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 Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The phase 3 MARIPOSA trial compared amivantamab–lazertinib (Ami-Laz) to osimertinib (Osi) in untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC), showing a significant overall survival (OS) benefit for Ami-Laz (3-yr OS was 60% vs 51%). Median OS was not reached for Ami-Laz vs 36.7 months for Osi, with a projected >12-month median OS advantage. Ami-Laz also improved time to symptomatic progression (43.6 vs 29.3 months) and showed durable intracranial control, though grade ≥3 adverse events (AEs) were higher (80% vs 52%), notably skin, venous thromboembolism (VTE), and infusion reactions. In short, Ami-Laz is emerging as a new standard for first-line EGFRm NSCLC, but we’ll need to be proactive about managing its toxicity profile in clinic and whether this is superior or equivalent to Osi + chemo is currently unclear.

Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial

Adagrasib demonstrated a median progression-free survival (PFS) of 5.5 months compared to 3.8 months with docetaxel in patients with KRAS G12C-mutated tumors. Treatment-related adverse events occurred in 47% of patients receiving Adagrasib and 46% in the docetaxel group. In my experience, Adagrasib is also more tolerable, making it a favorable option for this patient population.

Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer

There was a 28% reduction in mortality. Patients who achieved a complete response (CR) or clearance of circulating tumor DNA (ctDNA) also experienced better outcomes.