Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)

Author(s): Sehhoon Park, MD, PhD¹; Tae Min Kim, MD, PhD²; Ji-Youn Han, MD, PhD³; Gyeong-Won Lee, MD, PhD⁴; Byoung Yong Shim, MD, PhD⁵; Yun-Gyoo Lee, MD, PhD⁶; Sang-We Kim, MD, PhD⁷; Il Hwan Kim, MD, PhD⁸; Suee Lee, MD, PhD⁹; Yu Jung Kim, MD, PhD¹⁰; Ji Hyun Park, MD, PhD¹¹; Sang-Gon Park, MD, PhD¹²; Ki Hyeong Lee, MD, PhD¹³; Eun Joo Kang, MD, PhD¹⁴; Ju Won Kim, MD, PhD¹⁵; Seong-Hoon Shin, MD, PhD¹⁶; Chan-Young Ock, MD, PhD¹⁷; Byung-Ho Nam, PhD¹⁸; Jaebong Lee, MS¹⁹; Hyun-Ae Jung, MD, PhD¹; Jong-Mu Sun, MD, PhD¹; Se-Hoon Lee, MD, PhD¹; Jin Seok Ahn, MD, PhD¹; Myung-Ju Ahn, MD, PhD¹

Source: https://doi.org/10.1200/JCO.23.01891

Dr. Maen Hussein's Thoughts

Adding VEGF inhibitor to PD-1 blocker in addition to chemotherapy is better than a chemotherapy-alone regimen as a second-line therapy after TKI failure. This is true especially in patients with tumors with high PD-L1 expression, with not much besides chemotherapy as second-line therapy for those patients (or other clinical trials) that may be a better option that includes immunotherapy.

PURPOSE

In the treatment of non–small-cell lung cancer (NSCLC) with a driver mutation, the role of anti–PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy.

MATERIALS AND METHODS

We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS).

RESULTS

A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm.

CONCLUSION

To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti–PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.

Author Affiliations

¹Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; ²Department of Internal Medicine, Seoul National University Hospital, Seoul National University Cancer Research Institute, Seoul, Korea; ³Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si Gyeonggi-do, Korea; ⁴Divisions of Hematology and Oncology, Department of Internal Medicine, Institute of Health Science, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Korea; ⁵Division of Medical Oncology, Department of Internal Medicine, St Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea; ⁶Division of Hematology & Medical Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; ⁷Division of Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; ⁸Department of Internal Medicine, Division of Hemato-Oncology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea; ⁹Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea; ¹⁰Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; ¹¹Department of Hemato-oncololgy, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea; ¹²Department of Internal Medicine, Hemato-oncology, Chosun University Hospital, Gwangju, Korea; ¹³Division of Hematology-Oncology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea; ¹⁴Division of Hematology-Oncology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea; ¹⁵Divisions of Hematology-Oncology, Department of Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea; ¹⁶Division of Hemato-Oncology, Department of Internal Medicine, Kosin University Gospel Hospital, Busan, Korea; ¹⁷Lunit, Seoul, Korea; ¹⁸Herings, Seoul, Korea; ¹⁹Seoul CRO, Seoul, Korea

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.