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Updated CheckMate 649 results support nivolumab plus chemotherapy as primary standard of care for advanced gastric cancers
The 4-year follow-up results from the Phase III CheckMate 649 (NCT02872116) demonstrating that the combination of nivolumab with chemotherapy compared to chemotherapy alone in patients with newly diagnosed with advanced gastric cancer, gastro-esophageal junction cancer, or esophageal adenocarcinoma continues in delivering lasting survival advantages.1
Previously, the randomized, open-label, global study successfully achieved its primary endpoint by demonstrating enhanced progression-free survival (PFS) and overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 5 or higher. Following this, in April 2021 the FDA granted approval for the use of nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma. 2 This marked a milestone in gastric malignancies as nivolumab became the first immune checkpoint inhibitor to receive approval in the United States for this specific patient population. 3 At 2 and 3-year follow-ups, nivolumab plus chemotherapy continued to exhibit significant and clinically meaningful improvement in efficacy.
The 4-year follow-up results of CheckMate 649 were presented at the 2024 ASCO GI Cancers Symposium.
1581 patients were randomized to receive nivolumab plus chemotherapy (n=789) or chemotherapy alone (n=792). At a minimum follow-up of 48.1 months, median OS in the overall population was 13.7 months (95% CI, 12.4-14.5) versus 11.6 (95% CI, 10.9-12.5) favoring the combination (n = 792; HR, 0.79; 95% CI, 0.71-0.88). Patients with a PD-L1 CPS of 5 or greater exhibited a median OS of 14.4 months (95% CI, 13.1-16.2) when treated with the combination (n = 473), compared to 11.1 months (95% CI, 10.1-12.1) with chemotherapy alone (n = 482) (HR, 0.70; 95% CI, 0.61-0.81). For those with a PD-L1 CPS of 1 or higher, the median OS was 13.8 months (95% CI, 12.4-14.8) and 11.4 months (95% CI, 10.7-12.3) with the combination and chemotherapy, respectively. (HR, 0.75; 95% CI, 0.67-0.85).
The median progression-free survival (PFS) for the overall population was 7.7 months (95% CI, 7.1-8.6) when treated with nivolumab plus chemotherapy, compared to 6.9 months (95% CI, 6.7-7.2) with chemotherapy alone (95% CI, 6.7-7.2). In patients with a PD-1 CPS of 5 or higher, the median PFS was 8.3 months (95% CI, 7.0-9.3) and 6.1 months (95% CI, 5.6-6.9) in the nivolumab/chemotherapy and chemotherapy arms, respectively (HR, 0.71; 95% CI, 0.61-0.82). Within the subgroup with a PD-L1 CPS of 1 or higher, the median PFS was 7.5 months (95% CI, 7.0-8.4) and 6.9 months (95% CI, 6.2-7.1) for the nivolumab/chemotherapy and chemotherapy arms, respectively (HR, 0.77; 95% CI, 0.68-0.88). Additionally, in patients with a PD-L1 CPS of ≥ 5 and across all randomly assigned patients, nivolumab plus chemotherapy demonstrated higher objective response rates (ORR) and more enduring responses compared to chemotherapy alone. No new safety signals were identified, consistent with the 3-yr follow-up.
Overall, the four-year survival data derived of the CheckMate 649 study confirms that the incorporation of chemotherapy along with nivolumab is a validated standard of care (SOC) option for first-line treatment in patients diagnosed with advanced gastric cancer, GEJ cancer, or esophageal adenocarcinoma.
MATTERHORN trial reveals consistent improvements in resectable gastric cancer with durvlumab plus FLOT
Recent updates from the ongoing Phase III MATTERHORN trial (NCT04592913) continue to highlight the promising outcomes of perioperative immunotherapy in patients with locally advanced, resectable gastric or gastroesophageal junction cancer. Detailed findings on the pathologic complete response (pCR) were presented at the 2024 ASCO Gastrointestinal Cancers Symposium, shedding light on the global impact of combining durvalumab with standard chemotherapy.4
MATTERHORN, a randomized, double-blind study, is the first of its kind, successfully evaluating the addition of durvalumab, an anti–PD-1 agent, to the perioperative standard of care, FLOT chemotherapy (fluorouracil, leucovorin, oxaliplatin, docetaxel). The trial enrolled 948 patients from Europe (53%), Asia (19%), South America (19%), and North America (9%), offering a comprehensive assessment of the global applicability of this approach.
At the first interim analysis, the addition of durvalumab demonstrated a statistically significant improvement in pathologic complete response (pCR) rates compared to placebo plus FLOT. The pCR rate with durvalumab plus FLOT was 19% versus 7% with placebo plus FLOT, representing an absolute difference of 12% (odds ratio [OR] = 3.08, P < .00001). This improvement was consistent across various subgroups, including those stratified by geographic region and tumor characteristics. In Asia, where baseline characteristics showed a higher percentage of patients with poor performance status, lymph-node positivity, and T4 stage tumors, the benefits of durvalumab were almost identical to non-Asian populations. Absolute improvements of 13% and 12% were observed in Asia and non-Asia, respectively.
