Thoracic Oncology Highlights from the European Society for Medical Oncology Annual Meeting 2024: Targeted Therapies in Non-Small Cell Lung Cancer

The European Society for Medical Oncology (ESMO) 2024 Congress in Barcelona offered new insights and updates on translational research and practice-changing trials in thoracic oncology. Biomarker-guided targeted therapy improves disease outcomes of many patients with non-small cell lung cancer (NSCLC) across tumor stages. Nonetheless, therapy resistance, heterogeneous treatment response, sequencing treatment options and drug tolerability still present clinical challenges in patients with NSCLC and targetable genomic alterations. Novel drug targets, improved drug design, and deeper understanding of treatment failure may further improve patient outcomes. Here, we present highlights of ESMO 2024 with a focus on targeted therapy in patients with NSCLC, including biomarker analyses in patients receiving targeted therapies in the adjuvant setting, targeted therapies after progression on osimertinib, and novel drugs against ALK, BRAF, and ROS1 altered NSCLC. In a second article in this issue, we report on ESMO 2024 congress highlights regarding treatment options for patients with lung cancer without targetable genomic alterations including systemic treatment options in patients with resectable NSCLC, circulating tumor DNA (ctDNA) as a biomarker of therapy response and drug combinations to improve immunotherapy outcomes.

Patients with resectable NSCLC are at risk for relapses despite curatively intended surgery. The ALINA trial was a phase III, randomized trial, which compared adjuvant treatment with the oral anaplastic lymphoma kinase (ALK) inhibitor alectinib versus adjuvant chemotherapy in patients with ALK-positive NSCLC (Union internationale contre le cancer 8th edition (UICC) stages II – IIIB) [1]. Alectinib conferred a highly significant risk reduction of disease recurrence or death at 2 years with a hazard ratio (HR) of 0.24 (95% confidence interval [CI] 0.13–0.45; p < 0.001), which led to the approval of alectinib in the adjuvant setting by the US Federal Drug Agency (FDA) and the European Medical Association (EMA) [1]. At ESMO 2024, data of the exploratory biomarker analyses by next-generation sequencing (CDx Foundation One^®) showed sustained benefit regardless of EMAP like 4 (EML4)-ALK-fusion variant. Chromosome 9p21 deletions leading to loss of Cyclin-dependent kinase inhibitor 2A (CDKN2A), CDKN2B and S-methyl-thioadenosine phosphorylase occurred in a quarter of patients, but did not impair disease-free survival. A nonsignificant trend toward worse disease-free survival was seen in patients with TP53 co-mutation. Further analyses of noninvasive biomarkers like ctDNA are pending. These data underline the efficacy of ALK inhibitors in the adjuvant setting and the need for testing for molecular markers (minimally epidermal growth factor receptor (EGFR), ALK, programmed cell death 1 ligand 1 [PD-L1]) in patients with resectable NSCLC (UICC stages II – IIIB [N2]). It is unclear whether patients with ALK-positive NSCLC after curative surgery should receive additional adjuvant platinum-based chemotherapy as the label of Alectinib in the adjuvant setting includes patients without prior chemotherapy.

The phase I/II trial ALKOVE investigates the innovative 4th generation ALK-inhibitor NVL-655 in patients with ALK-positive tumors. Preclinically, NVL-655 presented activity against ALK-fusions as well as occurring resistance mutations, similar brain penetrance as lorlatinib and avoidance of tropomyosin receptor kinase (TRK) inhibition indicating less neurological toxicities. 131 NSCLC patients received NVL-655 once daily orally in a dosage ranging from 15 to 200 mg, determining 150 mg as recommended phase II dose (RP2D). All patients were pretreated with ALK-specific tyrosine kinase inhibitors (TKIs) of which 84% (111/131) received lorlatinib as prior treatment. 38% (39/103) of the response-evaluable population presented with an objective response rate (ORR) to the treatment with NVL-655 as evaluated by RECIST 1.1. Patients with ALK resistance mutations responded with better response rates: ORR 55% (30/55) for any ALK mutation, ORR 76% (22/29) for patients with G1202R resistance mutations and ORR 58% (15/26) for ≥2 compound mutations. Lorlatinib-naïve patients with ALK resistance mutation showed the highest ORR of 88% (7/8). The duration of response (DOR) lasted longer than 6 months for all patients treated with RP2D with median DOR yet not estimable. Concerning patients with brain metastases, 15% (2/13) in the lorlatinib-pretreated and 50% (1/2) in the lorlatinib-naïve collective had an intracranial objective response. For lorlatinib-pretreated patients whose intracranial disease did not progress, the DOR was 7–14 months. NVL-655 presented a favorable safety profile without neurotoxicity, with common side effects such as transaminase elevation (33%), constipation (15%), nausea (12%), and dysgeusia (11%), which caused treatment discontinuation in 2% and a dose reduction in 15% of patients. Although the results of ALKOVE promise advancement for particularly pretreated patients ALK-positive NSCLC with resistance mutations, concurrent clinical studies with NVL-655 will be needed.

