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Roche's Alecensa Lowers Recurrence in Adjuvant NSCLC, But Experts Await Overall Survival Data

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NEW YORK – In the ALINA trial, Roche's Alecensa (alectinib) improved outcomes for patients with early-stage ALK-positive non-small cell lung cancer after surgery more than chemotherapy did. But given the potential for long-term toxicity with the targeted agent, experts at the European Society for Medical Oncology Congress questioned whether the drug's benefits outweighed its risks.

In the Phase III study, adjuvant treatment with Alecensa improved disease-free survival in patients with completely resected stage Ib to IIIa ALK-positive NSCLC over chemo. The two-year disease-free survival rate was 94 percent in the Alecensa arm and 64 percent in the chemo arm. At three years, 89 percent of patients on Alecensa had not experienced disease recurrence versus 54 percent of those on chemo.

Benjamin Solomon, a medical oncologist at the Peter MacCallum Cancer Centre in Australia who presented the ALINA results at the meeting, noted that overall survival data were not yet mature, with only six mortality events occurring as of the June 26 cutoff.

"Patients with ALK-positive non-small cell lung cancer tend to be younger, they tend to be non-smokers, and they also have a high propensity to develop brain metastases," Solomon said. "For patients with resectable ALK-positive disease, advances in immunotherapy in the neoadjuvant and adjuvant setting do not seem to apply, and the current standard of care after surgery remains adjuvant platinum-based chemotherapy."

In ALINA, Alecensa also demonstrated longer central nervous system (CNS) disease-free survival for these patients who are typically at high risk of brain metastases. Nearly all patients, 98 percent, in the Alecensa arm had not developed CNS metastases at two years, compared to 86 percent who had no CNS disease at two years on chemo. Among 15 patients in the trial who did have disease recurrence on Alecensa, most had local or regional recurrence, not distant recurrence. In the chemo arm, a similar proportion of patients had local or regional and distant disease recurrence, including brain metastases.

"The effect on distant recurrences was particularly profound," Solomon said. "With marked effects not just in the brain, but also at extracranial sites, including bone."

This week, Roche said it would seek regulatory approval for Alecensa in the adjuvant setting. On a call to discuss its Q3 financial results on Thursday, Roche Pharmaceuticals CEO Teresa Graham estimated that this adjuvant indication would bring in around $500 million in additional sales per year if it is approved in the US and EU next year.

While these results demonstrated Alecensa improved outcomes and reduced disease recurrence in this patient population, experts still questioned the tolerability of the treatment and whether it will eventually improve overall survival compared to chemo, said Marina Garassino, a professor of medicine at the University of Chicago who discussed the ALINA trial results at the meeting.

Garassino, who was not involved with the study, emphasized that toxicity in the adjuvant setting is a potential issue. While the adverse events were different in the Alecensa and chemo arms, a similar proportion of patients, about 1 in 4, experienced grade 3 or grade 4 adverse events in both arms.

Solomon noted that the safety and tolerability seen with Alecensa in the ALINA trial were in line with what's previously been observed. In the study, the most common adverse events patients experienced included increased blood creatine phosphokinase and constipation as well as increased liver enzymes and blood bilirubin.

"Patients that are potentially cured with the surgery have to take eight capsules a day [for Alecensa treatment] for a couple of years," she said, pointing out that the rates of adverse events with the targeted therapy were similar to chemo, which was only given for about two months. In contrast, patients remained on Alecensa for a median of 23.9 months, which provides more opportunity for toxicities to build.

Trials testing other targeted therapies in the adjuvant setting for NSCLC have faced similar concerns from experts who want to make sure that toxicities aren't outweighing benefits in this early stage of cancer, when patients have the best chance for a cure. For instance, some oncologists were uncertain about prescribing AstraZeneca's Tagrisso (osimertinib) as an adjuvant treatment for early-stage EGFR-mutated NSCLC based on disease-free survival alone. However, data from the Phase III ADAURA trial confirmed the overall survival benefit with adjuvant Tagrisso earlier this year.

"What I will do tomorrow [in the clinic] is I will ask the patients if they want to have this kind of toxicity in the absence of a clear overall survival benefit," Garassino said.