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MADRID -- Disease-free survival (DFS) in resectable ALK-positive non-small cell lung cancer (NSCLC) improved by 76% with adjuvant alectinib (Alecensa) compared with chemotherapy, according to a randomized trial.

Across disease stages IB-IIIA, alectinib led to a hazard ratio of 0.24, as more than three times as many clinical events occurred in patients treated with chemotherapy. The hazard for DFS in the brain was 0.22 with alectinib. Median DFS had yet to be reached in the alectinib cohort versus 41.3 months with chemotherapy.

Total adverse events (AEs) and grade 3-5 AEs did not differ between the two treatment groups, reported Benjamin Solomon, MD, of the Peter MacCallum Cancer Center in Melbourne, Australia, at the European Society for Medical Oncology (ESMO) congress.

" is the first phase III trial of an ALK inhibitor in resected stage IB to IIIA non-small cell lung cancer," he said. "Treatment with adjuvant alectinib resulted in a statistically significant and clinically meaningful improvement in disease-free survival compared with chemotherapy. The disease-free survival benefit was seen consistently across subgroups. An improvement in CNS [central nervous system] disease-free survival was observed, with a hazard ratio of 0.22."

"Adjuvant alectinib for 2 years was tolerable, in line with the known safety profile of alectinib," Solomon stated. "Alectinib represents an important new treatment strategy for patients with resected stage IB to IIIA ALK-positive non-small cell lung cancer."

Despite an "impressive" win for the ALK inhibitor, the results should not be interpreted as a death knell for adjuvant chemotherapy in ALK+ NSCLC, said ESMO invited discussant Marina Chiara Garassino, MD, of the University of Chicago.

"I don't think we should give up on chemotherapy," she said. "I think we should discuss it with the patients, because we have to remember that chemotherapy is the regimen that in the overall population. We also know that , and the results in the adjuvant setting can be even better. Is 2 years of alectinib enough to impact the overall survival? I think that we don't know that yet because the results are very early."

In the comparing crizotinib (Xalkori) and alectinib, the median progression-free survival (PFS) with alectinib was 34.8 months, which meant that half the patients received alectinib for almost 3 years before resistance occurred, Garassino continued. In the , 3 years of osimertinib (Tagrisso) resulted in a significant improvement in DFS and, with longer follow-up, in OS.

In contrast, a trial of (Tarceva) showed an "impressive" PFS benefit after 2 years of treatment. However, that did not translate into an OS benefit.

"So I think we should wait for more results from this trial [ALINA]," said Garassino.

Resectable disease accounts for 30-40% of NSCLC, but patients remain at high risk of recurrence, Solomon noted. ALK rearrangements occur in 4-5% of NSCLC and are associated with younger age, non-smoker status, and a high risk of brain metastasis. The current standard of care for resectable ALK+ NSCLC is surgery followed by adjuvant platinum-containing chemotherapy.

Alectinib demonstrated superiority over crizotinib in three phase III trials of advanced ALK+ NSCLC, and long-term treatment with the ALK inhibitor has been well tolerated, Solomon continued.

The randomized, open-label ALINA trial compared alectinib and chemotherapy as adjuvant therapy for patients with resected stage IB-IIIA ALK+ NSCLC. Treatment continued until disease progression. The primary endpoint was investigator-assessed DFS in patients with stage II-IIIA disease. CNS DFS was a key secondary endpoint. If alectinib demonstrated statistical superiority over chemotherapy in stage II-IIIA disease, statistical significance for DFS was tested in the intention-to-treat population.

Data analysis included 257 patients. The primary analysis showed that alectinib reduced the HR for DFS by 76% compared with chemotherapy (95% CI 0.13-0.45, P<0.0001). Fourteen patients in the alectinib arm had recurrent disease, as compared with 44 recurrences and one death in the chemotherapy arm. Landmark analysis showed 24- and 36-month DFS of 93.8% and 88.3%, respectively, for alectinib versus 63.0% and 53.3% for chemotherapy.

The all-comer analysis yielded essentially the same results, including a 76% reduction in the HR in favor of alectinib (95% CI 0.13-0.43, P<0.0001). Two- and 3-year DFS with alectinib was 93.6% and 88.7% versus 63.7% and 54.0% with chemotherapy. A subgroup analysis favored alectinib for all prespecified groups. OS data remained immature, as only six deaths had occurred at data cut.

The secondary analysis of DFS in the brain showed a 78% reduction in the HR favoring alectinib (95% CI 0.08-0.58). Four patients randomized to alectinib had recurrence in the brain and one patient died. That compared with 14 brain recurrences and four deaths in the control arm.

Grade 3-5 AEs occurred in 30-31% of patients in both groups. Withdrawal rates were 5% with alectinib and 13% with chemotherapy. The most common (≥15% of patients) all-grade AEs with alectinib were increased creatine phosphokinase, constipation, increased liver function tests, increased bilirubin, COVID-19, myalgia, increased alkaline phosphatase, and anemia.

Three other trials of adjuvant alectinib (, , ) are underway, said Solomon.

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