First Line Combination Therapy Improves Progression-Free Survival In Advanced Lung Cancer

LUGANO-GENEVA - A new combination therapy for the first line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC) improves progression-free survival (PFS), according to results of the phase III IMpower150 trial presented at the ESMO Immuno Oncology Congress 2017. (1)

“This is the first phase III trial to report on the combination of chemotherapy, antiangiogenic treatment and immunotherapy as first line treatment for advanced non-squamous NSCLC,” said lead author Professor Martin Reck, chief oncology physician, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany. “The trial met its co-primary endpoint of PFS and the preliminary results of the co-primary endpoint of overall survival (OS), although immature, look encouraging.”

There is a scientific rationale to support the combinations that have been explored in the trial. Bevacizumab may enhance the ability of atezolizumab to restore anti-cancer immunity by inhibiting vascular endothelial growth factor (VEGF)-related immunosuppression and other mechanisms while chemotherapy may induce immune responses. The chemotherapy used in the trial was carboplatin plus paclitaxel. Atezolizumab is a monoclonal antibody that inhibits programmed death-ligand 1 (PD-L1), while bevacizumab is a biologic antiangiogenic drug.

IMpower150 enrolled 1,202 patients who were randomised to one of three arms: A) chemotherapy plus atezolizumab; B) chemotherapy plus atezolizumab plus bevacizumab; or C) chemotherapy plus bevacizumab.

The PFS survival comparison was made between arms B and C and showed that the combination of atezolizumab, bevacizumab and chemotherapy was superior to bevacizumab and chemotherapy alone with a median PFS of 8.3 versus 6.8 months (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.52, 0.74; P < 0.0001) in the intention-to-treat (ITT) wild type (WT) population, which excluded patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.

The corresponding median PFS in the Teff-WT population, which included patients with defined expression of a T-effector gene signature in the tumour tissue, was 11.3 versus 6.8 months (HR 0.51; 95% CI 0.38, 0.68; P < 0.0001). PFS benefit was seen regardless of PD-L1 immunohistochemistry status, including PD-L1–negative pts (TC0/IC0: HR 0.77; 95% CI 0.61, 0.99). (2)

There were no new safety signals with the combination therapy. Due to prespecified testing hierachy, Arm A versus C has not been formally tested yet.

Reck said: “There was a significant and clinically relevant improvement in progression-free survival favouring the addition of atezolizumab to bevacizumab and chemotherapy. The results show that there is a way to improve the efficacy of platinum-based chemotherapy in patients with advanced non-squamous NSCLC. There were no new safety signals or toxicity issues with this combination so it appears to be a feasible  approach for this group of patients.”

Commenting on treatment for advanced non-squamous NSCLC for ESMO, Professor Solange Peters, Head of Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, said: “Immunotherapy is a standard of care treatment after platinum-based chemotherapy in patients with advanced NSCLC. Frontline immunotherapy alone is beneficial in those with a high PD-L1 expression, who make up less than a third of NSCLC patients. (3) The combination of immunotherapy and platinum-based chemotherapy showed positive response rates in unselected non-squamous patients (without PD-L1 selection) in a hypothesis-generating phase II trial, which led to US Food and Drug Administration (FDA) approval.” (4)

“IMpower150 is the first phase III randomised trial to formally evaluate the combination of immunotherapy and chemotherapy versus chemotherapy frontline,” she continued. “The backbone therapy includes bevacizumab which might, by targeting VEGF, facilitate the immune response and the trafficking of T cells. Median PFS for the immunotherapy arm in patients without EGFR mutations or ALK rearrangements had a promising hazard ratio of 0.62 and a median PFS improvement of a little less than two months.”

Peters said the benefit of immunotherapy is best observed at later time points. “When you look at the 12-month PFS, you double the number of patients who have not progressed from 18% without immunotherapy to 37% when you add the immunotherapy,” she said. “This is very, very promising. Doubling PFS at one year is something we have not seen with any targeted therapy in unselected patients to date.”

