By Liseth Parra, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health
A biologics license application (BLA) for Tecentriq® (atezolizumab, Roche/Chugai) was accepted with priority review by the U.S. Food and Drug Administration (FDA) in April 2016 for the treatment of patients with PD-L1-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) patients who have progressed on or after platinum-containing chemotherapy, an indication in which Tecentriq also has Breakthrough Therapy Designation (BTD). This filing for accelerated FDA approval was based on the single-arm Phase II BIRCH trial, in which Tecentriq produced a 17% objective response rate (ORR) in PD-L1-positive second-line NSCLC.1 Supporting data for Tecentriq in second-line NSCLC also come from the randomized Phase II POPLAR study that showed an improved median overall survival (OS) of 12.6 months with Tecentriq compared with 9.7 months with docetaxel in second-line NSCLC (HR: 0.69, p=0.04).2 Confirmatory data to support its approval can now include the Phase III OAK trial, whose results were newly presented at the 2016 European Society of Medical Oncology (ESMO) Congress.3 A PDUFA regulatory decision for Tecentriq in second-line NSCLC treatment is expected as early as October 19, 2016.
Tecentriq is an engineered monoclonal antibody designed to block the PD-L1 protein, expressed on tumor cells and tumor-infiltrating immune cells (IC), whose main function is to inhibit T-cell immune response. Once this pathway is inactivated by a PD-L1 blocker, such as Tecentriq, the T-cell ability to attack tumor cells is restored, increasing the body’s ability to fight cancer.4 Tecentriq is one of several checkpoint inhibitors in development for NSCLC and is the first and only anti-PD-L1 cancer immunotherapy approved by the FDA to date, obtaining accelerated approval for second-line treatment of locally advanced or metastatic urothelial carcinoma (mUC) in May 2016. Genentech and Roche are aggressively developing Tecentriq in the NSCLC space, with initial commercial launch planned in the second- and third-line settings for patients who overexpress PD-L1 and with eight more Phase III trials ongoing in first-line and the adjuvant setting.
The OAK trial is a randomized, global, multicenter, open-label Phase III study, whose main objective is to evaluate the efficacy and safety of Tecentriq (1,200 mg IV, Q3W) when compared with a historical standard of care treatment, docetaxel (75 mg/m2, Q3W) in patients with locally advanced or metastatic NSCLC previously treated with platinum-containing chemotherapies. The data from OAK presented Sunday at the 2016 ESMO congress are the first Phase III results for a PD-L1 directed antibody. The trial enrolled 1,225 patients with any PD-L1 status with locally advanced or metastatic NSCLC who had one or two prior lines of chemotherapy, including at least one platinum-based. The primary and secondary endpoints for the first 850 enrolled patients were presented. Patients were randomized to receive Tecentriq (n=425) or docetaxel (n=425). Median OS was 13.8 months versus 9.6 months, respectively (HR 0.73, p=0.0003). In addition, the median OS of patients with ≥1% PD-L1 expression in immune cells (IC) or tumor cells (TC) (55% of enrolled patients) was 15.7 months with Tecentriq versus 10.3 months with docetaxel (HR 0.74, p=0.0102). Comparable clinical significance was found in patients with IC or TC, PD-L1 expression <1%, with a median OS of 12.6 months versus 8.9 months, respectively (HR 0.75, p=0.0205). Importantly, patients with ≥ 50% TC or ≥ 10% IC PD-L1 expression (16% of enrolled patients) treated with Tecentriq had an outstanding median OS of 20.5 months compared with 8.9 months in the docetaxel treatment arm (HR: 0.41, p<0.0001). An OS benefit with Tecentriq was observed regardless of histology, although the magnitude of benefit was more pronounced in patients with non-squamous histology (15.6 versus 11.2 months; HR 0.73, p=0.0015) than in patients with squamous histology (8.9 versus 7.7 months; HR 0.77, p=0.0383). Tecentriq had a significant OS benefit across all subgroups regardless of age, PD-L1 status and smoking status, with the exception of patients harboring active EGFR mutations, who showed no benefit with Tecentriq.
Secondary endpoint results were mixed, with Tecentriq-treated patients attaining a progression-free survival (PFS) per RECIST v1.1 numerically lower than the docetaxel arm (2.8 months versus 4.0 months; HR 0.95, p=0.4928). PFS benefit increased with higher PD-L1 expression, with TC3 or IC3 subgroups presenting a median PFS of 4.2 months in Tecentriq-treated patients compared with 3.3 months in the docetaxel group. Similarly, the ORR for Tecentriq was higher in high PD-L1 expressers, with an ORR of 31% compared with 11% of patients treated with docetaxel.
In summary, the OAK study presented the first Phase III data for a PD-L1 directed antibody in lung cancer. Tecentriq will be a new option for second-line NSCLC treatment, with an adverse event (AE) profile that appears to be similar to that of other immune-checkpoint inhibitors. This is a competitive space, with Opdivo currently dominating the second-line market5 and Keytruda also approved. How will Tecentriq be welcomed given that it is coming to market one year behind its biggest rivals?
A more important question may be what role immune checkpoint inhibitors will play in second-line given the positive results of the KEYNOTE-024 trial for Keytruda in first-line PD-L1 strongly positive patients. Given those data, up to one-third of NSCLC patients (those with PD-L1 tumor proportion score of ≥ 50%) may soon receive Keytruda in the first-line setting; given the lack of data to support multiple lines of immune checkpoint inhibition, it seems likely that any patient receiving first-line Keytruda would not be considered for checkpoint inhibitor therapy in second-line, shrinking the available market considerably. Although Opdivo has a broad label in second-line, irrespective of PD-L1 expression, its negative data in the first-line CheckMate 026 trial could have a trickle-down effect on its role in second-line patients who did not receive Keytruda in first-line; this is where Tecentriq will compete with both Opdivo and Keytruda.
Overall, immuno-oncology continues to generate significant enthusiasm, with several overflow rooms set up for the large number of people who attended Sunday’s Presidential Symposium. The entrance of Tecentriq will expand the competitive set in second-line, while other presentations during this ESMO session look to the future as these immuno-oncology agents move into earlier treatment settings. And this is only the tip of the iceberg, as multiple other checkpoint inhibitors are being studied in various treatment settings in NSCLC. OAK has borne fruit, but there’s still a whole forest that remains yet to bloom.
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