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Alectinib Reduces Risk Of Recurrence Or Death By 76% In Early-Stage, Resected, ALK+ NSCLC
Adjuvant alectinib significantly improved disease-free survival in patients with ALK-positive, early-stage, non–small-cell lung cancer.
Ben Solomon, MBBS, PhD, FRACP
Alectinib (Alecensa), an oral ALK inhibitor, significantly improved disease-free survival (DFS) among patients with resected ALK-positive non–small-cell lung cancer (NSCLC), according to data from the phase 3 ALINA trial (NCT0345076).1
The findings, which were presented at the 2023 ESMO conference, showed that the targeted therapy elicited superior outcomes than platinum-based chemotherapy across all prespecified subgroups.
Key FindingsThe median follow up was 27.9 months with alectinib and 27.8 months with chemotherapy.
Patients with stage II-IIIA who received alectinib (n = 116) had a 76% reduced risk of disease recurrence or death (HR, 0.24; 95% CI, 0.13-0.45; P < .0001), compared with those who received platinum-based chemotherapy (n = 115). Among these 2 groups, the median DFS was not reached (95% CI, 28.5-not evaluable [NE]) with alectinib vs 44.4 months (95% CI, 27.8-NE) with chemotherapy.
Further, the 2-year DFS rates were 93.8% vs 63.0%, respectively. The 3-year DFS rates were 88.3% vs 53.3%.
In the intention-to-treat population (ITT), which included the entire study population with stage IB-IIIA disease, the median DFS was not reached among patients who received alectinib (n = 130) vs 41.3 months (95% CI, 28.5-NE) among those who received chemotherapy (n = 127). Again, the improvement in DFS yielded a 0.24 hazard ratio (95% CI, 0.13-0.45; P < .0001).
Also in the ITT population, the rates of 2-year DFS were 93.6% vs 63.7% and the 3-year DFS rates were 88.7% vs 54.0%, respectively.
Of note, the rate of grade 3 or 4 adverse events (AEs) was similar between the 2 groups: 30% and 31% of patients receiving targeted or chemotherapy, respectively, reported high-grade AEs. No grade 5 events were reported in either cohort.
"Treatment with adjuvant alectinib resulted in a statistically significant and clinically meaningful improvement in DFS compared with chemotherapy," Ben Solomon, MBBS, PhD, FRACP, a Medical Oncologist at the Peter MacCallum Cancer Centre in Australia, said in a presentation of the data.
"The DFS benefit was seen consistently across subgroups and an improved in CNS-DFS was observed," Solomon said.
In terms of overall survival (OS), data were still immature at data cutoff, with only 6 events reported.
SignificanceAmong patients with NSCLC, approximately 4 to 5% will harbor an ALK rearrangement. These patients tend to be 55 years or younger, to not have a history of smoking, and to be at a higher risk of brain metastases—nearly half of patients with ALK alterations develop brain metastases.
Approximately 30% to 40% of patients with NSCLC will receive a diagnosis of resectable disease. Unfortunately, nearly half of patients with early-stage disease will experience disease recurrence after surgery, highlighting the importance of effective adjuvant options in this space.
The standard treatment approach following surgery is currently platinum-based chemotherapy for patients with stage IIB-IIIA, ALK-positive disease, however this modality is associated with modest improvements in survival outcomes. Similarly, immunotherapy approaches have not been fruitful for patients with resected, ALK-positive disease.
Alectinib already plays a role for certain patients with ALK-positive NSCLC. For patients with advanced disease who have not yet undergone resection, alectinib is the preferred front-line regimen. Three distinct phase 3 trials have demonstrated significant progression-free survival benefits and intracranial control with alectinib vs crizotinib in this setting. It is also associated with a high rate of intracranial activity. As of August 2023, it is estimated that more than 92,000 patients with ALK-positive disease have been treated with the oral TKI.
The current findings are the first to compare this agent against platinum-based chemotherapy in a population of ALK-positive patients in the adjuvant setting.
