The management of lung cancer and other thoracic malignancies has evolved significantly over the past decade. Thanks to many scientific advancements in the field, new therapeutic options, and improvements in screening and early detection, more patients are being cured, and many others are living longer and better lives. It is an era of hope for patients with lung cancer—but we still have a long way to go.
Guest Editor
Rami Manochakian, MD
Dr. Manochakian is Associate Professor of Medicine; Program Director, Hematology/Oncology Fellowship; and Vice Chair of Education in the Division of Hematology/Oncology at Mayo Clinic Florida. He specializes in the treatment of patients with thoracic malignancies including lung cancer, mesothelioma, and thymic tumors and is a leader in medical education.
The International Association for the Study of Lung Cancer (IASLC) is a global multidisciplinary organization dedicated to the eradication of lung cancer and other thoracic malignancies. Among the many excellent conferences IASLC organizes is the annual World Conference on Lung Cancer (WCLC), which is the largest international gathering in the field of lung cancer and thoracic oncology, during which the latest cutting-edge research and results of practice-changing clinical trials are presented. This year’s conference was held in Singapore on September 9 to 12.
In this supplement to The ASCO Post, we highlight some of the major presentations, data, and updates presented at the 2023 WCLC, including important updates on antibody-drug conjugates, targeted therapies, and immunotherapy for patients with advanced cancer; nonsystemic (local) therapies for early-stage cancers; and a major new national lung cancer screening program in Taiwan.
Novel Antibody-Drug Conjugates Move Forward
Antibody-drug conjugates are among the latest promising anticancer drugs. They typically comprise a monoclonal antibody covalently attached to a cytotoxic drug via a chemical linker and have shown activity in multiple cancers including lung cancer. They combine both the advantages of highly specific targeting ability and highly potent killing effect.1
Helena Yu, MD, of Memorial Sloan Kettering Cancer Center, and colleagues presented the results of HERTHENA-Lung01, a phase II study of patritumab deruxtecan (HER3-DXd) in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) who experienced disease progression on EGFR tyrosine kinase inhibitor therapy and platinum-based chemotherapy—a patient population with limited treatment options. HER3-DXd is an antibody-drug conjugate comprising a fully human anti-HER3 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload.
The authors reported clinical meaningful and durable efficacy of HER3-DXd. At a dose of 5.6 mg/kg, the overall response rate was 29.8%, the median duration of response was 6.4 months, and the disease control rate was 73.8%. Median progression free survival was 5.5 months, and median overall survival was 11.9 months. The safety profile of HER3-DXd was consistent with previous reports, with a treatment discontinuation rate of 7%.2 The results of the study were published in the Journal of Clinical Oncology in conjunction with the presentation at the 2023 WCLC.3
Another important study that was presented was TROPION-Lung04, a phase Ib open-label, dose-escalation/confirmation and -expansion study investigating datopotamab deruxtecan (Dato-DXd), which is an antibody-drug conjugate that consists of a humanized anti–TROP-2 IgG1 monoclonal antibody linked to a highly potent topoisomerase I inhibitor payload, in combination with different immunotherapy agents with or without chemotherapy (carboplatin) across 11 cohorts. Saiama N. Waqar, MBBS, MSCI, of the Washington University School of Medicine in St. Louis, and colleagues presented an interim analysis of preliminary data from two specific cohorts (2 and 4). In cohort 2, in which patients received Dato-DXd at a dose of 6 mg/kg plus the anti–PD-L1 checkpoint inhibitor durvalumab every 3 weeks, the overall response rate was 50%, and the disease control rate was 92.9%. In cohort 4, in which patients received Dato-DXd at a dose of 6 mg/kg plus durvalumab and carboplatin with an AUC of 5 every 3 weeks, the overall response rate was 76.9%, and the disease control rate was 92.3%. No new safety signals were observed in those two cohorts.4
Antibody-drug conjugates are being studied in small cell lung cancer (SCLC), as well. Melissa L. Johnson, MD, of the Sarah Cannon Research Institute, Nashville, and colleagues presented a subgroup analysis of the DS-7300 study, a phase I/II study of ifinatamab deruxtecan (I-DXd), which is an antibody-drug conjugate that consists of a humanized anti–B7-H3 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload. The authors reported robust and durable efficacy in patients with heavily pretreated SCLC, with an overall response rate of 52%, median duration of response of 5.9 months, median progression-free survival of 5.6 months, and median overall survival of 12.2 months. No new safety signals were observed, and the safety profile was consistent with previous reports.5
