Alectinib impressively enters the adjuvant setting for early-stage ALK-rearranged non-small cell lung cancer and outperforms chemotherapy—let’s define who benefits the most

Wu et al. have presented a phase 3 study comparing adjuvant treatment with the second-generation (2G) anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI), alectinib, vs. chemotherapy in patients with completely resected ALK-rearranged non-small cell lung cancer (NSCLC) stage IB–IIIA according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control (1). The primary endpoint was disease-free survival (DFS) tested hierarchically in patients with stage II–IIIA and subsequently in the intention-to-treat population. Secondary endpoints were overall survival (OS) and safety, while the exploratory endpoints included DFS in the central nervous system (CNS). Importantly, most patients in the ALINA study were in stage IIIA (53.1% and 55.1% in the alectinib and chemotherapy arm, respectively), and N2 disease was represented in 49.2% of patients treated with alectinib and in 52% of those receiving chemotherapy (while N1 lymph nodes were involved in 34.6% and 33.9% in alectinib and chemotherapy arms, respectively). Accordingly, the study population was at high risk of recurrence and suitable for investigating DFS as an endpoint. However, the number and localization of positive N2 lymph nodes as well as the percentage of patients pre-operatively investigated with positron-emission tomography scans were not specified, thus eligibility for surgery remains unclear. In addition, the study’s data indicate that nodal assessment in most patients of both arms was performed by complete mediastinal lymph node dissection or lymph node sampling during operation. This may raise questions regarding adequacy of the preoperative disease staging.

Furthermore, appropriate, and advantageous disease assessment, including magnetic resonance imaging of the brain, was conducted every 3 months, due to the high propensity of ALK-rearranged NSCLC for metastasizing to the CNS (2,3). The study has demonstrated a significantly better 2-year DFS in patients receiving alectinib (93.8%) as compared to patients treated with chemotherapy (63.0%). Moreover, exploratory endpoints demonstrated an impressive delay of intracranial relapse by alectinib [hazard ratio (HR) =0.22]. Indeed, fewer patients in the alectinib arm experienced intracranial progression (3.1% and 2-year CNS-DFS of 98.4%) as compared to patients in the chemotherapy arm (11% and 2-year CNS-DFS of 85.8%) (1).

The ALINA study is an innovative approach as it explores the impact of adjuvant targeted therapy with alectinib for 2 years and it omits standard adjuvant chemotherapy in potentially curable NSCLC patients with ALK rearrangement. The comparator arm was platinum-based chemotherapy, which is the current standard of care, though only providing a limited 5-year OS improvement of 5% through all the early tumor-node-metastasis (TNM) stages (4). Furthermore, adjuvant chemotherapy has considerable toxicity and transient effect (5). However, in the ALINA study most patients (80%) were treated with cisplatin and pemetrexed and 73.3% of them completed four cycles. A further 19.2% of patients were treated with cisplatin and vinorelbine, among those, 82.6% received four cycles. One patient (0.8%) with squamous histology was treated with cisplatin and gemcitabine and received four cycles. Only 11% of patients switched from cisplatin to carboplatin. This is in contrast to the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis, in which combinations of platinum with vinorelbine or paclitaxel were used, and only 50% of patients were able to receive four cycles predominantly because of toxicity (4). Importantly, 97.6% of patients in the chemotherapy arm of the ALINA trial had, as expected, non-squamous carcinomas, which respond better to pemetrexed than squamous carcinomas (6,7). Furthermore, in patients with ALK-rearranged NSCLC, increased sensitivity to pemetrexed was reported, possibly due to the influence of ALK-dependent signaling to folate-metabolizing enzymes (8). Importantly, in the real-world cohort of 82 patients operated with pathological stage II or IIIA of non-squamous NSCLC with unknown molecular profiling and treated with adjuvant carboplatin and pemetrexed, 85.4% of patients completed four cycles (9). Even though 2-year DFS was not reported in that study, median DFS (mDFS) for stage II and IIIA patients were 38.0 and 21.0 months, respectively (9). With the reservation that this is a historical reference, these data are comparable to the mDFS of stage II–IIIA patients in the ALINA trial, although the latter demonstrated better DFS of 44.4 months (1). Thus, the ALINA study implies that adjuvant platinum-pemetrexed chemotherapy provides superior benefit to the selected population of patients with ALK-rearranged pulmonary adenocarcinomas as compared to unselected populations. Moreover, as ALK-rearranged NSCLC is a clinically heterogeneous disease, including the possible emergence of multiclonal populations of tumor cells, chemotherapy may contribute with further therapeutic effect. Collectively, these factors may indicate that platinum-pemetrexed chemotherapy combined with alectinib in adjuvant setting may provide additional benefit to the outcome of ALK-rearranged NSCLC patients.

In the ALINA study (1), cross-over was not controlled, but there was a considerable difference in percentage of patients with any disease recurrence between the chemotherapy group (38.6%) and the alectinib group (11.5%). The most frequent site of recurrence in the chemotherapy group was the brain (14/49 patients), confirming the inherently high risk of CNS involvement in this group of patients. Among the patients having any recurrence in the chemotherapy group, 75.5% received an ALK-TKI (most commonly alectinib, 59.2%), while 18.4% were treated with radiotherapy. In the alectinib group, the most frequent therapy for any recurrence likewise was a 2G ALK-TKI (46.7%). Interestingly, 50% of these patients continued alectinib, presumably beyond progression. Other therapies used at recurrence were chemotherapy (40%) and radiotherapy (33.3%).

