GUEST EDITORS
Sandip P. Patel, MD
Tali Azenkot, MD
At the 2024 World Conference on Lung Cancer (WCLC), more than 7,000 clinicians and scientists gathered in San Diego in celebration of the 50th anniversary of the International Association for the Study of Lung Cancer (IASLC). In this supplement to The ASCO Post, we review impactful abstracts from the meeting. They include advances in resectable lung cancer via novel perioperative strategies, as well as the use of tyrosine kinase inhibitors, a bispecific antibody, and antibody-drug conjugates (ADC) in advanced non–small cell and small cell lung cancers.
Resectable NSCLC
Non–small cell lung cancer (NSCLC) accounts for nearly 85% of all lung cancers.1 An estimated one-third of patients with NSCLC present with stage I to III disease at initial diagnosis, with the median overall survival of patients with stage III disease remaining a modest 9 to 34 months.2 Recent phase III trials on neoadjuvant and perioperative chemotherapy/immunotherapy underscore the role for systemic therapies in early-stage disease and introduced the prognostic potential of pathologic complete response (pCR).3-5
At this year’s conference, Patrick M. Forde, MBBCh, PhD, and colleagues applied inverse probability of treatment weighting to assess cross-trial data from CheckMate 77T6 and CheckMate 816.3 They showed that perioperative nivolumab had superior event-free survival improvement when compared with neoadjuvant nivolumab in patients with resectable NSCLC, with a hazard ratio (unweighted HR = 0.59 [95% confidence interval (CI) = 0.38–0.92]).7 This difference was observed even in patients who had PD-L1–negative disease and in those who did not achieve pCR, supporting a widely applicable benefit from postoperative immune checkpoint inhibition.
Building on the AEGEAN regimen,5 Tina Cascone, MD, PhD, and colleagues reported preliminary data from NeoCOAST-2.8 This global phase II study examined pCR achieved after neoadjuvant durvalumab with chemotherapy and novel agents, including datopotamab deruxtecan (Dato-DXd), a TROP2-directed ADC. Patients in the Dato-DXd arm demonstrated major pathologic response and pCR rates of 65.9% and 34.1%, respectively; among patients with PD-L1–negative disease in this arm, rates remained high at 58.3% and 25.0%, respectively. The integration of ADCs into localized NSCLC treatment is a promising approach, as we identify optimal perioperative regimens and adjustments for patients who do not achieve pCR.
Advanced NSCLC: EGFR Mutation
Among patients with NSCLC, approximately one-third have an activating mutation in the EGFR gene that may be targeted with an EGFR tyrosine kinase inhibitor.9 In the past decade, subsequent generations of EGFR tyrosine kinase inhibitors have improved outcomes and reduced toxicity. Optimal therapies for patients with mutations co-occurring with EGFR, either de novo or acquired, remain unknown.
Earlier this year, the phase III -MARIPOSA trial showed superior efficacy with amivantamab (EGFR-MET bispecific antibody) and lazertinib vs osimertinib monotherapy as first-line treatment in EGFR-mutated advanced NSCLC.10 In an extended follow-up of this trial, Shirish M. Gadgeel, MD, and colleagues reported that the median overall survival was not reached for amivantamab/lazertinib vs 37.3 months for osimertinib (HR = 0.77; 95% CI = 0.61–0.96; P = .019).11 Intracranial progression-free survival showed a favorable trend for amivantamab/lazertinib vs osimertinib, although not formally tested for significance.
Jin-Ji Yang, MD, and colleagues reported results of the CTONG 2008 FLOWERS phase II trial in patients with de novo MET-aberrant and EGFR-mutant advanced NSCLC.12 At a median follow up of 8.2 months, 44 patients treated with osimertinib alone or in combination with savolitinib had confirmed objective response rates of 60.9% (95% CI = 38.5%–80.3%) and 90.5% (95% CI = 69.6%–98.8%), respectively. Median progression-free survival was 9.3 months (95% CI = 7.4 months to not evaluable) and 19.6 months (95% CI = 10.2 months to not evaluable) for the respective cohorts. Adverse events grade ≥ 3 were reported in 57.1% of the combination therapy group.
Firmonertinib is an EGFR tyrosine kinase inhibitor with high central nervous system (CNS) penetrance and efficacy among EGFR exon 20 insertion and p-loop and aC-helix compressing (PACC) mutations in preclinical models. David Planchard, MD, PhD, and colleagues presented preliminary data from FURTHER, a phase Ib study in treatment-naive patients with EGFR PACC mutation.13 Among 60 enrolled patients, responses were observed in patients across a broad range of PACC mutations. In those with brain metastases, CNS objective response rate was 46.2%. These studies emphasize the importance of appropriate molecular sequencing and the need for treatments targeted to noncanonical EGFR mutations.
