Attendees at the European Society for Medical Oncology (ESMO) Congress 2024 heard the results of many positive clinical trials that will advance the field of cancer treatment. However, a few late-stage trials of promising adjuvant therapies unexpectedly reported negative results. The ASCO Post considers these findings to be just as important to our readers and have summarized some of them here.
Endometrial Cancer: Adjuvant Pembrolizumab
New findings from the ENGOT-en11/GOG-3053/KEYNOTE-B21 trial showed that adding the PD-1 inhibitor pembrolizumab to adjuvant chemotherapy did not improve disease-free survival in the intention-to-treat population. However, in prespecified subgroup analyses, patients with mismatch repair–deficient (dMMR) tumors did experience a significant and clinically meaningful improvement in disease-free survival with the immune checkpoint inhibitor.1
Toon Van Gorp, MD, PhD
Toon Van Gorp, MD, PhD, of the Leuven Cancer Institute, Belgium, said this result is puzzling. It contrasts with the clinically meaningful improvement in progression-free survival seen for pembrolizumab in the recent NRG-GY018 trial, where the addition of pembrolizumab to chemotherapy significantly improved outcomes in advanced, metastatic, or recurrent endometrial cancer, regardless of MMR status.2
ENGOT-en11/GOG-3053/KEYNOTE-B21 evaluated this approach in 1,095 patients with newly diagnosed high-risk disease who had undergone surgery with curative intent and had no evidence of disease. Patients received adjuvant pembrolizumab at 200 mg or placebo every 3 weeks for six cycles plus carboplatin/paclitaxel, followed by pembrolizumab at 400 mg or placebo every 6 weeks for four or six cycles, with or without radiotherapy. The co-primary endpoints were investigator-assessed disease-free survival and overall survival in the intention-to-treat population. Median follow-up was 23.9 months.
In the overall intention-to-treat population, there was no difference in 2-year disease-free survival, which was 75% in the pembrolizumab group and 76% in the placebo group (hazard ratio [HR] = 1.02). In contrast, in the dMMR subgroup, the 2-year disease-free survival rate was significantly improved with pembrolizumab—92% vs 80% without (HR = 0.31). They were not improved in patients with MMR-proficient disease.
Christian Marth, MD, PhD
Although the overall results are “disappointing,” they are also “game-changing” and could represent a new standard of care for the dMMR subgroup, according to study discussant Christian Marth, MD, PhD, of the Medical University of Innsbruck in Austria. He maintained that carboplatin, paclitaxel, and pembrolizumab should be considered for adjuvant treatment in dMMR, high-risk endometrial carcinoma.
Hepatocellular Carcinoma: Adjuvant Combination Therapy
Adam Yopp, MD
The positive results for adjuvant atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma were not replicated in an updated analysis of IMbrave050, presented by Adam Yopp, MD, of UT Southwestern Medical School in Dallas.3
“Upon further extended follow-up, the early recurrence-free survival benefit we noticed in the interim analysis was not maintained. The curves did separate at the 12-month period but converged around 24 months,” Dr. Yopp said. Despite the latest results, he added, atezolizumab plus bevacizumab remains the first-line standard of care for unresectable hepatocellular carcinoma.
IMbrave050 was the first phase III study to demonstrate an adjuvant immunotherapy-based regimen could delay recurrence after curative-intent resection or ablation of tumors in patients with high-risk hepatocellular carcinoma. In the previous prespecified interim analysis, at a median follow-up of 17.4 months, IMbrave050 showed a significant 28% reduction in the risk of recurrence (P = .012), meeting its primary endpoint.4
At the ESMO Congress, Dr. Yopp presented the findings for maintenance therapy with atezolizumab at 1,200 mg plus bevacizumab at 15 mg/kg every 3 weeks for 17 cycles, vs active surveillance for 1 year at a median follow-up of 35 months; crossover was allowed upon recurrence. Median recurrence-free survival was 33.2 months with atezolizumab plus bevacizumab and 36.0 months with active surveillance.
Although the initial recurrence-free benefit was not sustained over time, a post hoc analysis showed a “pronounced delaying of recurrence” with atezolizumab plus bevacizumab within the first 12 months after resection in some patients. The recurrence-free survival was numerically better with atezolizumab plus bevacizumab in patients who underwent resection and were outside the “up-to-7” criteria, he said. (These criteria help predict postsurgical outcomes by assessing tumor burden in terms of tumor size and number. Specifically, a patient with hepatocellular carcinoma is a good candidate for liver resection or transplantation if the sum of the number of tumors and the diameter of the largest tumor [in centimeters] does not exceed seven.)
Overall survival data remained immature (HR = 1.26; 95% confidence interval = CI: 0.85–1.87). Median overall survival has not been reached, but there appears to be a numerical improvement with atezolizumab plus bevacizumab vs active surveillance since the last analysis.
