Frontline Alecensa Extends Survival in Advanced ALK-Positive Lung Cancer

Alecensa (alectinib) demonstrated a 22% reduction in the risk of death compared with Xalkori (crizotinib) in the frontline setting of patients with advanced ALK-positive non–small cell lung cancer (NSCLC), which was found to be clinically meaningful, according to final results of the phase 3 ALEX trial presented during the 2025 ESMO Congress.

Data showed that at a median follow-up of 53.5 months with Alecensa and 23.3 months with Xalkori, the median overall survival (OS) was 81.1 months compared with 54.2 months, respectively. The 7-year OS rate was 48.6% with Alecensa versus 38.2% with Xalkori.

“This is probably one of the longest OS [rates] we’ve ever reported for patients with stage 4 non–small cell lung cancer. Despite the numerical difference, the result was not significant,” lead study author Dr. Tony S. K. Mok said in a presentation of the data, explaining that the study was not powered for OS. “Fifty percent of patients alive at 5 years in a randomized phase 3 study of stage 4 lung cancer, I think this is actually an achievement.”

The long-term OS improvement with Alecensa, which was beneficial but not significant, was observed across most patient subgroups except for active smokers and those with an ECOG performance status of 2. In those with central nervous system (CNS) metastases, however, data showed that the largest benefit was observed in patients who had undergone radiation.

Earlier results of ALEX led to the Food and Drug Administration approval of Alecensa in April 2024 in the frontline setting for patients with advanced ALK-positive NSCLC.

In the open-label, multicenter phase 3 ALEX trial, patients with advanced ALK-positive NSCLC were randomly assigned to receive 600 milligrams (mg) of twice-daily Alecensa or 250 mg of twice-daily Xalkori until disease progression, unacceptable toxicity, withdrawal from study, or death. No crossover was permitted before disease progression. Patients also underwent imaging every eight weeks.

Patients must have been 18 years or older, have no prior systemic therapy, and an ECOG performance status of 0 to 2. Stratification factors included ECOG performance status (0 or 1 versus 2), race (Asian versus non-Asian), and baseline CNS metastases (yes versus no).

The primary end point was investigator-assessed progression-free survival (PFS) via RECIST 1.1 criteria, with secondary end points being independent review committee–assessed PFS, time to CNS progression, objective response rate, duration of response, OS and safety.

Prior reported data of the final PFS analysis showed an investigator-assessed median PFS of 34.8 months with Alecensa versus 10.9 months with Xalkori. At a median follow-up of 48.2 months, OS data were immature, and the median OS was not reached with Alecensa versus 57.4 months with Xalkori.

At the ESMO Congress 2025, Mok, who serves as the Li Shu Fan Medical Foundation endowed professor and chairman of the Department of Clinical Oncology at the Chinese University of Hong Kong, presented on the final OS analysis and long-term safety data after an additional 6 years of follow-up from the prior OS analysis. The data cutoff date was April 28, 2025.

Patient characteristics were generally well balanced between both arms. CNS metastases via an independent review committee were present in 42.1% of Alecensa-treated patients (152 patients) versus 38.4% of those on Xalkori (151 patients), and 17.1% and 13.9% of patients, respectively, received prior brain radiation.

Additional data showed that the next one or more lines of ALK TKI therapy in the Alecensa (37.5%) and Xalkori arms (47.7%) included lorlatinib (18.4% and 11.9%, respectively), Alunbrig (brigatinib; 10.5% and 10.6%), Xalkori (9.2% and 6.6%), Alecensa (8.6% and 25.2%), Zykadia (6.6% and 19.2%), ensartinib (0.7% and 0%), NVL 655 (0.7% and 0%), and APG 2449 (0 and 0.7%).

Mok noted these OS results are not statistically significant, potentially due to confounded data from the crossover arm of Xalkori-treated patients to Alecensa.

In exploring the OS of patients with CNS metastases at baseline, the median OS was 63.4 months in those on Alecensa (59 patients) compared with 30.9 months for those on the Xalkori arm (53 patients), leading to a 32% reduction in the risk of death. For those without CNS metastases on Alecensa (93 patients) or Xalkori (98 patients), the median OS was 94 months versus 69.8 months, respectively.

Furthermore, in the group of patients who received prior brain radiation, the median OS was 92 months with Alecensa (25 patients) compared with 39.5 months in those who received Xalkori (18 patients). Those who did not have prior brain radiation had a median OS of 46.9 months with Alecensa (34 patients) versus 23.7 months on Xalkori (35 patients).

Investigator-assessed duration of response in responders was a median of 42.3 months with Alecensa (126 patients) versus 11.1 months with Xalkori responders (11 patients).

Regarding side effects, the median duration of treatment was 28.1 months with Alecensa and 10.8 months with Xalkori. The most common side effects that led to dose reductions or discontinuations with Alecensa comprised increased blood bilirubin (5.3% and 3.3%, respectively). For Xalkori, this included increased alanine aminotransferase (8.6% and 6.6%). Grade 3 (severe) to 5 (death) side effects were similar between the Alecensa and Xalkori arms (57.9% versus 57.6%, respectively), and serious side effects were 46.1% versus 31.8%; treatment-related side effects were 82.2% versus 89.4%. Side effects with Alecensa that led to death, treatment discontinuation, dose reduction, and dose interruptions occurred in 6.6%, 17.8%, 23%, and 32.2%, respectively. On the Xalkori arm, these rates were 4.6%, 14.6%, 19.9%, and 28.5%, respectively.

The most common grade 3 to 5 side effects between both arms included anemia (7.2% with Alecensa versus 0.7% with Xalkori), increased alanine aspartase (5.3% versus 10.6%), pneumonia (5.3% versus 2%), urinary tract infection (5.3% versus 0.7%), increased ALT (4.6% versus 16.6%), increased blood bilirubin (4.6% versus 0%), increased blood CPK (3.3% versus 4.6%), and neutropenia (0% versus 6%).

Two percent of on-study deaths (3 patients) of unknown cause, with no autopsy performed, were suspected to be unrelated to Alecensa.

References

1. “Final Overall Survival and Safety Analysis of the Phase 3 ALEX Study of Alecensa versus Xalkori in Patients With Previously Untreated, Advanced ALK-positive Non-Small Cell Lung Cancer” by Dr. Tony S. K. Mok, et al., Annals of Oncology.
2. “Alecensa versus Xalkori in Untreated ALK-positive Non-Small Cell Lung Cancer” by Dr. Solange Peters, et al., New England Journal of Medicine.
3. “FDA Approves Alecensa as First Adjuvant Treatment for People With ALK-positive Early-Stage Lung Cancer,” Genentech news release, April 18, 2024.
4. “Updated Overall Survival and Final Progression-Free Survival Data for Patients With Treatment-Naive Advanced ALK-positive Non-Small Cell Lung Cancer in the ALEX Study” by Dr. Tony S. K. Mok, et al., Annals of Oncology.

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