Despite Shortcomings, Key Learnings Gleaned From Phase 3 Trials
Lung Cancer Outcomes Significantly Improved With Immunotherapy-based Treatment Given Before And After Surgery
A regimen of pre-surgical immunotherapy and chemotherapy followed by post-surgical immunotherapy significantly improved event-free survival (EFS) and pathologic complete response (pCR) rates compared to chemotherapy alone for patients with operable non-small cell lung cancer (NSCLC), according to results of a Phase III trial reported by researchers at The University of Texas MD Anderson Cancer Center.
The findings, published today in the New England Journal of Medicine, were first presented at the American Association for Cancer Research (AACR) Annual Meeting 2023.
The AEGEAN trial evaluated durvalumab given perioperatively, meaning therapy is given both before and after surgery. Participants on the trial received either pre-surgical (neoadjuvant) durvalumab and platinum-based chemotherapy followed by post-surgical (adjuvant) durvalumab or neoadjuvant placebo and chemotherapy followed by adjuvant placebo.
AEGEAN was the first Phase III trial investigating perioperative immunotherapy in patients with resectable NSCLC to report positive outcomes, and these data add to the growing evidence supporting the benefits of both neoadjuvant and adjuvant immunotherapy for these patients
"Our goal is to increase cures for lung cancer. Throughout decades of research with adjuvant and neoadjuvant chemotherapy, we only succeeded in increasing cures by around 5%,"
said principal investigator John Heymach, M.D., Ph.D., chair of Thoracic/Head & Neck Medical Oncology at MD Anderson. "This one study alone has the potential to increase that percentage significantly, and we look forward to many more improvements going forward."
Of the patients receiving perioperative durvalumab, 17.2% had a pCR compared to just 4.3% of those receiving chemotherapy alone. At the first interim analysis of EFS, with a median follow-up of 11.7 months, the median EFS was 25.9 months in the placebo arm, but it had not yet been reached in the durvalumab arm.
These data correspond to a 32% lower chance of patients experiencing disease recurrence, progression events or death with the immunotherapy-based treatment when compared to chemotherapy alone. Approximately four times as many patients treated with perioperative durvalumab plus chemotherapy achieved a pCR when compared to those treated with chemotherapy alone.
Durvalumab, an immune checkpoint inhibitor targeting PD-L1, has previously been approved for treating specific patients with biliary tract cancer, liver cancer, small cell lung cancer and NSCLC. Currently, durvalumab is used for treating patients with locally advanced, unresectable NSCLC following definitive chemoradiotherapy and for patients with metastatic NSCLC in combination with tremelimumab and platinum-based chemotherapy.
For resectable NSCLC, previous studies have shown some benefit from using adjuvant or neoadjuvant immunotherapy, but Heymach explained the benefits have been modest so far. MD Anderson is engaged in longstanding multidisciplinary efforts to use neoadjuvant treatments to improve outcomes for patients. Numerous clinical studies, such as the NEOSTAR and NeoCOAST trials, are evaluating neoadjuvant immunotherapy and novel combinations to eliminate viable tumors before surgery and to reduce recurrence rates.
The Phase III AEGEAN trial is a randomized, double-blind, placebo-controlled study to evaluate the benefits of perioperative durvalumab added to platinum-based chemotherapy in adults with untreated stage IIA-IIIB NSCLC. A total of 802 patients were randomized 1:1 into each arm. The study's primary endpoints are pCR, assessed by a central lab, and EFS using a blinded independent central review.
Patients with EGFR/ALK mutations were excluded from the modified intent-to-treat population. A total of 740 patients were included in the efficacy analysis, including 366 on the durvalumab arm and 374 on the placebo arm. The median age of participants in each arm was 65 and 71.6% were male. Patients were 53.6% white, 41.5% Asian and 4.9% other.
Overall, the treatments were well tolerated, and side effects were consistent with previous studies. The researchers observed maximum grade 3-4 any cause adverse events in 42.4% and 43.2% of patients on the durvalumab and placebo arms, respectively.
The benefits in both pCR and EFS largely were consistent across predefined patient subgroups, and the trial continues assessment for long-term EFS as well as disease-free survival and overall survival outcomes.
"This study shows that a combination of neoadjuvant and adjuvant durvalumab offers benefit for patients and may have the potential to change standard-of-care for patients with resectable non-small cell lung cancer," Heymach said. "Going forward, we face a series of questions about how to build more effective regimens without giving more treatment than is necessary."
Heymach explained that future studies must determine which patients receive the most benefit from neoadjuvant therapy and may be able to avoid further treatment as well as those who remain at high risk of recurrence and may require more intensive adjuvant regimens.
The study was conducted by AstraZeneca. Heymach serves on advisory committees for Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer Ingelheim, Regeneron, Takeda, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca, BioAtla, Sanofi, Spectrum Pharmaceuticals, GSK, EMD Serono, Blueprint Medicines and Chugai Pharmaceutical. He receives research support from AstraZeneca, Boehringer Ingelheim, Spectrum, Mirati Therapeutics, Bristol Myers Squibb and Takeda, as well as royalties and licensing fees from Spectrum.
Adjuvant Chemotherapy After Complete Resection Of Non-Small Cell Lung Cancer: In Reply
CorrespondenceDtsch Arztebl Int 2008; 105(25): 457. DOI: 10.3238/arztebl.2008.0457b
Laack, E
The finding of carcinomatous hemangiosis of the tumor (V1) in a completely resected non-small cell lung cancer is often associated with a higher risk of developing distant metastases at a later stage and therefore with a poorer prognosis. A large Japanese study made the same observation for tumor stage pIA (1).To deduce from this a general recommendation for adjuvant chemotherapy in stage pIA (V1) requires prospective randomized studies of patient groups of European or North American origin. Until such studies become available, no patient with tumor stage pIA should be offered adjuvant chemotherapy outside study settings. At this point in time, sufficient evidence is lacking for adjuvant chemotherapy at stage pIA, because prospective randomized studies of unselected patient groups with regard to V1 status have so far not shown a survival advantage for adjuvant chemotherapy in patients with tumor stage pIA. DOI: 10.3238/arztebl.2008.0457b
Prof. Dr. Med. Eckart LaackII. Medizinische Klinik,Onkologisches ZentrumUniversitätsklinikum Hamburg-EppendorfMartinistr. 5220246 Hamburg, Germanylaack@uke.Uni-hamburg.De
Conflict of interest statementThe authors of the letter and the reply declare that they have no conflict of interest as defined by the International Committee of Medical Journal Editors.
1.
Tsuchiya T, Akamine S, Muraoka M et al.: Stage IA non-small cell lung cancer: vessel invasion is a poor prognostic factor and a new target of adjuvant chemotherapy. Lung Cancer 2007; 56: 341–8.
1. Tsuchiya T, Akamine S, Muraoka M et al.: Stage IA non-small cell lung cancer: vessel invasion is a poor prognostic factor and a new target of adjuvant chemotherapy. Lung Cancer 2007; 56: 341–8.Adjuvant Chemotherapy After Complete Resection of Non-Small...
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."
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