Regional breakdowns revealed a consistent improvement in pCR rates across Asia (pCR: 19% vs 6%), Europe (pCR: 18% vs 8%), North America (pCR: 29% vs 8%), and South America (pCR: 17% vs 5%).
Exploratory analyses revealed that virtually all prespecified subgroups, except for patients with PD-L1 expression of < 1%, derived benefits from durvalumab. The improvements in pCR were consistent across microsatellite instability (MSI)-high and non–MSI-high subgroups. The safety profile of the combination therapy was consistent with previous findings, with no new safety signals identified.
As MATTERHORN progresses towards its primary endpoint of event-free survival, these findings mark a significant step forward in shaping the landscape of perioperative therapies for gastric and gastroesophageal junction cancers, underscoring the potential for durvalumab to enhance the efficacy of standard chemotherapy regimens.
SKYSCRAPER-08 demonstrated survival benefit with addition of atezolizumab to chemotherapy in ESCC
The groundbreaking Phase III SKYSCRAPER-08 trial (NCT04540211) has revealed promising results in the treatment of esophageal squamous cell carcinoma (ESCC). The study, presented at the 2024 ASCO Gastrointestinal Cancers Symposium, focused on the combination of PD-L1 and TIGIT inhibitors, along with chemotherapy, as a first-line treatment for unresectable locally advanced or metastatic ESCC in an Asian population. The dual immunotherapy approach demonstrated remarkable improvements in progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone. 5
ESCC accounts for a significant portion of esophageal cancer cases globally, posing substantial challenges to patient outcomes. With a 5-year survival rate as low as 5%, finding effective treatments is crucial. SKYSCRAPER-08 explored the efficacy and safety of tiragolumab (anti-TIGIT) in combination with atezolizumab (anti-PD-L1) and chemotherapy, compared to placebo plus chemotherapy.
The randomized, double-blind, placebo-controlled study included 461 patients, with 229 receiving the anti-PD-L1 and anti-TIGIT immunotherapy combination plus chemotherapy and 232 receiving placebo plus chemotherapy.
The results, with a minimum follow-up of 6.5 months, demonstrated a median independent review faculty (IRF)-assessed PFS of 6.2 months for the tiragolumab combination, compared to 5.4 months for the placebo group (HR 0.56; 95% CI: 0.45-0.70; P < 0.0001).
Furthermore, at a minimum follow-up of 14.5 months, the median overall survival (OS) was 15.7 months for the immunotherapy combination, showcasing a significant improvement when compared to the 11.1 months observed in the placebo group (HR: 0.70; 95% CI: 0.55-0.88; P = 0.0024). Importantly, the study met both primary endpoints of IRF-assessed PFS and OS.
The safety profile of the tiragolumab combination was generally consistent with known risks associated with individual treatments. Treatment-related adverse events (TRAEs) occurred in 98.2% of patients in both arms, with grade 3/4 TRAEs in 59.6% (tiragolumab combination) and 56.4% (placebo) of patients. Grade 5 TRAEs were observed in 2.6% and 0.9% of patients, respectively.
Ongoing studies will explore the potential of tiragolumab plus atezolizumab as maintenance therapy following definitive chemoradiotherapy and in combination with neoadjuvant chemoradiotherapy followed by surgery for locally advanced esophageal cancer. These investigations aim to further establish the role of this treatment combination in improving outcomes for patients with ESCC.
The SKYSCRAPER-08 trial marks a significant advancement in ESCC treatment, providing statistically significant and clinically meaningful improvements in both PFS and OS. The findings contribute to the evolving landscape of immunotherapy for esophageal cancer, offering hope for improved survival rates and enhanced quality of life for patients facing this challenging diagnosis.
EMERALD-1 shows PFS advantage with addition of durvalumab to TACE in unresectable, embolization-eligible hepatocellular carcinoma
The Phase III EMERALD-1 trial (NCT03778957) achieved its primary endpoint by demonstrating a significant enhancement in progression-free survival (PFS) in patients eligible for embolization with unresectable hepatocellular carcinoma (HCC) treated with concurrent transarterial chemoembolization (TACE) followed by durvalumab and bevacizumab, compared to those who underwent TACE alone.6
For over two decades, transarterial chemoembolization (TACE) has been the gold standard for patients with uHCC eligible for embolization. Despite its widespread use, a significant proportion of patients experience disease progression within a year, emphasizing the urgent need for more effective therapies. The EMERALD-1 trial introduced a promising paradigm shift, incorporating immunotherapy-based combination treatments to enhance the outcomes of TACE in uHCC.