Maeve Lowery, MD
IMbrave050 study discussant, Maeve Lowery, MD, a gastrointestinal oncologist and researcher at Trinity College, Dublin, Ireland, called the findings “disappointing but perhaps not entirely unexpected,” since the recurrence-free survival curves had started to come together around the 2-year mark. Additionally, she said, the overall survival outcomes will undoubtedly be confounded because of crossover to active treatment and because recurrences were treated with additional resections or ablations when possible.
“Where do we go from here? We await results...from ongoing studies,” Dr. Lowery said. They include EMERALD-2, a study of another PD-L1 blocker durvalumab—with bevacizumab as adjuvant therapy for high-risk liver cancer.
NSCLC: Adjuvant Durvalumab
Glenwood Goss, MD
With a median follow-up of 60 months, adjuvant durvalumab did not significantly improve disease-free survival compared with placebo after resection in patients with early-stage non–small cell lung cancer (NSCLC), according to findings from the phase III CCTG BR.31 trial.5 In the overall population, median disease-free survival was about 6 months longer with durvalumab than placebo, but the difference was not statistically significant. There appeared to be no correlation of statistical significance between PD-L1 expression and disease-free survival, said Glenwood Goss, MD, of the University of Ottawa, Canada.
Based on the observed benefit with durvalumab in metastatic, unresectable stage III NSCLC and in the perioperative setting in resectable NSCLC, the CCTG BR.31 study aimed to evaluate the drug as adjuvant treatment in early-stage disease. The study included 1,219 adults whose tumors were EGFR-ALK wild-type with completely resected stage IB–IIIA NSCLC; they were randomly assigned 2:1 to receive durvalumab or placebo every 4 weeks for 12 months. The primary patient population evaluated in the study had tumors with a PD-L1 expression of 25% or higher, and the secondary analysis included patients with lower or no PD-L1 expression.
In the overall population, regardless of PD-L1 expression, median disease-free survival was approximately 60 months with durvalumab and 54 months with placebo (HR = 0.89; P = .207). In patients with PD-L1 expression ≥ 25%, it was 70 vs 60 months, respectively (HR = 0.94; P = .64); in those with PD-L1 expression ≥ 1%, it was about 60 months in each arm (HR = 0.99; P = .93). Dr. Goss concluded that in the adjuvant setting in early-stage NSCLC, PD-L1 tumor expression is a poor biomarker for disease-free survival.
Of note, the control arm in CCTG BR.31 performed better than observed in two similar trials that were positive: KEYNOTE-091 with pembrolizumab and IMpower010 with atezolizumab. Dr. Goss drew attention to the placebo arms, which continued to do well after 36 months, whereas in the other two trials, the curves separated earlier. “That probably accounts for the negative trial,” Dr. Goss suggested. This difference may be by chance related to the patient population, the surgery, or “a number of other possibilities.”
DISCLOSURE: Dr. Van Gorp reported financial relationships with AbbVie, BioNTech, ImmunoGen, Incyte, Karyopharm, Seagen, and Zentalis. Dr. Marth reported financial relationships with Roche, Novartis, MSD, PharmaMar, AstraZeneca, GSK, ImmunoGen, Daiichi Sankyo, BioNTech, Novocure, and Eisai. Dr. Yopp reported financial relationships with Genentech and Maia Biotechnology. Dr. Lowery has served as an advisor or consultant to AstraZeneca, Astellas Pharma, Servier, and Roche/Genentech and has received institutional research grant/funding from MSD, Exelixis, Amgen, Zymeworks, Basilea, Daiichi Sankyo, Legend Biotech, and Genuity Science. Dr. Goss reported financial relationships with AstraZeneca and Merck.
REFERENCES
1. Van Gorp T, Rob L, Lu W, et al: ENGOT-en11/GOG-3053/KEYNOTE-B21: A phase III study of pembrolizumab or placebo in combination with adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. ESMO Congress 2024. Abstract LBA28. Presented September 14, 2024.
2. Eskander RN, Sill MW, Beffa L, et al: Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med 388:2159-2170, 2023.
3. Yopp A, Kudo M, Chen M, et al: Updated efficacy and safety data from IMbrave050: Phase III study of adjuvant atezolizumab + bevacizumab vs active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma. ESMO Congress 2024. Abstract LBA39. Presented September 13, 2024.
4. Qin S, Chen M, Cheng AL, et al: Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): A randomised, open-label, multicentre, phase 3 trial. Lancet 402:1835-1847, 2023.
5. Goss G, Darling GE, Westeel V, et al: CCTG BR.31: A global, double-blind placebo-controlled, randomized phase III study of adjuvant durvalumab in completely resected non–small cell lung cancer. ESMO Congress 2024. Abstract LBA48. Presented September 13, 2024.