MethodologyALINA enrolled patients with completely resected stage IB-IIIA, ALK-positive NSCLC. To be eligible, they needed an ECOG PS of 0 to 1, adequate end-organ function, and to be naïve to prior systemic therapies. They also needed to be eligible to receive platinum-based chemotherapy. Patients were stratified by stage (II vs IIIA) as well as by race (Asian vs non-Asian).
The 257 participants were randomly assigned 1:1 to undergo treatment with either alectinib or platinum-based chemotherapy. Patients in the alectinib cohort received 600 mg twice daily for 2 years and those receiving chemotherapy received their treatment every 3 weeks for 4 cycles. Both arms continued treatment until recurrence occurred — at which point their investigator chose their sequential treatment and survival follow-up commenced.
Baseline characteristics were balanced between the 2 arms, with a slightly higher proportion of females in the alectinib arm (58% vs 46%). Most patients were never smokers who had undergone a lobectomy and had non-squamous disease. Of note, 53% of patients in the alectinib arm and 55% of patients in the chemotherapy arm had stage IIIA disease. Additionally, 49% and 52% of patients, respectively, had N2 nodal status at baseline.
The primary end points were DFS per investigator assessment. DFS was tested hierarchically. First, it was assessed among those with stage II-IIIA disease. Then, it was assessed in the intention-to-treat population (stage IB-IIIA patients).
Secondary end points included central nervous system (CNS) DFS, OS, and safety.
These findings are from a pre-planned interim analysis, following 67% of events in the stage II-IIA subpopulation. The clinical cut-off date was June 26, 2023.
Secondary Outcomes"In terms of the subgroup analysis, benefit in favor of alectinib was seen across all the pre-defined subgroups evaluated, including stage and nodal status," Solomon emphasized in the presentation.
When looking at DFS by stage, the 2-year results continued to favor alectinib. For those with stage IB disease (n = 26), stage II (n = 92), and stage IIIA (n = 139) disease, respectively, the rates of DFS after 2 years were 92.3%, 95.6%, and 92.7% with alectinib vs 71.6%, 66.3%, and 60.7%, respectively.
Therefore, the reduced risk of death or recurrence was 79% with stage IB (HR, 0.21; 95% CI, 0.02-1.84), 76% with stage II (HR, 0.24; 95% CI, 0.09-0.65) and 75% with IIIA disease (HR, 0.25; 95% CI, 0.12-0.53), respectively.
In addition, 4 patients receiving alectinib vs 14 patients receiving chemotherapy in the ITT population experienced brain recurrence (HR, 0.22; 95% CI, 0.08-0.58). The rate of CNS DFS at 2 years was 98.4% vs 85.8%, respectively. At 3 years, the rates were 95.5% vs 79.7%.
"CNS [DFS] was an important exploratory end point of the study," Solomon noted. "CNS imaging was mandated at baseline and serially with disease assessments with MRI, if feasible."
Regarding the agent's safety summary, the median duration of treatment was 23.9 months with alectinib and 2.1 months with chemotherapy, leading to a longer safety follow-up time with the targeted treatment. The rate of any-grade AEs was 98% vs 93%, respectively. Of note, a higher percentage of patients receiving alectinib needed to dose reduce because of an AE (26% vs 10%) or interrupt treatment because of an AE (27% vs 18%), although fewer needed to discontinue treatment overall (5% vs 13%).
The most common AEs reported with alectinib were increased in blood creatinine phosphokinase, constipation, and increases in aspartate aminotransferase and alanine aminotransferase increase, as well as an increased in blood bilirubin. In the chemotherapy arm, the most common AEs were nausea, constipation, anemia, and decreased appetite.
There are currently 3 other clinical trials studying alectinib in stage I-III NSCLC, including the phase 2 NAUTIKA1 trial (NCT04302025), the phase 2 ALNEO trial (NCT05015010), and the phase 3 HORIZON-01 trial (International NCT05170204). The manufacturers have announced that they intend to file these data with the FDA and the European Medicines Agency following the presentation of the data.2
"Adjuvant alectinib was tolerable and in line with the known safety profile of alectinib," Solomon concluded. "Adjuvant alectinib represents an important new treatment strategy for patients with resected, stage IB-IIIA, ALK-positive, NSCLC."