The double-blind, global study enrolled 616 participants with embolization-eligible uHCC. The inclusion criteria comprised patients with Child-Pugh A to B7 liver function, Eastern Cooperative Oncology Group performance status 0–1, and no evidence of extrahepatic disease. The study arms included durvalumab plus bevacizumab plus TACE, durvalumab plus TACE, and TACE alone. The primary endpoint of the study was PFS for the durvalumab plus bevacizumab plus TACE arm compared to TACE alone. Secondary endpoints included PFS for the durvalumab plus TACE arm versus TACE alone, overall survival (OS), objective response rate (ORR), time to progression (TTP), and safety assessments.
The double-blind, global study enrolled 616 participants with embolization-eligible uHCC. The inclusion criteria comprised patients with Child-Pugh A to B7 liver function, Eastern Cooperative Oncology Group performance status 0–1, and no evidence of extrahepatic disease. The study arms included durvalumab plus bevacizumab plus TACE, durvalumab plus TACE, and TACE alone. The primary endpoint of the study was PFS for the durvalumab plus bevacizumab plus TACE arm compared to TACE alone. Secondary endpoints included PFS for the durvalumab plus TACE arm versus TACE alone, overall survival (OS), objective response rate (ORR), time to progression (TTP), and safety assessments.
The primary endpoint of PFS was met successfully, demonstrating a significant improvement for durvalumab plus bevacizumab plus TACE compared to TACE alone (median PFS 15.0 vs. 8.2 months; HR 0.77; p=0.032).
The results were consistent across most prespecified subgroups, providing robust evidence for the efficacy of the combination therapy. Durvalumab plus bevacizumab plus TACE exhibited an ORR of 43.6% compared to 29.6% with TACE alone.
The median TTP was 22.0 months for durvalumab plus bevacizumab plus TACE, 11.5 months for durvalumab plus TACE, and 10.0 months for TACE. The secondary endpoint of PFS for durvalumab plus TACE versus TACE alone did not reach statistical significance (median PFS 10.0 vs 8.2 months; HR, 0.94; 95% CI, 0.75–1.19; p=0.638), suggesting bevacizumab may enhance the efficacy of durvalumab, or possibly have an independent benefit.
The safety analysis revealed that durvalumab plus bevacizumab plus TACE had a manageable safety profile, with no identified new safety signals. Grade 3/4 treatment-related adverse events (TRAEs) were observed in 32.5% of patients, and discontinuation due to TRAEs occurred in 8.4%. Importantly, no deaths were attributed to TRAEs, affirming the safety and tolerability of the combination.
These findings suggest a potential paradigm shift in the treatment of uHCC by showcasing the first immunotherapy-based regimen to achieve statistically significant and clinically meaningful improvements in PFS in a global Phase III trial. The combination of durvalumab and bevacizumab plus TACE holds the potential to redefine the standard of care for embolization-eligible uHCC. Further follow-up for OS outcomes and ongoing trials, such as EMERALD-Y90 (NCT06040099) and EMERALD-3 (NCT05301842), will provide additional insights into the role of checkpoint inhibitors in combination with TACE in the evolving landscape of uHCC treatment.
References
- Shitara K, Moehler M, Ajani, J, et al. Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4 year (yr) follow-up of CheckMate 649. J Clin Oncol. 2023;42(suppl 3):306.
- Shitara K, Janjigian YY, Moehler MH. Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): Expanded efficacy, safety, and subgroup analyses from Checkmate 649. Journal of Clinical Oncology. 2022 Feb 1;40(4_suppl):240–240
- FDA. April 16, 2021. Accessed January 29, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-initial-treatment-gastric-cancer
- Janjigian YY, Al-Batran S-E, Wainberg ZA, et al. Pathological complete response (PCR) to 5-fluorouracil, leucovorin, Oxaliplatin and docetaxel (FLOT) with or without durvalumab (d) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): Subgroup analysis by region from the phase 3, randomized, double-blind matterhorn study. Journal of Clinical Oncology. 2024 Jan 20;42(3_suppl).
- Hsu C-H, Lu Z, Gao S, et al. Skyscraper-08: A phase III, randomized, double-blind, placebo-controlled study of first-line (1L) tiragolumab (TIRA) + atezolizumab (atezo) and chemotherapy (CT) in patients (PTS) with esophageal squamous cell carcinoma (ESCC). Journal of Clinical Oncology. 2024 Jan 20;42(3_suppl):245–245.
- Lencioni R, Kudo M, Erinjeri J, et al. Emerald-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. Journal of Clinical Oncology. 2024 Jan 20;42(3_suppl).
Written by Ellie Jackson
