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

Neoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer

Results showed the median event-free survival (EFS) was 54.8 months with nivolumab plus ipilimumab vs 20.9 months with chemotherapy. Three-year EFS rates were 56% vs 44%. Three-year overall survival (OS) rates were 73% vs 61% pathologic complete response rates were 20.4% vs 4.6%. This was three cycles of nivolumab and one dose of ipilimumab vs chemotherapy.

Datopotamab Deruxtecan in Advanced or Metastatic Non–Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study

Dato showed a confirmed overall response rate (ORR) of 42.7% with a complete response (CR) of 4.3%. The median duration of response was 7.0 months, with a disease control rate of 86.3% and a median overall survival (OS) of 15.6 months. This could be another option for EGFR mutant patients who had multiple lines of therapy.

A Multicenter Open-Label Randomized Phase II Study of Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor–Naïve EGFR-Mutant Metastatic Non–Small Cell Lung Cancer (RAMOSE trial)

Improved progression-free survival (PFS), now we have osimertinib and ramucirumab, amivantamab and Lazertinib (PFS 24.8 vs 23 months but NOT head to head).

Thoracic Radiotherapy Improves the Survival in Patients With EGFR-Mutated Oligo-Organ Metastatic Non–Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors: A Multicenter, Randomized, Controlled, Phase III Trial

Patients were treated with thoracic and extrathoracic radiation to oligometastatic sites and it seems to help with improving survival, something to consider especially with SBRT now. Do our radiation oncologists have additional input?

De-Escalation Strategies With Immune Checkpoint Blockers in Non–Small Cell Lung Cancer: Do We Already Have Enough Evidence?

Very thought-provoking review of immune checkpoint blockade therapy and strategies to possibly de-escalate therapy in the future. Could we reduce doses, extend dose intervals or diminish the duration of treatment? There is some (low-level) data supporting these ideas. However, ongoing prospective studies, mostly being done in countries with nationalized systems, will be informative on these topics. Expect interest in this topic to increase in a couple of years.