Analogously to the RADIANT and ADAURA studies in resected epidermal growth factor receptor (EGFR)-mutated NSCLC (10,11), in which the slope of the DFS curves increased after 2 years, the 3-year DFS in the ALINA study fell to 88.7% in the alectinib group. In the RADIANT trial, despite a higher 2-year DFS in patients treated with adjuvant erlotinib, the OS did not differ between erlotinib and placebo group (10). Furthermore, a recent meta-analysis exploring the effect of adjuvant EGFR-TKIs in eight trials showed a waning effect after EGFR-TKI withdrawal (12). Hence, the length of targeted adjuvant treatment remains to be more personalized, both with respect to the potential long-term side effects and better clinical and molecular selection of the patients expected to profit from treatment continuation after 2 years. For identification of the group at high risk for recurrence in resected stage I to IIIA EGFR-mutated NSCLC, a longitudinal monitoring of circulating tumor DNA (ctDNA) to better define such patients has been recently explored (13). A similar approach via monitoring of ctDNA in ALK-rearranged NSCLC patients receiving adjuvant alectinib treatment in the ALINA trial is awaiting. Furthermore, future studies are needed to assess the potential additional benefit of combined alectinib and chemotherapy in the adjuvant setting.

As described in the European Public Assessment Report (EPAR; pages 31–32) of the ALINA study, the diagnostic methods used for screening in the ALINA study was a Food and Drug Administration (FDA)-approved test at site and/or by central confirmation (14). Among the 257 patients in the intention-to-treat population, ALK rearrangement was assessed by local test for enrollment in 102 patients (78.5%) in the alectinib arm and 95 patients (74.8%) in the chemotherapy arm. The most common local ALK-testing method was the Ventana ALK immunohistochemistry assay (alectinib arm: 74.5% vs. chemotherapy arm: 84.2%), followed by the Abbott fluorescence in situ hybridization test (alectinib arm: 20.6% vs. chemotherapy arm: 13.7%). Among patients who had both local and central ALK testing (96 patients in the alectinib arm vs. 86 patients in the chemotherapy arm), concordance between local and central positive results was above 90% in both arms (14).

No further molecular characterization of patients included in the ALINA study was reported in the article by Wu et al. (1), implying difficulties in defining subgroups of patients with potential different DFS. However, exploratory biomarker analyses of baseline tissue samples from 75% of patients of the ALINA trial (193/257), including both the alectinib (99/130) and chemotherapy (94/127) arms, were recently presented at the European Society for Medical Oncology 2024 Congress (15). These analyses performed by next-generation sequencing (FoundationOne CDx assay) confirmed the presence of ALK-fusion in this subset of patients and showed that the DFS benefit by alectinib occurred regardless of EML4-ALK fusion variant. The presence of TP53 co-mutations, detected in 46/193 (24%) patients in the biomarker-evaluable population of the ALINA study, was associated with a trend towards worse DFS (HR =2.73) compared with patients with wild-type TP53 (15). However, molecular profiling was not available for the remaining 25% of patients in the ALINA trial, which may represent one of the study limitations that have extensively been discussed by others (16).

Treatment-related adverse events in the ALINA trial were observed in 1.6% in alectinib group and in 6.7% in chemotherapy group with fewer discontinuations due to adverse events in the alectinib arm. No new signals about toxicity were reported (1). However, long-term compliance to alectinib-treatment including a considerable number of tablets to be taken (4 twice a day) can be a challenge for some patients, despite the better tolerability compared with chemotherapy (16).

To summarize, the ALINA study represents a novel concept to directly compare the efficacy of adjuvant alectinib vs. standard-of-care chemotherapy in resected NSCLC patients with ALK rearrangement. The study has resulted in hitherto unreported impressive DFS in patients treated with alectinib in all early stages. Particularly noteworthy is the strong protective effect against recurrence in the CNS. However, further molecular characterization may help to better define early-stage patients deriving most benefit from adjuvant alectinib. Finally, although the duration of treatment remains unresolved, and data regarding OS is still awaiting, the ALINA trial, by omitting chemotherapy, represents a breakthrough in targeted adjuvant treatment of NSCLC and has been approved by both the United States FDA and the European Medicines Agency as a new standard of care. Hereby, adjuvant alectinib has joined the new, more personalized, therapeutical strategy using TKIs in early stages of resected oncogene-driven NSCLC (10,11). In this respect, the results from ongoing trials with other TKIs are highly anticipated (17).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-961/coif). E.S.R. has received research grants from Sanofi and Takeda; honoraria for lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, and Takeda; and payment for participation in Advisory Board from Roche and Takeda. J.B.S. has received consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, Janssen, and Roche; honoraria for lectures from Bristol-Myers Squibb and Janssen; support for attending meetings and travel from AstraZeneca, Janssen, and Merck; payment for participation in Advisory Board from AstraZeneca, Bristol-Myers Squibb, Genmab, Janssen, Merck and Roche. E.M.U. has received research grants from AstraZeneca and Merck; speaker fees from Amgen; travel support related to participation in international scientific meeting from AstraZeneca, MSD, and Roche; and payment for participation in Advisory Board from AstraZeneca and Pfizer. The authors have no other conflicts of interest to declare.

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