AACR Annual Meeting 2023: Phase III Immunotherapy Trials Offer Hope for Patients With Lung, Liver, and Biliary Tract Cancers 

AEGEAN is a global, multicenter, phase III, double-blind, placebo-controlled randomized clinical trial, in which investigators tested the PD-L1-targeted ICI durvalumab (Imfinzi) as perioperative therapy, meaning before and after surgery, in patients with resectable NSCLC. 

Presenter John V. Heymach, MD, PhD, chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, noted that data from recent phase III trials have shown the benefit of ICIs as neoadjuvant or adjuvant treatment for patients with NSCLC, leading to the U.S. Food and Drug Administration (FDA) approving ICIs in these settings.  

In AEGEAN, investigators aimed to study whether a comprehensive approach with ICI-based treatment in both neoadjuvant and adjuvant settings would be more beneficial than neoadjuvant chemotherapy alone. They hypothesized that this approach could help prime the immune system when the draining lymph nodes are still present prior to surgery, and also help eliminate micrometastases. 

In this phase III trial, patients with treatment-naïve resectable NSCLC, irrespective of PD-L1 expression, were randomly assigned to receive either neoadjuvant durvalumab plus platinum-based chemotherapy or neoadjuvant placebo plus platinum-based chemotherapy every three weeks for four cycles; following surgery, patients continued to receive either durvalumab or placebo every four weeks for up to 12 cycles.  

In June 2022, the investigators reported that the trial met one of its primary endpoints of pathological complete response (pCR), defined as no viable tumor left in the surgical specimen (including lymph nodes) following neoadjuvant therapy. 

In the interim analysis presented at the Annual Meeting, the investigators reported data on the final analysis of pCR and on another primary endpoint, event-free survival (EFS), defined as the length of time from randomization to an event, such as disease progression precluding definitive surgery, disease recurrence, or death. 

The trial met both its primary endpoints. Final analysis showed a pCR of 17.2% in the treatment arm, versus 4.3% in the placebo arm—a difference of nearly 13.0%. Of note, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy, suggesting that neoadjuvant treatment with durvalumab did not have any negative impact on the patients’ ability to undergo surgery. 

After a median follow-up time of 11.7 months, median EFS was not reached in the durvalumab-based regimen arm, versus 25.9 months in the chemotherapy alone arm. Patients in the durvalumab-based regimen arm had a 32% reduction in the risk of disease progression precluding definitive surgery, disease recurrence, or death compared with those in the chemotherapy alone arm. 

Discussant Roy Herbst, MD, PhD, professor of medicine and deputy director of Yale Cancer Center, noted that AEGEAN definitely defines “a” new standard of care, but not “the” new standard of care, as the trial arms did not include current standard of care involving immunotherapy regimens as a comparison. He added that mature data with overall survival will be needed to fully understand the benefit of additional adjuvant durvalumab. 

In IMbrave050 trial, adjuvant atezolizumab-bevacizumab combination improved recurrence-free survival for patients with resectable liver cancer 

The rate of disease recurrence in patients with early-stage hepatocellular carcinoma (HCC) following standard-of-care treatments is typically higher because of the absence of an established adjuvant treatment regimen, according to study presenter Pierce Chow, FRCS(E), PhD, senior consultant surgeon at National Cancer Centre Singapore and Singapore General Hospital, and professor and program director at Duke-NUS Medical School, Singapore. 

Data from a prior phase III trial, IMbrave150, demonstrated that a combination of the ICI atezolizumab (Tecentriq) and the angiogenesis inhibitor bevacizumab (Avastin) given as first-line treatment improved outcomes for patients with unresectable HCC, compared with sorafenib (Nexavar). Based on these data, the FDA approved this combination in 2020 as a standard of care for this indication. 

Correlative biomarker analyses of patient samples from IMbrave150, published in Nature Medicine in 2022, suggested that combining the two agents may improve outcomes by targeting angiogenesis, T-cell proliferation, and myeloid cell inflammation, and provided proof of concept for further evaluation of this combination strategy. 

In IMbrave050, a global, multicenter, open-label, randomized phase III clinical trial, Chow and colleagues investigated whether this combination given as adjuvant therapy for patients with resectable HCC could delay or prevent recurrence, compared with active surveillance, the current standard of care after complete surgical resection or ablation for this patient population. 

Patients with high risk of recurrence of HCC were randomly assigned to either receive atezolizumab plus bevacizumab every three weeks for a year or to undergo active surveillance for a year. The primary endpoint of independent review facility-assessed recurrence-free survival was evaluated. 

The trial met its primary endpoint: After a median follow-up of 17.4 months, patients in the combination treatment arm had a 28% reduction in the risk of recurrence compared with those in the active surveillance arm. Benefit was seen across all clinical subgroups. Many patients who are currently not eligible for surgery because of expected rapid disease progression may potentially benefit from surgery if a promising adjuvant treatment option becomes available, according to Chow. 

Discussant Stephen Lam Chan, MD, professor in the department of clinical oncology at Chinese University of Hong Kong, noted that the data from this trial are potentially practice-changing, but cautioned that mature data with information on overall survival will be needed to guide patient selection. 

In KEYNOTE-966 trial, first line pembrolizumab-chemotherapy combination improved overall survival in patients with biliary tract cancer 

The incidence of biliary tract cancers, a group of rare and aggressive cancers that arise from the bile ducts and gall bladder are on the rise and typically have a poor prognosis, noted presenting author Robin “Katie” Kelley, MD, a professor of clinical medicine at the Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco. 

The tumor microenvironment of biliary tract cancers is immunosuppressive, precluding benefit from ICI monotherapies. Chemotherapies, however, are known to modulate the immune system, leading researchers to hypothesize that a combination of ICI and chemotherapy could be of benefit. Data from the phase III trial TOPAZ-1 showed that a combination of durvalumab and standard-of-care chemotherapies in the first-line setting improved long-term outcomes for patients with biliary tract cancer, and in 2022, the FDA approved this combination for this indication. 

KEYNOTE-966 is a global, multicenter, randomized, double-blind, phase III trial, in which a combination of the ICI pembrolizumab (Keytruda) and the current standard-of-care chemotherapeutics gemcitabine and cisplatin were compared with placebo plus gemcitabine and cisplatin as first-line therapy in patients with advanced and/or unresectable biliary tract cancers. 

Data showed that patients in the pembrolizumab arm had a median overall survival of 12.7 months, compared with 10.9 months for those in the placebo arm. An improvement was seen in the median duration of response (9.7 months versus 6.6 months), and benefit was seen across all prespecified subgroups. Data from this trial were simultaneously published in The Lancet. 

Kelley noted that KEYNOTE-966 is a larger study of 1,069 patients compared with TOPAZ-1 (685 patients), with a higher proportion of patients from western and non-Asian sites. A commentary on the paper notes that because of this, the conclusions from KEYNOTE-966 may be more applicable to a global population. 

Discussant Rachna T. Shroff, MD, associate professor of medicine at University of Arizona Cancer Center, noted that these two large clinical trials confirm that the ICI-chemotherapy combination “is here to stay” for this patient population. She pointed out that compared to TOPAZ-1, KEYNOTE-966 had more detailed information on microsatellite instability status and hepatitis B viral status, both of which are considerations when treating patients with ICI. She added that these data, along with in-depth biomarker analyses and quality-of-life measures, are crucial in designing future clinical trials for this population.