The phase III LAURA trial investigates osimertinib after definitive chemoradiotherapy (CRT) in unresectable stage III EGFR-mutated (EGFRm) NSCLC. The primary analyses demonstrated a significant PFS benefit with a median PFS of 39.1 months with osimertinib versus 5.6 months with placebo (HR 0.16) [2]. At ESMO 2024, analyses of central nervous system (CNS) and distant progression were presented. Median time to distant metastases with osimertinib was not reached (HR 0.21), while time to distant metastases was 13 months in the placebo arm. Osimertinib after CRT also showed a significant benefit in preventing CNS progression, which is common in patients with EGFRm NSCLC. Median CNS PFS was not reached in the osimertinib arm vs. 14.9 months in the placebo group (HR 0.17), confirming prior data of the LAURA trial [2]. These data have already led to FDA approval of osimertinib in stage III NSCLC after CRT in EGFR NSCLC. The overall survival (OS) analysis and data on second-line treatment outcomes are pending.

MARIPOSA is a phase III trial in patients with EGFRm (EGFRm; Ex19del, L858R) advanced NSCLC comparing amivantamab plus lazertinib (ami-laz) versus lazertinib versus osimertinib in the first-line treatment. Amivantamab, as a bispecific antibody, targets both EGFR and MET alterations. The previously reported improved PFS of ami-laz versus osimertinib (23.7 vs. 16.6) with a HR of 0.7 (CI: 0.58–0.85) [3], recently led to FDA approval of ami-laz in the first-line setting. Besse B et al. presented an early analysis of mechanisms of acquired resistance to the first-line regimen [4]. 56% (140/252) of osimertinib treated and 53% (113/215) of ami-laz treated patients with treatment discontinuation had fitting baseline and end of treatment ctDNA data. In this population, MET amplifications decreased by a factor of three in the ami-laz group with 4.4% compared to osimertinib treated patients with 13% (p = 0.017). Secondary EGFR resistance mutations (C797S, L718X, G724X) were decreased by a factor of eight with 0.9% versus 7.9% (p = 0.014), respectively. Analysis of MET- and EGFR-independent resistance mechanisms (HER2 amplifications, RAS/RAF, PI3K, cell cycle, TP53/RB1 loss) revealed no significant differences between both arms. Additionally, patients treated with osimertinib displayed a more heterogeneous mutational landscape, especially complex resistance mechanisms (defined as two resistance mutations) appeared more often with 42.6% than in ami-laz treated patients with 27.8%. Interestingly, 60–70% of patients in both groups had no defined resistance mutations. This liquid biomarker analysis provides valuable data to understand and further challenge resistance mechanisms in EGFRm NSCLC. However, subsequent studies are needed to evaluate its clinical impact.