Advanced NSCLC: HER2 Mutation
ERBB2 (also known as HER2) mutations are present in 2% to 4% of patients with NSCLC.14 Although this oncogenic target led to the first ADC approval in the lung cancer treatment arsenal, tyrosine kinase inhibitors likely also have a role in HER2-mutated NSCLC.
BAY 2927088 is a reversible oral, tyrosine kinase inhibitor that inhibits activating HER2 mutations. Xiuning Le, MD, PhD, and colleagues presented the expansion cohort of the SOHO-01 trial,15 in which 44 patients with HER2-mutant NSCLC naive to HER2-targeted therapy were treated with this tyrosine kinase inhibitor. During a median follow up of 10.9 months, patients demonstrated an objective response rate of 72.1% (95% CI = 56.3%–84.7%). Median duration of response and progression-free survival were 8.7 months (95% CI = 4.5 months to not evaluable) and 7.5 months (95% CI = 4.4–12.2 months), respectively. Grade 3 adverse events were reported in 40.9% of patients, and one grade 5 event (dyspnea) occurred.
Zongertinib is another oral HER2-specific tyrosine kinase inhibitor that selectively binds to the tyrosine kinase domain of HER2, sparing EGFR-related toxicity. Gerrina Ruiter, MD, PhD, and colleagues shared Beamion LUNG-1, an ongoing phase Ia/Ib study.16 In the phase Ib component, 132 patients with HER2-mutated NSCLC were treated with zongertinib. The confirmed objective response rate was 95.5%, with a majority of patients (69.7%) achieving a partial response. Grade ≥ 3 adverse events were reported in 18.2% of patients, resulting in treatment discontinuation in four patients. These studies pave the way for combination regimens with tyrosine kinase inhibitors and ADCs, such as trastuzumab deruxtecan, or to apply tyrosine kinase inhibitors as second line therapy in HER2-mutated NSCLC.
Advanced NSCLC: First-Line Therapy Without Driver Mutations
The inhibition of PD-1 and PD-L1 remains a cornerstone of treatment for patients with NSCLC and no driver mutations. Ivonescimab (AK112) is a novel bispecific antibody against both PD-1 and vascular endothelial growth factor (VEGF). Caicun Zhou, MD, PhD, and colleagues presented the results of HARMONi-2, a phase III study that randomly assigned 398 Chinese patients to receive either ivonescimab or pembrolizumab as first-line treatment for PD-L1–positive advanced NSCLC.17 Median progression-free survival was significantly longer with ivonescimab than with pembrolizumab (11.1 months vs 5.8 months; HR = 0.51; 95% CI = 0.38–0.69; P < .0001). Statistical superiority in progression-free survival was maintained across histologies and tumor proportion scores of 1% to 9% vs ≥ 50%. We await longer-term follow-up and replication of this promising study in global cohorts.
Advanced NSCLC: Antibody-Drug Conjugates
Several ADCs and the utility of biomarkers to guide their use were showcased at the 2024 WCLC. In the phase III CARMEN-LC03 trial, Benjamin Besse, MD, PhD, and colleagues presented outcomes in previously treated patients with CEACAM5-expressing advanced nonsquamous NSCLC treated with docetaxel or tusamitamab ravtansine (a CEACAM5-directed ADC).18 Median progression-free survival and overall survival were similar among the two treatment arms, although there was a trend favoring tusamitamab ravtansine on the interim overall survival analysis. The rate of adverse events leading to discontinuation of therapy and dose reduction was lower with tusamitamab ravtansine than docetaxel; ocular adverse events were consistent with previous studies of tusamitamab ravtansine.
Two additional abstracts focused on datopotamab deruxtecan (Dato-DXd) in advanced NSCLC. Jacob M. Sands, MD, and colleagues reported updated data from the TROPION-Lung01 study.19 This global phase II study randomly assigned patients 1:1 to receive Dato-DXd (n = 299) or docetaxel (n = 305). Median overall survival was not statistically different between the two groups. There was, however, a clinically meaningful trend in the prespecified nonsquamous subgroup, with median overall survival of 14.6 months (95% CI = 12.4–16.0 months) with Dato-DXd vs 12.3 months (95% CI = 10.7–14.0 months) with docetaxel (HR = 0.84; 95% CI = 0.68–1.05). Grade ≥ 3 adverse events were more frequent with docetaxel than with Dato-DXd (42% vs 26%).
Marina Chiara Garassino, MD, and colleagues presented data on TROP2 target expression interpretation of digitized immunohistochemical by a deep learning algorithm to predict therapeutic response to Dato-DXd.20 Among 352 patients with evaluable biomarker from the TROPION-Lung01 trial, the objective response rate was higher, and the median progression-free survival was longer with Dato-DXd vs docetaxel in subgroups with higher frequency TROP2 expression. Higher expression of TROP2 was seen in patients with nonsquamous vs squamous histologies. Such results emphasize the need for biomarker development beyond the capabilities of immunohistochemistry and the potential for machine learning to optimize biomarker interpretation.
