New standard of care for advanced NSCLC again proven superior to chemotherapy

First-line treatment with the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab significantly prolonged overall survival (OS) compared to chemotherapy in patients with PD-L1-expressing, metastatic non-small cell lung cancer (NSCLC), the phase III, IMpower110 randomized trial found.


In an interim analysis of OS among patients with the highest levels of PD-L1 expression, median OS was 7.1 months (41%) longer in the PD-L1 inhibitor arm at 20.2 months compared with 13.1 months in the chemotherapy arm, at a Hazard Ratio (HR) of 0.59 (95% CI, 0.40-0.89; P=0.01), Roy Herbst, MD, PhD, Yale School of Medicine, New Haven, Connecticut, and colleagues reported in The New England Journal of Medicine.


Median OS among patients who had either high or intermediate levels of PD-L1 expression was 28% longer at 18.2 months in the immunotherapy arm versus 14.9 months in the chemotherapy arm (HR of 0.72 [95% CI, 0.52-0.99; P=0.04]), investigators added. However, OS among patients who had any PD-L1 expression was not formally tested, they observed.


“Inhibitors of programmed death 1 (PD-1) and its ligand PD-L1, either as monotherapy or combined with chemotherapy, with or without bevacizumab [Avastin], have emerged as a new standard of care for the first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC) without mutations of epidermal growth factor receptor (EGFR) or translocations of anaplastic lymphoma kinase (ALK),” Herbst and colleagues observed, and noted, “Results for overall survival according to level of PD-L1 expression were similar to those seen in the phase III KEYNOTE-042 trial comparing pembrolizumab with chemotherapy; in both trials, the patients with high PD-L1 expression had the most benefit.”


IMpower110 Trial


IMpower110 is a global, open-label trial designed to evaluate the safety and efficacy of atezolizumab versus a platinum-based regimen in patients positive for PD-L1 on the SP142 immunohistochemical assay.


Patients had not been previously treated with chemotherapy and all patients had EGFR and ALK wild-type tumors, meaning they did not carry either mutation. They received either atezolizumab at a dose of 1200 mg given intravenously (IV) or 4 to 6 cycles of a platinum-based chemotherapy regimen, once every 3 weeks.


In the chemotherapy arm, patients with nonsquamous NSCLC received either cisplatin at a dose of 75 mg/m2 or carboplatin at an area under the curve (AUC) of 6, plus pemetrexed at a dose of 500 mg/m2.


Those with squamous NSCLC were treated with the same dose of cisplatin plus gemcitabine at a dose of 1250 mg/m2 or carboplatin, this time given at an AUC of 5, together with gemcitabine, 1000 mg/m2.


Overall, 38.6% of patients treated with immunotherapy and 35.4% of patients in the chemotherapy group had high levels of PD-L1 expression while 59.9% in the PD-L1 inhibitor group and 58.5% in the chemotherapy group had either high or intermediate levels of PD-L1 expression.


Median follow-up varied by level of PD-L1 expression. For those with high levels of PD-L1 expression, the median follow-up was 15.7 months (range, 0 to 35 months) while for those with high or intermediate levels of expression, the median follow-up was 15.2 months (range 0 to 35 months). For those with any level of PD-L1 expression, the median follow-up was 13.4 months (range, 0 to 35 months), the authors noted.


At 12 months, OS rates were roughly similar in both treatment arms regardless of the level of PD-L1 expression:


– High PD-L1 expression: Atezolizumab: 64.9% (95% CI, 55.4-74.4%)
– High PD-L1 expression: Chemotherapy: 50.6% (95% CI, 40.0-61.3%)
– High or Intermediate PD-L1 expression: Atezolizumab: 60.7% (95% CI, 52.6-68.7)
– High or Intermediate PD-L1 expression: Chemotherapy: 56.0% ((5% CI, 47.7-64.3%)
– Any PD-L1 expression: Atezolizumab: 57.6% (95% CI, 51.2-64.0%)
– Any PD-L1 expression: Chemotherapy: 54.3% (95% CI, 47.7-60.8%)


Progression-free survival (PFS) was also 37% longer in patients treated with atezolizumab at 8.1 months compared with 5 months for their chemotherapy counterparts, at a HR of 0.63 (95% CI, 0.45-0.88). Among those who had either high or intermediate levels of PD-L1 expression, PFS was 33% longer for the same PD-L1 inhibitor group at 7.2 months compared with 5.5 months for their chemotherapy counterparts at a HR of 0.67 (95% CI, 0.52-0.88), investigators pointed out.


The researchers noted that the response rates and duration of response also varied depending on levels of PD-L1 expression, as follows:


– Among those with high PD-L1 expression, response rates were 38.3% in the PD-L1 inhibitor group versus 28.6% in the chemotherapy group. And, at the point of data cutoff, responses were still ongoing in over two-thirds of PD-L1 inhibitor patients versus approximately one-third of those treated with chemotherapy.
– For those with either high or intermediate PD-L1 expression levels, responses at approximately 31% were similar in both arms. However, ongoing responses were more durable in patients treated with atezolizumab, with approximately 71% of patients having an ongoing response compared to only about one-third of those in the chemotherapy group.
– Responses at approximately 30% were again similar in both treatment groups among patients who had any level of PD-L1 expression, but they again persisted for much longer in the immunotherapy arm, as Herbst and colleagues pointed out.


Safety Results


Patients randomized to the immunotherapy arm also received more treatment than those in the chemotherapy group, the researchers noted.


For those randomized to atezolizumab, the median treatment duration was 5.3 months, while for those who received chemotherapy, the median treatment duration was between 2.1 months and 3.5 months, depending on the drug used.


Grade 3 or 4 adverse events (AEs) were also more common for patients receiving chemotherapy. In the PD-L1 inhibitor arm, grade 3 or 4 AEs occurred in approximately 30% of patients compared to approximately 52% of patients treated with chemotherapy; AEs in the chemotherapy group were mostly hematological in nature. Nevertheless, serious AEs were reported in almost identical numbers of patients in both treatment arms at approximately 28% and approximately 4% of patients in each treatment arm had a grade 5 AE.


“The observed safety profile was consistent with that observed in previous studies of atezolizumab monotherapy across indications, histologic type, and lines of therapy,” the authors noted. “Toxic effects were consistent with those that have been reported previously.”


Take Home Message


– The PD-L1 inhibitor, atezolizumab, significantly prolonged overall survival in PD-L1 expressing metastatic non-small cell lung cancer compared with chemotherapy.
– The benefit of immunotherapy was largely limited to NSCLCs with the highest levels of PD-L1 expression.


Pam Harrison, Contributing Writer,


Supported by F. Hoffmann–La Roche/Genentech, a member of the Roche Group.


Herbst disclosed consultant, grant or contract agreements with Abbvie Pharmaceuticals, ARMO Biosciences, AstraZeneca Biodesix, Bolt Biotherapeutics, Bristol-Myers Squibb, Eli Lilly and Company, EMD Serrano, Genentech/Roche, Genmab, Halozyme Inc., Heat Biologics, IMAB Biopharma, Immuncore, Infinity Pharmaceuticals, Junshi Pharmaceuticals, Lexo Oncology, Merck, Midas Health Analytics, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Pfizer, Sanofi Pasteur, Inc., Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, Symphogen, Takeda Oncology, TESARO, Inc., and Tocagen.


Cat ID: 117
Topic ID: 78,117,117,24,935,192,195,65,925