Updated results of MARIPOSA-2, a randomized controlled three-arm phase III trial in patients with EGFRm (Exon 19 deletion or L858R point mutation) advanced NSCLC after disease progression on osimertinib treated with chemotherapy (chemo; carboplatin/pemetrexed), chemo in combination with amivantamab (ami-chemo) or with chemo plus ami-laz were presented at ESMO Congress 2024 [5]. First survival data have been published recently [6] showing a superior median PFS of 6.3 months (CI 5.6–8.4) in ami-chemo versus 4.2 months (CI: 4.0–4.4) in the chemo arm with a HR of 0.48 (CI: 0.36–0.64) leading to EMA approval for ami-chemo in this indication. New results of the second interim analysis (>75% of events) revealed an 18-month OS of 50% (95% CI: 40–59%) with ami-chemo compared to 40% (CI: 33–46%) with chemo alone. Median OS was 17.7 (CI: 16.0–22.4) vs. 15.3 months (CI: 13.7–16.8), respectively. With a HR of 0.73 (CI: 0.54–0.99, p = 0.039), the required prespecified significance threshold was not reached, yet a numerical benefit in OS was demonstrated. Post-regression endpoints like time to symptomatic progression (HR 0.73; CI: 0.55–0.96; p = 0.026), time to treatment discontinuation (HR 0.73; CI: 0.55–0.96; p = 0.026), time to subsequent therapy (HR 0.51; CI: 0.39–0.65; p < 0.0001) and PFS after first subsequent therapy (HR 0.64; CI: 0.48–0.85; p = 0.002) showed a significant benefit for ami-chemo compared to chemo alone.

In conclusion, the follow-up second interim results confirm the superior outcomes in the combination of ami-chemo compared to chemo alone, making it a possible second-line treatment option for advanced EGFRm NSCLC after progression on osimertinib. The final survival results will be of great interest. However, severe treatment-related toxicities leading to therapy discontinuation may not be disregarded [6].

The ARROS-1 study presented promising data on zidesamtinib, a brain-penetrating, ROS1-selective inhibitor developed for patients with ROS1-positive NSCLC. Zidesamtinib is designed as a TRK-sparing TKI to avoid undesirable side effects such as dizziness and ataxia, which may result from TRK inhibition. The phase I/II study is ongoing and has enrolled 107 patients to date. Zidesamtinib showed significant activity in heavily pretreated patients, 69% of whom had developed resistance to at least two prior ROS1 TKIs such as crizotinib, lorlatinib, or repotrectinib. 66% of patients received prior chemotherapy. Response data were available for 71 patients. The ORR was 44% with two confirmed complete remissions. In the subset of patients who progressed on at least two ROS1 TKIs, the ORR was 41%. Activity was seen even in patients with G2032R mutation, which confers resistance to other ROS1 inhibitors. The median DOR was not reached in the allcomers group, but 67% (CI: 45–81) had a response for more than 12 months. The median DOR was 12.1 months (CI: 4.7 – not evaluable [NE]) in the heavily pretreated subgroup of patients, who had received more than 2 prior ROS1 TKI therapies prior to enrolment.

Additionally, zidesamtinib demonstrated the ability to target brain metastases with intracranial responses observed in all treated patients with measurable brain lesions. Notably, the drug was well tolerated, with no dose-limiting toxicities reported and minimal neurological side effects, a common issue with other TKIs in this category due to adverse TRK inhibition.

Oncogenic BRAF V600E point mutations occur in 1–2% of patients with metastatic NSCLC [7]. Currently, the combination treatment with the BRAF kinase inhibitor dabrafenib and MEK inhibitor trametinib is approved in this patient population and recommended by ESMO guidelines [8]. Dabrafenib and trametinib achieve an ORR of 64% in treatment-naïve patients and 63% in previously treated patients and a median PFS of 14.6 and 8.6 months, respectively [8, 9]. However, primary and acquired therapy resistance as well as drug related adverse events limit treatment efficacy.

At ESMO 2024, outcome of treatment-naïve patients in the IFCT-1904 ENCO-BRAF study and additional follow-up of the PHAROS study (treatment-naïve and pretreated patients) were presented. ENCO-BRAF and PHAROS are open-label, single-arm, phase II trials, which investigate treatment with the half-life increased BRAF inhibitor encorafenib and MEK inhibitor binimetinib. Both trials reached the respective primary endpoint of ORR in treatment-naïve patients with BRAF V600E-mutated NSCLC (ORR 65.6% and 75%, respectively) and showed no new safety signals. In the PHAROS study, pretreated patients achieved an ORR of 46% (CI: 30–63), median PFS of 9.3 months (CI: 6.2–24.8) and a median OS of 22.7 months (CI: 14.1–32.2). Treatment-naïve patients in both trials had similar baseline characteristics and included patients with stable brain metastases. Nonetheless, patients in the ENCO-BRAF trial had a higher rate of brain metastases at baseline (17.2 vs. 7%). Median PFS was 10.9 months (CI: 6.4–16.7) in the ENCO-BRAF trial and 30.2 (CI: 15.7 – NE) in the PHAROS trial. Median OS of treatment-naïve patients was not reached in either trial (CI: 20.7 – NE and 31.3 – NE, respectively).

