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【AACR 2023年会】Ⅲ期免疫疗法试验为肺癌、肝癌和胆道癌患者带来希望

2023年06月28日

来源：癌症研究UPDATE

以下内容原文发布于AACR官方博客《Cancer Research Catalyst》, 中文内容仅做参考，请点击文末“阅读原文”，阅览原文内容。

在刚刚过去的AACR 2023年会上，提交的临床试验摘要数量创造了新记录。会议期间，四个临床试验全体会议、三个临床试验小型研讨会以及其他专题讨论会和壁报环节共计展示了240余份摘要。

本次年会临床试验委员会联合主席Timothy A. Yap博士表示：“临床试验全体会议期间展示的研究真正代表了目前癌症研究领域最具创新性且可能改变临床实践的临床试验和转化研究。”

本次年会临床试验委员会的另一位联合主席Shivaani Kummar博士表示：“身为一名肿瘤内科医生，同时也是临床研究人员，对我来说这无疑是一次令人兴奋的会议。”Kummar博士补充道，会议上展示的进展有助于让研究人员在病人与正确疗法的匹配方面取得进展，并为开发下一代革命性疗法奠定基础。

临床试验全体会议上报告的众多研究中，三项III期临床试验的数据说明了基于免疫检查点抑制剂（immune checkpoint inhibitor，ICI）的组合在扩大多种类型癌症（包括罕见癌症）治疗选择方面的应用范围。相关试验中测试的治疗方法也可用于于扩大基于免疫疗法的治疗方案范围，以用于疾病的更早期阶段以及更早的治疗线。

了解更多内容，请阅读以下原文。

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

By Srivani Ravoori, PhD

The AACR Annual Meeting 2023 set a new record this year with the number of clinical trial abstracts submitted to the meeting. More than 240 abstracts were showcased over the course of the meeting in four Clinical Trials Plenary Sessions, three Clinical Trials Minisymposia, and in other symposia and poster sessions.

“The studies presented during the Clinical Trials Plenary Sessions truly represent some of the most highly innovative and potentially practice-changing clinical trials and translational studies being conducted in cancer research today,” said Annual Meeting Clinical Trials Committee cochair Timothy A. Yap, MD, PhD.

“As a medical oncologist and a clinical researcher, this has been a truly exciting meeting,” noted Shivaani Kummar, MD, another cochair of this year’s Annual Meeting Clinical Trials Committee. Kummar added that the advances presented at the meeting will help investigators make inroads into matching patients to the right therapies and lay the groundwork for developing the next wave of innovative therapeutics.

Among studies featured in the Clinical Trials Plenary Sessions, data from three phase III clinical trials illustrated the scope of immune checkpoint inhibitor (ICI)-based combinations in broadening treatment options for many cancer types—including rare ones. The treatment approaches tested in these trials also help expand the array of immunotherapy-based regimens for earlier stages of the disease and earlier lines of treatment.

In AEGEAN trial, perioperative durvalumab-based treatment improved outcomes for patients with resectable lung cancer

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.

John V. Heymach, MD, PhD. Photo by © AACR/Scott Morgan 2023

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.

Pierce Chow, FRCS(E), PhD,. Photo by © AACR/Scott Morgan 2023

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.

Robin “Katie” Kelley, MD. Photo by © AACR/Scott Morgan 2023

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.

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