References
Patients With Resectable NSCLC See Benefits From Pre- And Post-Surgical Opdivo
Treatment with neoadjuvant Opdivo, followed by Opdivo after surgery led to significantly improved event-free survival in the first phase 3 perioperative study in patients with resectable non-small cell lung cancer.
Perioperative Opdivo improved outcomes for certain patients with non-small cell lung cancer.
Neoadjuvant (pre-surgical) treatment with Opdivo (nivolumab) plus chemotherapy followed by surgery and adjuvant (treatment administered following the main treatment) Opdivo significantly improved event-free survival (EFS, the time a patient lives without complications from the disease), compared with placebo plus chemotherapy, in patients with previously untreated resectable (able to be removed via surgery) stage 2 to 3B non-small cell lung cancer (NSCLC), according to data from the phase 3 CheckMate-77T trial presented at ESMO Congress 2023.
"CheckMate-77T is the first phase 3 perioperative study to build on the standard-of-care neoadjuvant (Opdivo) plus chemo and supports perioperative (Opdivo) as a potential new treatment option for patients with resectable non-small cell lung cancer," Dr. Tina Cascone, assistant professor in the department of thoracic, head and neck medical oncology at The University of Texas MD Anderson Cancer Center, said during a presentation of the data.
After a median follow-up of 25.4 months, perioperative Opdivo demonstrated a statistically significant and clinically meaningful improvement in EFS. Median EFS with Opdivo was not reached, compared with 18.4 months with placebo. Per investigator assessment, treatment with Opdivo reduced the risk for recurrence, disease progression or death by 44%, compared with placebo.
Further, 18-month EFS was superior with Opdivo vs placebo (70% vs 50%, respectively), "suggesting greater benefit for our patients over time," Cascone said.
PFS benefit with Opdivo was observed across subgroups, regardless of disease stage — with a particular benefit in those with stage 3 disease – N2 status (single-station vs multi-station), type of disease (squamous vs non-squamous), smoking status and PD-L1 status.
"However, given the small sample size of this subgroup, results should be taken with caution," Cascone noted.
In exploratory analyses, the investigators evaluated EFS by baseline disease stage, tumor PD-L1 expression, pathologic complete response (pCR, when cancer cannot to be found on biopsy samples taken during surgery or after treatment) and major pathologic response (MPR, 10% of the tumor remains after post-surgical treatment) status, adjuvant treatment status and pCR status in patients who received adjuvant treatment.
Among patients with stage 2 disease, median EFS was not reached in both the Opdivo and placebo arms, while those with stage 3 disease demonstrated a median EFS of 30.2 monthsand 13.4 months, respectively. The 12-month EFS rates in patients with stage 2 disease treated with Opdivo and placebo were 78% and 73%, respectively, and 71% and 52% in those with stage 3 disease.
When evaluating patients by PD-L1 status, those with less than 1% induced a median EFS of 29 months with Opdivo, compared with 19.8 months with placebo, while those with 1% or greater had a median EFS not yet reached and 15.8 months, respectively.
Opdivo, compared with placebo, was superior for both pCR and MPR. The pCR benefit was also seen across the subgroup analysis.
"We know that patients have a better prognosis if pre-surgical treatment of lung cancer leads to tumor disappearance on pathology reports after surgery than if there are still obvious cancer cells present in post-surgical material," Elene Mariamidze of Todua Clinic, Tbilisi, Georgia, said in a press release issued by ESMO. "The new results show that adding immunotherapy to chemotherapy before surgery, and then continuing with maintenance immunotherapy for a year after surgery, is more effective than just giving chemotherapy before surgery."
Any-grade surgery-related side effects occurred in 73 patients (41%) in the Opdivo arm and 69 patients (39%) patients in the placebo arm, while 21 (12%) patients in each arm experienced grade 3 to 4 side effects. Treatment-related deaths occurred in 2 (1%) patients in the Opdivo arm: one due to grade 5 pneumonitis (lung inflammation) and one due to grade 4 pneumonitis, both occurring after completion of neoadjuvant treatment.
Of the 229 patients who received Opdivo plus chemotherapy, 15% discontinued neoadjuvant therapy, while 20% went on to cancel their definitive surgery and 17% of this arm did not receive adjuvant therapy as a result of study drug toxicity (6%), disease progression (2%) or another reason (9%).