The encouraging results of the PHAROS trial led to FDA approval of encorafenib plus binimetinib for the treatment of patients with advanced BRAF V600E-mutated NSCLC. Approval by EMA is awaited. Despite overlapping confidence intervals for PFS, the notable difference in median PFS in treatment-naïve patients with similar baseline characteristics and identical treatment intervention remains an open question. Biological differences between the cohorts of PHAROS and ENCO-BRAF may account for different PFS and numerically lower ORR in the ENCO-BRAF trial. Co-occurring mutations [10] and potentially higher PD-L1 expression [11] may impair BRAF-targeted therapy efficacy. Furthermore, Binimetinib exposure is negatively influenced by CYP1A2, which is induced by environmental factors like smoking [12], dietary choices and oral medications. Additionally, genetic factors like single nucleotide polymorphisms may differ between ethnic groups and influence both expression and enzymatic function of CYP1A2 [13].

The choice of the first-line treatment of patients with advanced, BRAF V600E-mutated NSCLC remains a clinical challenge. At ESMO 2024, a German retrospective, multicentric analysis of patients with BRAF V600E-mutated NSCLC (n = 204) showed similar OS in patients treated with approved BRAF-targeted therapy or checkpoint inhibitor-based the first-line treatment. Interestingly, the first-line BRAF-targeted therapy was associated with superior OS in women (HR 0.65, p = 0.049), while high PD-L1 status was negatively associated with time to next treatment regardless of choice of first-line treatment [14]. This highlights the need for improved biomarker-guided patient selection to maximize treatment outcomes in this subgroup of patients.

Encorafenib plus binimetinib is a new treatment option for patients with advanced, BRAF V600E-mutated NSCLC. Longer follow-up, data on pretreated patients in the ENCO-BRAF trial and a potential analysis of combined trial data may provide a clear picture of cohort differences and the intricacies of BRAF-targeted therapy.

Targeted therapy of patients with NSCLC is rapidly evolving and the ESMO congress 2024 highlighted significant advancements in the field. Exploratory biomarker analysis of the ALINA trial showed the benefit of adjuvant alectinib treatment in patients with ALK-positive NSCLC regardless of ALK-fusion variant. Next generation small molecule inhibitors like NVL-655 in advanced stage, ALK-positive NSCLC or zidesamtinib in ROS1-positive NSCLC offer new treatment options to patients with the respective molecular alterations and progressive disease despite approved targeted therapies. While both the ENCO-BRAF trial and the PHAROS trial set the stage for treatment with encorafenib/binimetinib, discrepancies in PFS, pending final OS analyses and individual patient characteristics still make the choice of first-line treatment in BRAF V600E-mutated NSCLC a clinical challenge. Osimertinib after CRT in unresectable stage III NSCLC offered significant benefits regarding PFS, especially in the CNS.

The Thoracic Oncology Working Group of the AIO (Association of Internal Oncology) congress scholarship program sponsored five young physicians to attend the ESMO in Barcelona in 2024. The aim of the program is to enable young doctors and medical doctoral students to attend congresses and exchange ideas with expert mentors. The scholarship recipients co-authored this manuscript. We acknowledge the German AIO thoracic oncology steering board (Leitgruppe Thorakale Onkologie) for their support. The 2025 AIO Thoracic Oncology Scholarship will sponsor junior physicians to attend ESMO 2025 in Berlin. For information on this year’s scholarships and the application process for junior physicians see the AIO website: https://www.aio-portal.de/

M.W., S.H., M.-E.L., C.S., and L.R. received the 2024 ESMO congress scholarship by the Association of Internal oncology (AIO); S.H.: research funding: Novartis; honoraria and advisory role: BeiGene, AstraZeneca Travel Costs: BeiGene. M.-E.L.: honoraria: AstraZeneca, ORCID: 0009-0005-7029-0028.

