Over the past few years, we have seen rapid and dramatic transformation in the therapeutic landscape of non–small cell lung cancer (NSCLC). We have had multiple new targeted therapies for newer targets (previously undruggable targets) and better diagnostic strategies to workup patients to realize the potential of personalized medicine.
The International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC) meetings uniquely focus on advances in the multidisciplinary management of lung cancer globally.
GUEST EDITOR
Vamsidhar Velcheti, MD, FACP, FCCP
Dr. Velcheti is Professor, Department of Medicine, at NYU Grossman School of Medicine and Director, Thoracic Medical Oncology, at NYU Langone’s Perlmutter Cancer Center. His research focuses on the development of novel immunotherapies and biomarker discovery.
The 2022 WCLC in Vienna highlighted the progress made in lung cancer management from screening to treatment of metastatic lung cancer. There were three major themes from the meeting: (1) advances in lung cancer screening and smoking cessation; (2) incorporation of immunotherapy into the perioperative management of early-stage and locally advanced NSCLC; and (3) continued advances and challenges with systemic therapy for patients with metastatic NSCLC.
Advances in Lung Cancer Screening and Smoking Cessation
Koen de Nijs, a PhD candidate at Erasmus University Medical Center, and colleagues presented updates from the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) consortium trial evaluating the role of low-dose computed tomography (CT) in smokers with a high risk for lung cancer.1 In this NELSON study, compared with the National Lung Screening Trial (NLST), the sensitivity of detection of lung cancer was estimated to be higher across all stages. The differences in sensitivity were as follows: stage IA, 73% vs 57% in the NLST; stage IB, 90% vs 64% in the NLST; and stage II, 75% vs 39% in the NLST. The optimization of nodule management approaches and volumetric nodule assessments appears to be important in lung cancer screening to maximize the efficiency of lung cancer screening and avoiding unnecessary procedures.
Alexandra L. Potter, a researcher at Massachusetts General Hospital and President of the American Lung Cancer Screening Initiative, and colleagues focused on data from the NLST study.2 The incidence of second primary lung cancer was approximately 4% among the entire cohort of patients with lung cancer and was as high as 8% among patients undergoing surgery for stage IA disease. Ms. Potter’s study highlights the need for continued monitoring of patients after completion of lung cancer surgery in this high-risk population. In another study,3 Ms. Potter and colleagues focused on the U.S. Cancer Statistics database and National Cancer Database (NCDB); younger patients (< age 50) with lung cancer were significantly more likely than older patients to be diagnosed at advanced stages of lung cancer. These findings highlight the need for incorporating more effective early-detection strategies for lung cancer screening in younger patients.
In another interesting study presented at the 2022 WCLC, Rachael L. Murray, PhD, and colleagues presented updates from the Yorkshire Enhanced Stop Smoking (YESS) trial.4 The study evaluated the effectiveness of a personalized smoking cessation approach on an opt-out basis to all eligible smokers at a lung health clinic for low-dose CT screening. The YESS study was a randomized controlled trial, with the interventional arm comprising an enhanced, personalized smoking cessation program. The personalized program included visual cues of CT images of the participants’ heart and lungs, highlighted emphysema or coronary artery calcification, and was interlaced with behavior modification support by a trained smoking cessation counselor. The other treatment arm included standard smoking cessation approaches. The study showed 7-day tobacco abstinence rates of 33.6% with the personalized intervention vs 30.3% with standard approaches 3 months after the initial intervention.
Immunotherapy in the Perioperative Management of Early-Stage and Locally Advanced NSCLC
In previous updates from the IMpower010 study, atezolizumab demonstrated a statistically significant disease-free survival benefit with adjuvant atezolizumab compared with best supportive care in patients with resected NSCLC after platinum-based chemotherapy. Atezolizumab was subsequently approved by the U.S. Food and Drug Administration (FDA) for adjuvant therapy following adjuvant chemotherapy for patients with PD-L1–positive (tumor cells ≥ 1%) early-stage NSCLC. The much-anticipated key secondary overall survival endpoint was presented at the 2022 WCLC.5Enriqueta Felip, PhD, Head of the Thoracic Cancer Unit, Oncology Department, Vall d’Hebron University Hospital, Barcelona, and colleagues demonstrated a trend toward improved overall survival among patients with PD-L1–positive stage II–IIIA NSCLC, further confirming the clinical benefit of atezolizumab in the postoperative setting. At 5 years, the overall survival rate was 84.8% for patients with stage II–IIIA disease and PD-L1 expression of at least 50% vs 67.5% in the control arm.