Novel Targeted Therapies and Combination Therapies
Targeted therapies have revolutionized the treatment of patients with lung cancer, with a growing number of such agents approved by the U.S. Food and Drug Administration (FDA) as well as other regulatory agencies in the world. Those drugs have shown efficacy and are considered standard-of-care treatment for patients with lung cancer with a particular relevant genomic mutation or alteration. Many other new targeted therapeutic agents and combinations are being actively studied—whether to overcome developed resistance to some of the already approved drugs or to target some newly discovered mutations that are driving lung cancer growth.6
Pasi Jänne, MD, PhD, of the Dana-Farber Cancer Institute, and colleagues reported the results of FLAURA2, a phase III randomized clinical trial of osimertinib with and without platinum-based chemotherapy as first-line treatment in patients with EGFR-mutated advanced NSCLC. The study demonstrated a clinically and statistically significant improvement in progression-free survival (assessed by investigator), the primary endpoint, with a hazard ratio (HR) of 0.62 (95% confidence interval [CI] = 0.40–0.79, P < .0001) for patients who received the combination of osimertinib and chemotherapy compared with osimertinib alone. Median progression-free survival was 25.5 months with osimertinib plus chemotherapy vs 16.7 months with osimertinib alone. The benefit was consistent in all subgroups. Of note, patients with brain metastases had more benefits (HR = 0.47) compared with those without brain metastases (HR = 0.75). As expected, the improvement in progression-free survival has come at the cost of more toxicity. Grade ≥ 3 adverse events were reported in 64% of patients given osimertinib plus chemotherapy vs 27% of patients given osimertinib alone. With immature overall survival data at the time of this analysis, the main question remains whether this combination treatment will be worth the increased toxicity.7
In another presentation, Runxiang Yang, MD, of the Yunnan Cancer Hospital in China, and colleagues presented the results of the INSPIRE trial, a randomized phase III study of first-line iruplinalkib vs crizotinib in patients with advanced ALK-positive NSCLC. Iruplinalkib is another novel, potent ALK tyrosine kinase inhibitor with preclinical and clinical activity against wild-type ALK and ALK resistance mutations. Iruplinalkib was approved in June 2023 in China for the treatment of ALK-positive, crizotinib-resistant or -intolerant advanced NSCLC. The authors reported clinically and statistically significant improvement in progression-free survival, with a HR of 0.344 (95% CI = 0.226–0.523, P < .0001) for patients who received iruplinalkib compared with those who received crizotinib. Median progression-free survival was 27.7 months with iruplinalkib vs 14.62 months with crizotinib. Although response rates were similar in the two arms (93% vs 89%), the intracranial response rate was significantly better with iruplinalkib (90% vs 60%).8 Iruplinalkib may join alectinib, lorlatinib, and brigatinib as a first-line treatment option for advanced ALK-positive NSCLC.
Immunotherapy Makes Headway in SCLC
Immune checkpoint inhibitors have become a major standard-of-care backbone treatment in patients with NSCLC, especially those whose cancer that does not harbor an actionable mutation. On the other hand, immunotherapy has shown only mild benefit in patients with SCLC. Ying Cheng, MD, of Jilin Cancer Hospital in China, and colleagues presented impressive results of ETER701, a phase III randomized double-blind trial of first-line benmelstobart, a PD-L1 checkpoint inhibitor, in combination with the antiangiogenic VEGFR inhibitor anlotinib and chemotherapy vs placebo plus chemotherapy in patients with extensive-stage small cell lung cancer. The authors reported a significant improvement in progression-free survival in favor of benmelstobart plus anlotinib plus chemotherapy, with a HR of 0.32 (95% CI = 0.26–0.41, P < .0001. Median progression-free survival was 6.9 vs 4.2 months. In addition, there was a significant improvement in overall survival (HR = 0.61, 95% CI = 0.46–0.79, P = .0002. Median overall survival was 19.3 vs 11.9 months. The toxicity profile was consistent with known adverse events of checkpoints inhibitors and antivascular agents and reported by authors as manageable.9 It is noteworthy to mention that the comparable control arm in this study did not include immunotherapy in combination with chemotherapy, which is considered standard-of-care first-line treatment in extensive-stage SCLC (although has minimal benefit). Nevertheless, the study has shown an unprecedented historical improvement in overall survival in this patient population.
