First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study

Author(s): Prof Siow Ming Lee, FRCP¹;Prof Christian Schulz, MD²;Kumar Prabhash, MD³; Prof Dariusz Kowalski, MD, PhD⁴;Aleksandra Szczesna, MD, PhD⁵;Prof Baohui Han, MD⁶;Achim Rittmeyer, MD⁷;Toby Talbot, MBBS⁸;David Vicente, MD⁹;Prof Raffaele Califano, MD¹⁰;Diego Cortinovis, MD¹¹;Anh Tuan Le, MD, PhD¹²;Dingzhi Huang, MD¹³;Prof Geoffrey Liu, MD¹⁴;Federico Cappuzzo, MD¹⁵;Jessica Reyes Contreras, MD¹⁶;Prof Martin Reck, MD, PhD¹⁷;Ramon Palmero, MD¹⁸;Milena Perez Mak, PhD¹⁹;Youyou Hu, MSc²⁰;Stefanie Morris, PhD²⁰;Elen Höglander, PhD²⁰;Mary Connors, BSN²¹;Alice M Biggane, PhD^20,22;Hans Kristian Vollan, MD, PhD²⁰;Prof Solange Peters, MD PhD²³;

Source: DOI:https://doi.org/10.1016/S0140-6736(23)00774-2

Dr. Maen Hussein's Thoughts

Patients with poor performance status do better on atezolizumab monotherapy vs. single agent chemotherapy.

BACKGROUND

Despite immunotherapy advancements for patients with advanced or metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were limited to patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 and a median age of 65 years or younger. We aimed to compare the efficacy and safety of first-line atezolizumab monotherapy with single-agent chemotherapy in patients ineligible for platinum-based chemotherapy.

METHODS

This trial was a phase 3, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0–1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 by permuted-block randomisation (block size of six) to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly cycles. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy. This trial is registered with ClinicalTrials.gov, NCT03191786.

FINDINGS

Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled and randomised to receive atezolizumab (n=302) or chemotherapy (n=151). Atezolizumab improved overall survival compared with chemotherapy (median overall survival 10·3 months [95% CI 9·4–11·9] vs 9·2 months [5·9–11·2]; stratified hazard ratio 0·78 [0·63–0·97], p=0·028), with a 2-year survival rate of 24% (95% CI 19·3–29·4) with atezolizumab compared with 12% (6·7–18·0) with chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related quality-of-life functioning scales and symptoms and fewer grade 3–4 treatment-related adverse events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three [1%] vs four [3%]).

INTERPRETATION

First-line treatment with atezolizumab monotherapy was associated with improved overall survival, a doubling of the 2-year survival rate, maintenance of quality of life, and a favourable safety profile compared with single-agent chemotherapy. These data support atezolizumab monotherapy as a potential first-line treatment option for patients with advanced NSCLC who are ineligible for platinum-based chemotherapy.

FUNDING

F Hoffmann-La Roche and Genentech Inc, a member of the Roche group.

Author Affiliations

¹Department of Oncology, University College London Hospitals NHS Foundation Trust, CRUK Lung Cancer Centre of Excellence and UCL Cancer Institute, London, UK;²Bereich Pneumologie Klinik und Poliklinik für Innere Medizin II, University Hospital Regensburg, Regensburg, Germany;³Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India;⁴Department of Lung Cancer and Thoracic Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland;⁵Department of Lung Diseases, Mazowieckie Centrum Leczenia Chorób Płuc i Gruźlicy, Otwock, Poland;⁶Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China;⁷Department of Thoracic Oncology, LKI Lungenfachklinik Immenhausen, Immenhausen, Germany;⁸Department of Oncology, Royal Cornwall Hospitals NHS Trust, Truro, UK;⁹Medical Oncology Department, Hospital Universitario Virgen Macarena, Seville, Spain;¹⁰Department of Medical Oncology, The Christie NHS Foundation Trust and Division of Cancer Sciences, University of Manchester, Manchester, UK;¹¹Department of Medical Oncology, AAST H S Gerardo Monza, Monza, Italy;¹²Cho Ray Cancer Centre, Cho Ray Hospital, Ho Chi Minh City, Viet Nam;¹³Department of Thoracic Oncology, National Clinical Research Centre for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China;¹⁴Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada;¹⁵Department of Oncology, National Cancer Institute IRCCS Regina Elena, Rome, Italy;¹⁶Oncologico Potosino, San Luis Potosí, Mexico;¹⁷Department of Thoracic Oncology, Lungen Clinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Grosshansdorf, Germany;¹⁸Department of Medical Oncology, Catalan Institute of Oncology, Hospital Duran i Reynals, L’Hospitalet, Barcelona, Spain;¹⁹Department of Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil;²⁰F Hoffmann-La Roche, Basel, Switzerland;²¹Genentech, San Francisco, CA, USA;²²Pfizer, Kent, UK;²³Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland

Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non–Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial

Preliminary results of DESTINY-Lung02 show strong efficacy with trastuzumab deruxtecan (T-DXd). Overall response rate (ORR) was about 50%, with duration of response of 16.8 months. This is now FDA-approved and is an available therapy for patients with ERBB2 mutations after 1st line platinum-based chemo +/- immunotherapy. This is preferred over traditional trastuzumab or afatinib. Interestingly, some responses were seen in the ERBB2-negative patients who had over-expression by IHC. Please continue to sequence your patients and enroll in targeted therapy trials.

Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions

Phase III study of amivantamab + chemotherapy vs. chemotherapy alone as first-line therapy in patients with Exon-20 EGFR mutations. While the results of this study are impressive, one wonders what the results would be if the comparator arm were a targeted option. This is not yet reflected in the NCCN guidelines but likely will be added.

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC

Osimertinib with chemotherapy improved the chance of being alive at two years compared to targeted therapy alone at 57 vs 41%. Further analysis of FLAURA2 and new studies will surely look to identify which patients benefit most from the combination of targeted therapy and chemotherapy. For young or healthy patients, this is an acceptable first line option. This is not yet reflected on NCCN but is likely to be added soon.

Perioperative Durvalumab for Resectable Non–Small-Cell Lung Cancer

Adding Durvalumab to chemotherapy preop improved CR (17.2 vs4.3%) regardless of PLD -1 status. We already have approval for neoadjuvant chemotherapy and immunotherapy combinations in resectable lung cancer, so not sure if this regimen will be favored.
The unique thinkg about this one is that durva was also given post op ( not in the opidvo trial) but you can give pembrolizumab as adjuvant in those pts who had opdivo preop, and now pembrolizumab just got its approval in the neoadjuvant setting (last month) in which nit is given post op too.

Phase II Trial of Atezolizumab Combined With Carboplatin and Pemetrexed for Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer With Untreated Brain Metastases (Atezo-Brain, GECP17/05)

A nicely done Spanish study showing that in metastatic NSCLC, asymptomatic patients with brain metastases can have radiation therapy deferred.
Starting with systemic therapy was found to be reasonable and effective, validating a common practice. Patients were treated with atezolizumab + carboplatin + pemetrexed + steroids, and any number of brain mets was allowed as long as they had at least one 10mm in size or greater. This study excluded patients harboring EGFR/ALK driver mutations.

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