In another important trial update, Mariano Provencio, MD, PhD, of the Puerta de Hierro University Hospital and the Autonomous University of Madrid, and colleagues presented updates from the NADIM II trial.6 This trial evaluated neoadjuvant chemoimmunotherapy in patients with resectable clinical stage IIIA NSCLC. Patients were randomly assigned to receive nivolumab and paclitaxel with carboplatin for three cycles every 21 days as neoadjuvant treatment followed by surgery and postoperatively received adjuvant nivolumab (480 mg every 4 weeks) for 6 months or paclitaxel with carboplatin for three cycles every 21 days followed by surgery.
The authors reported that nivolumab in combination with platinum-based chemotherapy in patients with resectable stage IIIA NSCLC improved overall survival at 24 months (85.3% vs 64.8%; hazard ratio = 0.37; 95% confidence interval [CI] = 0.14–0.93; P =.003). In addition, in the PD-L1–positive (≥ 1%) patients, there was a significant improvement in progression-free survival (HR = 0.26; 95% CI = 0.08–0.77; P = .015), and the pathologic complete response rate was 36.2% in the experimental arm vs 6.8% in the control arm (P = .007). Neoadjuvant chemoimmunotherapy with nivolumab and platinum-based chemotherapy was approved by the FDA based on the results of the CheckMate 816 data, and these findings from the NADIM II trial further confirm the clinical benefit of neoadjuvant chemoimmunotherapy for resectable NSCLC.
The key question though is the use of immunotherapy in the postoperative setting in patients treated with the “CheckMate 816 regimen,” which did not allow for postoperative nivolumab. For patients with early-stage surgically operable NSCLC who have tumors expressing PD-L1, both neoadjuvant (CheckMate 816 regimen) and adjuvant treatments (IMpower010 regimen) are standard, FDA-approved therapeutic options at this time. However, ongoing trials incorporating both neoadjuvant and adjuvant immunotherapies (KEYNOTE-671, CheckMate 77T, and AEGEAN) may potentially change perioperative treatment strategies for patients with surgically operable NSCLC.
Continued Advances and Challenges With Systemic Therapy for Patients With Metastatic NSCLC
Solange Peters, MD, PhD, of the University Hospital of Lausanne, Switzerland, and colleagues presented an important exploratory subset analysis of KRAS, STK11, and KEAP1 mutation status from the phase III POSEIDON trial.7 In previous updates from the POSEIDON trial in patients with metastatic NSCLC, front-line systemic treatment with tremelimumab, durvalumab, and chemotherapy demonstrated statistically significant improvements in both progression-free survival and overall survival vs chemotherapy alone. Several previously published preclinical and clinical retrospective studies demonstrated that patients with mutations in STK11 and KEAP1 have poor outcomes and are relatively refractory to both chemotherapy and immunotherapy.8,9 These mutations often co-occur with KRAS mutations.
In the exploratory analysis of the POSEIDON trial,7 Dr. Peters and colleagues reported clinical outcomes based on the KRAS, STK11, and KEAP1 mutational status. They reported that for the patients with KRAS mutations, the likelihood of disease progression and death was reduced by 43% and 44%, respectively, with tremelimumab, durvalumab, and chemotherapy. The objective response rate was 55%, and the median duration of response was not reached vs 21.2% and 5.4 months with chemotherapy alone. In patients with STK11 mutation, tremelimumab, durvalumab, and chemotherapy reduced the risk of disease progression and death by 53% and 44%, respectively. It also induced a higher objective response rate (45.2% vs 27.3%) and a longer median duration of response (13.6 months vs 3.3 months) compared with chemotherapy alone. Though these results are exploratory in nature, these findings are suggestive of a potential benefit from combination immunotherapy with a CTLA-4 agent for patients with mutations in STK11 and KEAP1. Prospective trials to evaluate this combination in this molecularly defined group of patients with immunotherapy-resistant disease would be needed.