Landmark Trial in Mesothelioma
Eric Lim, MD, of the Royal Brompton Hospital in London, and colleagues presented the results of the MARS-2 trial, a multicenter randomized trial comparing extended pleurectomy decortication plus chemotherapy (platinum and pemetrexed) vs chemotherapy alone (no radical surgery) for patients with resectable pleural mesothelioma.
Authors reported significantly worse overall survival, the primary endpoint, in patients randomly assigned to surgery and chemotherapy vs chemotherapy alone. In the first 42 months, the HR was 1.28 (95% CI = 1.02–1.60, P = .032), indicating a 28% increase in the risk of death in the surgery group with no significant difference in survival after 42 months (HR = 0.48, 95% CI = 0.18–1.29, P = .15). The study also showed worse quality of life and additional financial costs with surgery.10 This unprecedented and impressive trial, which was deemed by many to be a practice-changing landmark trial, is the first randomized trial ever to show harm and worse outcome with surgery in patients with early-stage mesothelioma.
DISCLOSURE: Dr. Manochakian has served as a consultant or advisor for Alpha 2, AstraZeneca, Cardinal Health, Daiichi Sankyo, Inc., Guardant Health, Janssen, Novocure, OncoHost, Takeda, and Turning Point Therapeutics.
REFERENCES
1. Fu Z, Li S, Han, S et al: Antibody drug conjugate: The ‘biological missile’ for targeted cancer therapy. Sig Transduct Target Ther 7:93, 2022.
2. Yu HA, Goto Y, Hayashi H, et al: Patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC following EGFR TKI and platinum-based chemotherapy: HERTHENA-Lung01. 2023 World Conference on Lung Cancer. Abstract OA05.03. Presented September 10, 2023.
3. Yu HA, Goto Y, Hayashi H, et al: HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor-mutated non-small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. September 10, 2023 (early release online).
4. Papadopoulos KP, Bruno D, Kitazono S, et al: Datopotamab deruxtecan + durvalumab ± carboplatin in advanced/mNSCLC: Initial results from phase Ib TROPION-Lung04. 2023 World Conference on Lung Cancer. Abstract OA05.06. Presented September 10, 2023.
5. Johnson M, Awad M, Koyama T, et al: Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with refractory SCLC: A subgroup analysis of a phase 1/2 study. 2023 World Conference on Lung Cancer. Abstract OA05.05. Presented September 10, 2023.
6. Li S, de Camargo Correia GS, Wang J, et al: Emerging targeted therapies in advanced non-small-cell lung cancer. Cancers (Basel) 15:2899, 2023.
7. Jänne P, Planchard D, Cheng, et al: Osimertinib with/without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). 2023 World Conference on Lung Cancer. Abstract PL03.13. Presented September 11, 2023.
8. Shi Y, Chen J, Yang R, et al: A randomized, phase 3 study of iruplinalkib (WX-0593) vs crizotinib in locally advanced or metastatic ALK+ non-small cell lung cancer (NSCLC). 2023 World Conference on Lung Cancer. Abstract OA03.05. Presented September 10, 2023.
9. Cheng Y, Yang R, Chen J, et al: Benmelstobart with anlotinib plus chemotherapy as first-line therapy for ES-SCLC: A randomized, double-blind, phase III trial. 2023 World Conference on Lung Cancer. Abstract OA01.03. Presented September 10, 2023.
10. Lim E, Waller D, Lau K, et al: MARS-2: A multicentre randomised trial comparing (extended) pleurectomy decortication versus no radical surgery for mesothelioma. 2023 World Conference on Lung Cancer. Abstract PL03.10. Presented September 11, 2023.