In total, 85 patients (60%) in the Opdivo arm completed treatment, compared with 92 patients (60%) in the control arm, and eight (6%) are ongoing in the study, compared with eight (5%) with placebo. Nearly two-thirds of patients received adjuvant treatment with a median number of 13 doses administered in each arm, Cascone said.
Opdivo is the current standard of care for the adjuvant treatment of patients with resectable NSCLC. Therefore, Cascone and colleagues believed the agent has a role in the neoadjuvant setting as well.
"A perioperative treatment approach, including adjuvant (Opdivo), could potentially further reduce the risk of disease relapse and improve clinical benefit in patients with resectable non-small cell lung cancer," Cascone said.
Investigators randomized 461 patients to receive either:
To be eligible for the trial, patients had to have resectable, stage 2A to 3B NSCLC, have received no prior systemic anti-cancer treatment and no EGFR mutation or known ALK alterations.
Patients were stratified by disease histology, disease stage and PD-L1 status.
Cascone noted that, in the Opdivo arm, median age was 66 years, while the majority of patients had stage 3A-B disease (64%), were current or former smokers (93%) and had either PD-L1 less than 1% (41%) or PD-L1 1% or greater (56%).
Lobectomy was the most common type of surgery and was performed in 80% of patients in the Opdivo arm and 72% of those in the chemotherapy arm, while 9% and 14% of patients, respectively, underwent pneumonectomy. Approximately 90% of patients in each arm had an R0 resection.
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ESMO: Roche's Alecensa Claims A First In ALK-positive NSCLC
Roche's Alecensa has become the first drug in the ALK inhibitor class to significantly improve disease-free survival across all disease stages in a phase 3 trial involving patients with ALK-positive non-small cell lung cancer (NSCLC).
The findings – trumpeted as "practice-changing" at the symposium during the ESMO conference – came from an interim analysis of data that found a 76% improvement in DFS for Alecensa (alectinib) compared to platinum-based chemotherapy when used as adjuvant treatment after surgery.
Two-year DFS rates with Alecensa and chemotherapy were 93.8% and 63.0%, respectively, after around 28 months' follow-up, and Roche's drug also a 78% reduction in disease recurrence or death related to recurrence of the cancer in the central nervous system, a common area of relapse following surgery in patients with ALK-positive NSCLC.
"The findings…will absolutely help to change practice as they give a very clear signal, in a head-to-head comparison with chemotherapy, that adjuvant targeted treatment with alectinib improves DFS in this setting," said Prof Martin Reck from the Lung Clinic Grosshansdorf in Germany, who presented the results at ESMO.
Roche said that with about one in two people with early-stage NSCLC experiencing disease recurrence following surgery, despite adjuvant chemotherapy, more effective treatment options are urgently needed to provide the best chance for a cure.
"Alecensa can potentially alter the course of this disease as we aim to provide the best chance for cure," said Roche's chief medical officer Levi Garraway.
The company said it plans to file the data with global regulatory authorities, including the FDA in the US and EMA in the EU. Meanwhile, the patients in ALINA are continuing to be followed to see if the DFS improvement translates to an increase in overall survival, a secondary endpoint.
Around 5% of all NSCLC cases carry ALK mutations, and patients with advanced disease have multiple treatment options, including Alecensa, Takeda's Alunbrig (brigatinib), and Novartis' Zykadia (ceritinib), as well as Pfizer's older therapy Xalkori (crizotinib) and follow-up Lorbrena (lorlatinib).
Roche is vying to become the first company to get approval for an ALK inhibitor in early-stage NSCLC and seems to be firmly in front of its rivals with that plan, as there is no indication that any of the other companies are testing their ALK inhibitors in this setting.
There are some answers still needed to gauge Alecensa's potential role in this setting, according to Reck.
"We need to look at biomarkers and to investigate if the effect of alectinib is homogeneous across ALK translocations or if there is a different variant partner, or a specific variant, that is indicative of a particularly good response – or, conversely, a detrimental effect – with treatment," he told the congress.
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