medical officer and head of Global Product Development at Genentech, the developer of Tecentriq, said in a statement. “Tecentriq is the first and only approved cancer immunotherapy designed to target the PD-L1 protein, which may play an important role in the way the medicine works.”

The international, open-label randomized phase 3 OAK trial included 1,225 patients with locally advanced or metastatic NSCLC — regardless of histology or PD-L1 status — who progressed during or after platinum-containing chemotherapy. Patients were randomized in a 1-1 ratio to 75 mg/m² of intravenous docetaxel or 1200 mg of intravenous Tecentriq every three weeks.

Patient demographics were well balanced between the two arms at baseline. The median patients age was 64 years, 61 percent of patients were male, 18 percent had never smoked and 25 percent had received two prior lines of therapy. Patients had an ECOG performance status of 0 (37 percent) or 1 (63 percent). Among patients randomized to docetaxel, 17 percent received immunotherapy as their next treatment.

The coprimary endpoints of the trial were OS in the entire study population and in a PD-L1—defined subgroup. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR). The primary efficacy assessment included only the initial 850 randomized patients, and the secondary efficacy analysis will include data from all 1,225 randomized patients.

In the intent to treat population (850 patients), the median OS was 13.8 months in the Tecentriq arm (425 patients) versus 9.6 months in the docetaxel arm (425 patients). The PFS was 2.8 months versus 4 months, respectively. The ORR and DoR were 13.6 percent versus 13.4 percent, and 16.3 versus 6.2 months, respectively.

In nonsquamous patients, the median OS was 15.6 months in the Tecentriq group (313 patients) compared with 11.2 months in the control group (315 patients). Among patients with squamous histology, the median OS was 8.9 months in the Tecentriq cohort (112 patients) versus 7.7 months on the docetaxel arm (110 patients).

Regarding PD-L1 status, PD-L1—positive patients (TC1/2/3 or IC1/2/3) had expression on at least 1 percent of their tumor cells (TC) or tumor-infiltrating immune cells (IC). PD-L1 negative patients (TC0 or IC0) had less than 1 percent expression on their TC and IC.

Among the PD-L1—positive group, the median OS was 15.7 months in the Tecentriq arm (241 patients) compared with 10.3 months in the control arm (222 patients). Among PD-L1–negative patients, the median OS was 12.6 months in the Tecentriq cohort (180 patients) versus 8.9 months in the docetaxel group (199 patients).

The safety profile with Tecentriq in the OAK trial was consistent with adverse event (AE) outcomes observed in previous studies of the PD-L1 inhibitor. AEs occurring more frequently in the Tecentriq arm included musculoskeletal pain (11 percent vs 4 percent with docetaxel) and pruritus (8 percent vs 3 percent).

The rate of grade 3/4 AEs was lower in the Tecentriq arm versus the control arm at 15 percent versus 43 percent, respectively. No treatment-related deaths occurred in the Tecentriq cohort compared with one in the docetaxel arm.

The phase 2 BIRCH and POPLAR studies also demonstrated the efficacy of Tecentriq in this setting. In the BIRCH study, responses were observed in up to 27 percent of previously treated patients with NSCLC who had the highest levels of PD-L1 expression

The open-label, single-arm study enrolled 667 patients with stage 3B/4 or recurrent NSCLC who did not have active CNS metastases. Patient characteristics were balanced across cohorts; the median age was 64 years, 35 percent were ECOG PS 0, 28 percent had squamous NSCLC, and 17 percent of patients were never-smokers. EGFR and KRAS mutations were identified in 327 and 177 patients overall, respectively.

All patients had disease that expressed PD-L1 as measured on tumor cells (TC) and tumor-infiltrating immune cells (IC) by Roche’s investigational IHC test. An IHC score of TC2/3 or IC2/3 was the inclusion criteria established by the trial design.

Tecentriq was administered at 1200 mg IV at three-week intervals as frontline therapy to 142 patients (cohort 1), as second-line to 271 patients who had progressed after one prior platinum therapy (cohort 2) and to 254 patients who had undergone two or more prior chemotherapy regimens (cohort 3).

ORR was the primary endpoint, with secondary outcome measures including duration of response, PFS, OS and safety.

Among the 659 evaluable patients, the median treatment duration across all cohorts was 4.2 months (range, 0-15). The ORR in cohort 1 was 19 percent and 17 percent in cohorts 2 and 3 in patients with TC2/3 or IC2/3 expression. Stronger response was seen in patients with higher expression; ORR rates were 26 percent, 24 percent and 27 percent in cohorts 1, 2 and 3 in patients with PD-L1 expression of level TC3 or IC3.

At a median follow-up of 8.8, 7.9 and 8.6 months, median OS was 14 months, not reached (NR), and NR, across cohorts 1, 2 and 3, respectively. Six-month OS was achieved by 82 percent, 76 percent and 71 percent of patients TC2/3 or IC2/3 expression levels in cohorts 1, 2 and 3, respectively, and by 79 percent, 80 percent and 75 percent of patients in cohorts 1, 2 and 3 having TC3 or IC3 expression levels.

Six-month PFS rates were 46 percent, 29 percent, and 31 percent at the PD-L1 expression level of TC2/3 and IC2/3 and 48 percent, 34 percent and 39 percent in patients with TC3 or IC3 expression levels in cohorts 1, 2 and 3, respectively.

The safety data for Tecentriq in BIRCH were similar to those observed in other trials. The most commonly reported adverse events (AEs) were fatigue (18 percent) and nausea (10 percent). Grade 3/4 treatment-related AEs occurred in 11 percent of patients overall and 6 percent of patients discontinued therapy due to a treatment-related AE. All-cause grade 3/4 AEs occurred in 38 percent of patients.

The phase 2 POPLAR trial randomized 287 patients with previously treated NSCLC to receive Tecentriq (144 patients) or docetaxel (143 patients). Intravenous Tecentriq was administered at 1,200 mg every three weeks and docetaxel was used at 75 mg/m² every three weeks.

In the overall study population, the results did not significantly favor Tecentriq; however, as in the BIRCH trial, PD-L1 expression was strongly associated with Tecentriq's efficacy in POPLAR.

In high PD-L1 expressing tumors (TC/IC 3), the median PFS was 7.8 versus 3.9 months, for Tecentriq and docetaxel. The ORR was 38 percent and 13 percent, respectively.

In patients without PD-L1 expression (TC/IC 0), a difference was not observed between the two groups. Across all expression levels, the ORR was 15 percent with both treatments. In this group, the median OS was 12.6 and 9.7 months and the median PFS was 2.7 and 3.0 months, for Tecentriq and docetaxel, respectively.

In the study, fewer grade 3 to 5 adverse events were experienced by patients treated with Tecentriq compared with docetaxel (44 percent vs 56 percent). There was a higher incidence of respiratory side effects with immunotherapy versus chemotherapy. Tecentriq was associated with aspartate and alanine aminotransferase increases (4 percent each), colitis (1 percent), hepatitis (1 percent) and pneumonitis (2 percent).