SCLC: Antibody-Drug Conjugates
ADCs also showed promise in small cell lung cancer (SCLC). Charles M. Rudin, MD, PhD, and colleagues presented the phase II IDeate-Lung01 trial. In this study, 88 patients with previously treated extensive-stage SCLC were given with ifinatamab deruxtecan (I-DXd), a first-in-class ADC directed to the immune checkpoint protein B7-H3.21 At this interim analysis, the objective response rate with I-DXd at 12 mg/kg was approximately twice that with I-DXd at 8 mg/kg (52.4% vs 26.1%). The incidence of interstitial lung disease was similar at both doses (8 mg/kg, 8.7%; 12 mg/kg, 7.1%).
Future Directions
Despite decades of advancements, lung cancer remains the leading cause of cancer-related deaths worldwide.1 Future progress will depend on robust low-dose computed tomography–based screening programs and the optimization of perioperative regimens for early-stage disease. Improved outcomes with targeted therapies will rely on the development of more specific biomarkers and improved access to molecular sequencing. This year’s WCLC underscored advancements in novel drug delivery platforms and the need for improved patient selection tools in targeted thoracic oncology.
DISCLOSURE: Dr. Patel reported a consulting or advisory role with Novartis, Bristol Myers Squibb, AstraZeneca/MedImmune, Nektar, Compugen, Illumina, Amgen, Certis, Eli Lilly, Roche/Genentech, Merck, Pfizer, Tempus, and Iovance Biotherapeutics; a speakers bureau role with Merck and Boehringer Ingelheim; research funding (individual) from Rubius; and research funding (institutional) from Bristol Myers Squibb, Pfizer, Roche/Genentech, Amgen, AstraZeneca/MedImmune, Fate, Merck, Iovance Biotherapeutics, and Takeda. Dr. Azenkot reported no conflicts of interest.
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8. Cascone T, Florian G, Bonanno L, et al: Neocoast-2: Efficacy and safety of neoadjuvant durvalumab + novel anticancer agents + CT and adjuvant durvalumab ± novel agents in resectable NSCLC. 2024 World Conference on Lung Cancer. Abstract PL02.07. Presented September 8, 2024.
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11. Gadgeel S, Cho BC, Lu S, et al: Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: Longer follow-up of the MARIPOSA study. 2024 World Conference on Lung Cancer Abstract OA02.03. Presented September 8, 2024.
12. Yang J, Li A, Feng WN, et al: Osimertinib with or without savolitinib as 1L in de novo MET aberrant, EGFRm advanced NSCLC (CTONG 2008): A phase II trial. 2024 World Conference on Lung Cancer. Abstract PL04.10. Presented September 9, 2024.
13. Le X, Yu Y, Zhao Y, et al: FURTHER: A global, randomized study of firmonertinib at two dose levels in TKI-naive, advanced NSCLC with EGFR PACC mutations. 2024 World Conference on Lung Cancer. Abstract PL04.07. Presented September 9, 2024.
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15. Le X, Girard N, Jänne PA, et al: Safety and efficacy of BAY 2927088 in patients with HER2-mutant NSCLC: Expansion cohort from the phase I/II SOHO-01 study. https://www.jto.org/article/S1556-0864(24)00891-8/abstract. Presented September 9, 2024.
16. Ruiter G, Tu HY, Ahn MJ, et al: Primary phase Ib analysis of Beamion LUNG-1: Zongertinib (BI 1810631) in patients with HER2 mutation-positive NSCLC. 2024 World Conference on Lung Cancer. Abstract PL04.04. Presented September 9, 2024.
17. Zhou C, Chen J, Wu L, et al: Phase 3 study of ivonescimab (AK112) vs. pembrolizumab as first-line treatment for PD-L1-positive advanced NSCLC: Primary analysis of HARMONi-2. 2024 World Conference on Lung Cancer. Abstract PL02.04. Presented September 8, 2024.
18. Besse B, Lo Russo G, Lena H, et al: Tusamitamab ravtansine vs docetaxel in previously treated advanced nonsquamous NSCLC: Results from phase 3 CARMEN-LC03 trial. 2024 World Conference on Lung Cancer. Abstract OA08.05. Presented September 9, 2024.
19. Sands J, Lisberg A, Okamoto I, et al: Datopotamab deruxtecan vs docetaxel in patients with non-small cell lung cancer: Final overall survival from TROPION-Lung01. 2024 World Conference on Lung Cancer. Abstract OA08.03. Presented September 9, 2024.
20. Garassino MC, Sands J, Paz-Ares L, et al: Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung 01. 2024 World Conference on Lung Cancer. Abstract PL02.11. Presented September 8, 2024.
21. Rudin CM, Ahn MJ, Johnson M, et al: Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer: Interim analysis of Ideate-lung01. 2024 World Conference on Lung Cancer. Abstract OA04.03. Presented September 8, 2024.