Even more important was that the combination of chemotherapy and immunotherapy was beneficial regardless of expression of PD-L1 or a T-effector gene signature. It was also beneficial in patients with alterations in EGFR and ALK, who usually do not do well with immunotherapy. Peters said: “We know that for immunotherapy monotherapy, we need to highly select patients for PD-L1 expression. This trial shows that by combining chemotherapy and immunotherapy you completely delete any need for patient selection according to a particular biomarker. This strategy has the potential to benefit large numbers of patients with advanced NSCLC without the practical difficulties of biomarker testing.”

Peters concluded: “These exciting results pave the way for a new standard of care in advanced non-squamous NSCLC. The initial overall survival data looks encouraging, but we must wait for it to mature. We will also need to understand the impact of this combination in patients who have already received other immunotherapies. In the next year, other trials will report results in frontline treatment-naïve NSCLC patients using the combination of chemotherapy and immunotherapy or the combination of two immunotherapy drugs. The challenge will then be to judge which strategy is the best.”

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO Immuno Oncology Congress 2017

Official hashtag: #ESMOImmuno17

References and notes

1. Abstract LBA1_PR ‘Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150)‘ will be presented by Martin Reck during the Proffered Paper session ‘Combining immune checkpoint inhibitors and VEGF targeted therapies in cancer treatment’ on Thursday, 7 December, 18:15 to 19:15 (CET) in Room A. Annals of Oncology, Volume 28, 2017 Supplement 11.
2. PD-L1 expression was assessed on both tumour cells (TC) and tumour-infiltrating immune cells (IC); and patients were scored as TC 0, 1, 2, or 3 and IC 0, 1, 2, or 3 with an immunohistochemistry test.
3. Reck M, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.N Engl J Med. 2016; 375:1823–1833.
4. Langer CJ, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497–1508.

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LBA1_PR

Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMPOWER150)

M. Reck¹, M.A. Socinski², F. Cappuzzo³, F. Orlandi⁴, D. Stroyakovskii⁵, N. Nogami⁶, D. Rodríguez-Abreu⁷, D. Moro-Sibilot⁸, C.A. Thomas⁹, F. Barlesi¹⁰, G. Finley¹¹, C. Kelsch¹², A. Lee¹³, S. Coleman¹³, Y. Shen¹⁴, M. Kowanetz¹⁵, A. Lopez-Chavez¹³, A. Sandler¹³, R. Jotte^16 
1Thoracic Oncology, Lungen Clinic Grosshansdorf, Grosshansdorf, Germany, ²Thoracic Oncology Program, Florida Hospital Cancer Institute, Orlando, FL, USA, ³Oncology and Hematology Department, Azienda Unità Sanitaria Locale della Romagna, Ravenna, Italy, ⁴Medical Oncology Unit, Instituto Nacional del Torax, Santiago, Chile, ⁵Chemotherapy Department, Moscow City Oncology Hospital, Moscow, Russian Federation, ⁶Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan, ⁷Oncology, Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain, ⁸Thoracic Oncology, Centre Hospitalier Universitaire de Grenoble Alpes, Grenoble, France, ⁹Clinical Research, New England Cancer Specialists, Scarborough, ME, USA, ¹⁰Multidisciplinary Oncology & Therapeutic Innovations, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France, ¹¹Allegheny Cancer Center, Pittsburgh, PA, USA, ¹²Product Drug Safety, Oncology, Genentech, Inc., South San Francisco, CA, USA, ¹³Product Development Oncology, Genentech, Inc., South San Francisco, CA, USA, ¹⁴Biostatistics, Genentech, Inc., South San Francisco, CA, USA, ¹⁵Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA, ¹⁶Rocky Mountain Cancer Centers, Denver, CO, USA

Background: Atezolizumab (atezo; anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. Bev may further enhance atezo efficacy by inhibiting VEGF immunosuppression and promoting T-cell tumour infiltration. IMpower150 evaluates the addition of atezo to carboplatin (C) + paclitaxel (P) ± bevacizumab (bev) in chemo-naive patients (pts) with non-squamous (NSQ) mNSCLC.

