Atezolizumab Gets FDA Approval for Lung Cancer

JASON M. BRODERICK @jasoncology
Wednesday, October 19, 2016
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Atezolizumab Gets FDA Approval for Lung Cancer
Patients with previously treated metastatic non–small cell lung cancer (NSCLC) have a new treatment option with the FDA’s approval of the immunotherapy atezolizumab (Tecentriq). The approval is based on multiple clinical trials, the largest being the phase III OAK trial, which was presented at the 2016 ESMO Congress. The agent is approved for those patients with NSCLC who have progressed after a platinum-containing regimen and an FDA-approved targeted therapy for those patients harboring EGFR or ALK abnormalities.

In the OAK study, atezolizumab reduced the risk of death by 26% 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 atezolizumab was observed regardless of PD-L1 status or histology.1

This international, open-label randomized phase III trial included 1225 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 atezolizumab every 3 weeks.

Patient demographics were well balanced between the 2 arms at baseline. The median patient age was 64 years, 61% of patients were male, 18% had never smoked, and 25% had received 2 prior lines of therapy. Patients had an ECOG performance status of 0 (37%) or 1 (63%). Among patients randomized to docetaxel, 17% received immunotherapy as their next treatment.

The co-primary 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 1225 randomized patients.

In the intent-to-treat population (N = 850), the median OS was 13.8 months in the atezolizumab arm (n = 425) versus 9.6 months in the docetaxel arm (n = 425; HR, 0.74; 95% CI, 0.63-0.87; P = .0003). The PFS was 2.8 months versus 4 months (HR, 0.95), respectively. The ORR and DoR were 13.6% versus 13.4%, and 16.3 versus 6.2 months, respectively.

In nonsquamous patients, the median OS was 15.6 months in the atezolizumab group (n = 313) compared with 11.2 months in the control group (n = 315; HR, 0.73; 95% CI, 0.60-0.89). Among patients with squamous histology, the median OS was 8.9 months in the atezolizumab cohort (n = 112) versus 7.7 months on the docetaxel arm (n = 110; HR, 0.73; 95% CI, 0.54-0.98).

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

Among the PD-L1–positive group, the median OS was 15.7 months in the atezolizumab arm (n = 241) compared with 10.3 months in the control arm (n = 222; HR, 0.74; 95% CI, 0.58-0.93; P = .0102). Among PD-L1–negative patients, the median OS was 12.6 months in the atezolizumab cohort (n = 180) versus 8.9 months in the docetaxel group (n = 199; HR, 0.75; 95% CI 0.59-0.96; P = .0205).

The safety profile with atezolizumab 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 atezolizumab arm included musculoskeletal pain (11% vs 4% with docetaxel) and pruritus (8% vs 3%).

The rate of grade 3/4 AEs was lower in the atezolizumab arm than the control arm at 15% versus 43%, respectively. No treatment-related deaths occurred in the atezolizumab cohort compared with 1 in the docetaxel arm.

The phase II BIRCH and POPLAR studies also demonstrated the efficacy of atezolizumab in this setting. In the BIRCH study, responses were observed in up to 27% (P = .0001) of previously treated patients with NSCLC who had the highest levels of PD-L1 expression. 2

The open-label, single-arm study enrolled 667 patients with stage IIIB/IV or recurrent NSCLC who did not have active CNS metastases. Patient characteristics were balanced across cohorts; the median age was 64 years, 35% were ECOG PS 0, 28% had squamous NSCLC, and 17% 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.

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

Overall response rate 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% and 17% 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%, 24%, and 27% 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%, 76%, and 71% of patients TC2/3 or IC2/3 expression levels in cohorts 1, 2, and 3, respectively, and by 79%, 80%, and 75% of patients in cohorts 1, 2, and 3 having TC3 or IC3 expression levels.

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

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

The phase II POPLAR trial randomized 287 patients with previously treated NSCLC to receive atezolizumab (n = 144) or docetaxel (n = 143). Intravenous atezolizumab was administered at 1200 mg every 3 weeks and docetaxel was used at 75 mg/m2 every 3 weeks.3,4

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

Among high PD-L1 expressing tumors (TC/IC 3), the median PFS was 7.8 versus 3.9 months, for atezolizumab and docetaxel, respectively (HR, 0.60; 95% CI, 0.31-1.16). The ORR was 38% and 13%, respectively.

In patients without PD-L1 expression (TC/IC 0), a difference was not observed between the 2 groups. Across all expression levels, the ORR was 15% 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 atezolizumab and docetaxel, respectively.

Fewer grade 3 to 5 AEs were experienced by patients treated with atezolizumab in this study compared with docetaxel (44% vs 56%). There was a higher incidence of respiratory side effects with immunotherapy versus chemotherapy. Atezolizumab was associated with aspartate and alanine aminotransferase increases (4% each), colitis (1%), hepatitis (1%), and pneumonitis (2%).
References
  1. Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract for LBA44.
  2. Besse B, Johnson M, Jänne PA, et al. Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 16LBA.
  3. Vansteenkiste J, Fehrenbacher L, Spira AI, et al. Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 14LBA.
  4. Spira AI, Park K, Mazières J, et al. Efficacy, safety and predictive biomarker results from a randomized phase II study comparing atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015;(suppl; abstr 8010).


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