In another important update from the CodeBreaK 100/101 study,10 Bob T. Li, MD, PhD, MPH, of Memorial Sloan Kettering, and colleagues presented the data from the dose-exploration phase Ib trial of safety and efficacy of sotorasib with either pembrolizumab or atezolizumab anti–PD-1/PD-L1 immunotherapy. In the study, the combination of sotorasib with pembrolizumab or atezolizumab led to a significantly higher incidence of grade 3 or 4 treatment-related adverse events, primarily liver enzyme elevations. In patients receiving concurrent pembrolizumab and sotorasib, grade 3 or 4 hepatotoxicity across dose levels occurred at a rate of 80% in the 120-mg group (n = 5), 75% in the 360-mg group (n = 8), 100% in the 720-mg group (n = 2), and 75% in the 960-mg group (n = 4). This study has significant implications on the strategy to use sotorasib and perhaps other KRAS G12C inhibitors in combination with immunotherapy, particularly in the front-line setting.
DISCLOSURE: Dr. Velcheti has served as a consultant or advisor to Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, EMD Serono, Foundation Medicine, GlaxoSmithKline, Lilly, Merck, and Novartis; has received Research Funding from Alkermes, Altor BioScience, Atreca, Bristol Myers Squibb, Eisai, Genentech, Genoptix, GlaxoSmithKline, Heat Biologics, Leap Therapeutics, Merck, NantOmics, OncoPlex Diagnostics, RSIP Vision, and Trovagene; and has received honoraria from ITeos Therapeutics.
REFERENCES
1. de Nijs K, ten Haaf K, van der Aalst CM, et al: A comparison of stage- and histology-specific CT sensitivity in the NELSON trial and the NLST. 2022 World Conference on Lung Cancer. Abstract OA05.04. Presented August 7, 2022.
2. Potter AL, Pan M, Mathey-Andrews C, et al: Incidence, timing, and survival of second primary lung cancer in patients in the National Lung Screening Trial. 2022 World Conference on Lung Cancer. Abstract OA05.03. Presented August 7, 2022.
3. Potter AL, Senthil S, Mansur A, et al: Early diagnosis of lung cancer among younger vs. older adults: Widening disparities in the era of lung cancer screening. 2022 World Conference on Lung Cancer. Abstract OA05.06. Presented August 7, 2022.
4. Murray RL, Brain K, Britton J, et al: Personalised smoking cessation support in a lung cancer screening programme: The Yorkshire Enhanced Stop Smoking Study (YESS). 2022 World Conference on Lung Cancer. Abstract PL03.03. Presented August 8, 2022.
5. Wakelee H, Altorki NK, Vallieres E, et al: IMpower010: Overall survival interim analysis of a phase III study of atezolizumab vs best supportive care in resected NSCLC. 2022 World Conference on Lung Cancer. Abstract PL03.09. Presented August 8, 2022.
6. Serna R, Nadal E, Larriba JLG, et al: Pre-treatment ctDNA levels significantly predicts of OS and PFS in NADIM II trial. 2022 World Conference on Lung Cancer. Abstract MA06.03. Presented August 8, 2022.
7. Peters S, Cho BC, Luft A, et al: Association between KRAS/STK11/KEAP1 mutations and outcomes in POSEIDON: Durvalumab ± tremelimumab + chemotherapy in mNSCLC. 2022 World Conference on Lung Cancer. Abstract OA15.04. Presented August 9, 2022.
8. Skoulidis F, Byers LA, Diao L, et al: Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 5:860-877, 2015.
9. Singh A, Daemen A, Nickles D, et al: NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes. Clin Cancer Res 27:877-888, 2021.
10. Li BT, Falchook G, Durm GA, et al: CodeBreaK 100/101: First report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. 2022 World Conference on Lung Cancer. Abstract OA03.06. Presented August 7, 2022.