Methods: 1202 pts received atezo 1200 mg + C AUC 6 + P 200 mg/m² (Arm A) or atezo + bev 15 mg/kg + C + P (Arm B) vs bev + C + P (Arm C) IV q3w for 4 or 6 cycles per investigator (INV) discretion, then maintenance atezo, atezo + bev or bev, respectively. Co-primary endpoints assessed at this data cutoff (15 Sep 2017; minimum follow up, 9.5 mo) were INV-assessed PFS in the ITT-WT (EGFR or ALK negative) population and in WT pts with expression of a tumour T-effector gene signature (Teff-WT; centrally assessed), and OS in the ITT-WT population, for the Arm B vs Arm C comparison. Due to pre-specified statistical testing hierarchy, Arm A vs Arm C has not been formally tested yet.

Results: 356 pts in Arm B and 336 pts in Arm C were enrolled in the ITT-WT. Median age was 63 y; 60% were previous smokers (both arms). 61% and 62% were male, and 39% and 43% had ECOG PS 0 in Arms B and C, respectively. The HRs for INV-assessed PFS in Arm B vs C were 0.62 (95% CI: 0.52, 0.74; P < 0.0001) in the ITT-WT and 0.51 (0.38, 0.68; P < 0.0001) in the Teff-WT populations. Median PFS in Arm B vs C was 8.3 mo vs 6.8 mo and 11.3 mo vs 6.8 mo in the ITT-WT and Teff-WT populations, respectively. PFS benefit was seen regardless of PD-L1 IHC status, including PD-L1–negative pts (TC0/IC0; HR, 0.77 [95% CI: 0.61, 0.99]). Landmark PFS and ORR are shown (Table). Arm B had a comparable safety profile to Arm C; treatment-related serious AEs were 25% vs 19%, respectively.

Conclusions: IMpower150 is the first Ph 3 study to show a statistically significant and clinically meaningful PFS benefit with atezo + bev + chemo vs bev + chemo in pts with 1L NSQ mNSCLC. 

Table: LBA1_PR IMpower150 Primary PFS Analysis, landmark PFS and ORR

Clinical trial identification: NCT02366143

Legal entity responsible for the study: F. Hoffmann La-Roche

Funding: F. Hoffmann La-Roche

Disclosure: M. Reck: Consulting/Advisory Role: Lilly, Roche, BI, BMS, MSD, AstraZeneca, Merck, Novartis, Pfizer, Celgene. Speakers’ Bureau: Roche, Lilly, Pfizer, BI, AstraZeneca, MSD, BMS, Merck, Novartis, Pfizer, Celgene.
M.A. Socinski: Honoraria: Genentech. Speakers Bureau: Genentech. Research Funding: Genentech.
F. Cappuzzo: Participation in advisory boards for Roche, AZ, BMS, Takeda, MSD, Lilly, Pfizer.
F. Orlandi: Research grants from AstraZeneca, MSD, Genetech-Roche. Advisory tasks for AstraZeneca, Roche, Boehringer Ingelheim, Pfizer.
N. Nogami: Honoraria: Meiji Seika Pharma Co., Ltd., AstraZeneca, Pfizer Inc., Bristol‐Myers Squibb, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin, Taiho Phamaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd, Eli Lilly Japan, Boehringer Ingelheim.
D. Rodríguez-Abreu: Honoraria for lectures and advisory board from Bristol- Myers-Squibb, Merck Sharp & Dohme, F. Hoffmann-La Roche.
D. Moro-Sibilot: Advisory boards for Roche, MSD, Pfizer, Novartis, BMS, AstraZeneca, Lilly.
F. Barlesi: Honarium from Genentech & Roche. G. Finley: Promotional speaking on behalf of Bristol Myers, Boehringer Ingelheim, Astellas Medivation, Merck. No compensation or funding from Roche/Genentech aside from general support required to conduct clinical research. Full time employee of a nonprofit health care provider, Allegheny Health Network.
C. Kelsch, A. Lee, S. Coleman, Y. Shen, A. Lopez-Chavez: Genentech employee with Roche stock.
M. Kowanetz: Genentech employee with Roche stock. Patent with Genentech.
A. Sandler: Genentech/Roche employee with Roche stock.
All other authors have declared no conflicts of interest.