C.K.-S.: research funding: AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Novartis, Roche. Honoraria and advisory role: AstraZeneca, Amgen, Art tempi/medtoday, BMS, Boehringer Ingelheim, Celgene, Daiichi, Johnson and Johnson, Lilly, Novartis, onkowissen, MSD, Pfizer, Regeneron, Roche, Sanofi, Streamed Up, Takeda. Travel Cost: AstraZeneca, Amgen, Boehringer Ingelheim, Daiichi, Johnson and Johnson, Roche. C.K.-S. receives funding from the Hector Foundation II (no grant number.)

M.T.: research funding – AstraZeneca, Bristol-Myers Squibb, Roche, Takeda, Merck; honoraria and advisory boards – AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck, Daiichi Sankyo, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Sanofi, Beigene, Johnson and Johnson, G.S.-K., onkowissen. A.T.: Consulting fees from Boehringer Ingelheim, Daiichi, AstraZeneca, Roche, Pfizer, BMS, MSD, Sanofi, Lilly, Novartis; speaker’s honoraria from Boehringer Ingelheim, Daiichi, AstraZeneca, Roche, Pfizer, BMS, MSD, Sanofi, Lilly, Novartis; travel grants from Sanofi, Janssen, Daiichi; BMS, MSD, AstraZeneca. A.B. has served institutionally or personally on advisory boards for Bayer, BMS, Takeda, MSD, Boehringer, AstraZeneca, Sanofi, Pfizer, Lilly, Amgen, Roche, Novartis, Janssen, Daiichi Sankyo, Merck, Pierre Fabre, Gilead; has received institutional or personal fees or travel support from Bayer, BMS, Takeda, MSD, Boehringer, Mirati, AstraZeneca, Sanofi, Pfizer, Lilly, Amgen, Roche, Novartis, Janssen, Daiichi Sankyo. M.W.: honoraria and advisory role: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda. Travel costs: Amgen, Janssen, Daiichi Sankyo. Research funding: Bristol-Myers Squibb, Takeda. F.G.: Scientific support (reimbursement to the institution): CRISP (NSCLC stage IV, IIIB/C palliative) is supported or has been supported by grants from Amgen Ltd, AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co.KG, Bristol-Myers Squibb GmbH & Co.KGaA, Celgene GmbH, Daiichi Sankyo Deutschland GmbH, Gilead Sciences GmbH, GlaxoSmithKline Research and Development Limited, Janssen-Cilag GmbH, Lilly Deutschland GmbH, MSD Sharp and Dohme GmbH, Novartis Pharma GmbH, Pfizer Pharma GmbH, Regeneron GmbH, Roche Pharma AG and Takeda Pharma Vertrieb GmbH & Co.KG. Speaker for (reimbursement to the person): ASTRA, Boehringer, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, Tesaro/GSK, Amgen, Sanofi, Daiichi Sankyo, Beigene, Gilead. Advisory Board: reimbursement to the person: ASTRA, Boehringer, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GSK, Siemens, Tesaro, Amgen, Sanofi, Daiichi Sankyo, Beigene, Gilead. T.R.O.: AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen-Cilag, Merck, MSD, Novartis, Pierre Fabre, Roche, Takeda, Tesaro/GSK, Lilly, Pfizer and Roche. ORCID: 0000-0002-2579-0171. M.W., C.S., and L.R. declare no conflict of Interest.

The AIO scholarship 2024 was funded by an unrestricted grant by donations from Amgen, AstraZeneca, BionTech, Janssen-Cilag, OncoConsult Overkamp, Roche Pharma, and Takeda Pharma.

M.W., S.H., C.S., M.-E.L., C.K.-S., M.T., A.T., A.B., M.W., F.G., L.R., and T.R.O. fully contributed to the conception and design of the work, drafted the work, revised it critically, gave final approval of the version to be published, and gave agreement to be accountable for all aspects of the work.

Maximilian Webendörfer, Sophie Heinzen, Lea Reitnauer and Tobias Raphael Overbeck contributed equally to this work.