Add-on bispecific antibody may alter treatment landscape of G/GEJ cancer

Adding the PD-1/CTLA-4 bispecific antibody cadonilimab to chemotherapy improves overall survival (OS) and progression-free survival (PFS) in individuals with untreated, HER2-negative, locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) cancer, including patients with PD-L1–low tumours, according to the interim results of the phase III COMPASSION-15 trial.

“Cadonilimab is the first PD-1/CTLA-4 bispecific antibody to demonstrate statistically significant and clinically meaningful OS benefit in combination with chemo vs chemo alone in previously untreated patients with advanced G/GEJ adenocarcinoma,” said Dr Jiafu Ji from the Beijing Cancer Hospital, Beijing, China, at AACR 2024.

After a median follow-up of 18.69 months, median OS was longer in the cadonilimab vs placebo arm (15 vs 10.8 months; hazard ratio [HR], 0.62, 95 percent confidence interval [CI], 0.50–0.78; p<0.001). [AACR 2024, abstract CT006]

The OS benefit with the combination regimen was consistently observed at all prespecified Combined Positive Score (CPS) cutoffs, especially in patients with low PD-L1 expression (CPS <5; median 14.8 vs 11.1 months; HR, 0.7, 95 percent CI, 0.51–0.95; p=0.011). Of note, the survival advantage in this subgroup was not seen in other phase III studies with PD-1 antibodies, said Ji.

In the CPS ≥5 subgroup, median OS with cadonilimab-chemo was not reached vs 10.6 months with placebo-chemo, yielding an HR of 0.56 (95 percent CI, 0.39–0.8; p<0.001).

The survival benefit with the combo regimen vs chemo alone was consistently observed across all subgroups evaluated and was accompanied by PFS improvements in the overall cohort (median 7 vs 5.3 months; HR, 0.53, 95 percent CI, 0.44–0.65; p<0.001) and the CPS <5 (median 6.9 vs 4.6 months; HR, 0.6, 95 percent CI, 0.45–0.79; p<0.001) and CPS ≥5 subgroups (median 6.9 vs 5.5 months; HR, 0.51, 95 percent CI, 0.37–0.7; p<0.001).

The addition of cadonilimab to chemo also yielded an improvement in overall response rate as opposed to chemo alone (65.2 percent vs 48.9 percent; p=0.000) and doubled the median duration of response (8.8 vs 4.4 months).

Grade ≥3 treatment-related adverse event (TRAE) rate was higher in the cadonilimab vs placebo arm (65.9 percent vs 53.6 percent), as was the rate of drug discontinuation owing to grade ≥3 TRAEs (15.4 percent vs 5.3 percent). No new safety signals were observed.

Tx options for PD-L1–low tumours limited

“Immune checkpoint inhibitors are typically most effective in patients whose tumours express high levels of PD-L1 … For patients whose tumours have low PD-L1 expression, treatment options are limited,” Ji noted in a press release. [https://www.aacr.org/about-the-aacr/newsroom/news-releases/bispecific-immune-checkpoint-inhibitor-improves-survival-in-gastric-cancer-patients-regardless-of-pd-l1-status]

“In many countries, chemo is still the optimal treatment option for these patients, who have an OS of less than a year … There is a great unmet medical need to explore new treatment options for patients with PD-L1–low, HER2-negative G/GEJ adenocarcinoma,” Ji continued.

Cadonilimab – approved in China for the treatment of relapsed or metastatic cervical cancer that has progressed on or after platinum-based chemo – is a bispecific antibody that inhibits both PD-1 and CTLA-4. [Drugs 2022;82:1333-1339] “We anticipated that by blocking both PD-1 and CTLA-4, cadonilimab plus chemo could yield longer survival than a PD-1 inhibitor plus chemo,” Ji said.

Moreover, Ji noted that PD-L1–low tumours may rely on other immune checkpoints such as CTLA-4 and may thus respond to CTLA-4 inhibition. “Dual blockade of PD-1 and CTLA-4 may improve the sensitivity of patients with PD-L1-low tumours to immunotherapy. There may also be synergistic effects between the targets of the two bispecific antibodies.”

Potential new standard of care

Ji and team randomized 610 participants (median age 64 years, 78 percent men) 1:1 to receive cadonilimab 10 mg/kg plus a chemo regimen comprising oral capecitabine 1,000 mg/m² BID daily (days 1–14) and IV oxaliplatin 130 mg/m² Q3W (maximum six cycles) or placebo plus chemo.

Although the study was limited to Chinese patients, Ji noted that the results “may change the current practice of gastric cancer treatment. Cadonilimab-chemo represents a new potential standard first-line treatment of gastric cancer, even for patients with low PD-L1 expression.”

Ji and colleagues will continue to monitor participants to evaluate long-term outcomes.

“[I am] looking forward to the subgroup analyses and more mature OS data in more patients living with this disease and potentially being cured with this combination therapy,” said discussant Dr Yelena Janjigian from the Memorial Sloan Kettering Cancer Center, New York City, New York, US, at AACR 2024.

“Despite the suboptimal comparator arm, I think the study is very important and offers rationale for dual anti-PD-1/CTLA-4 blockade. We need to see additional efficacy and safety potentially in Western populations, with comparison to chemo/anti-PD-1,” Janjigian added.

The cadonilimab-chemo regimen is awaiting approval from the China National Medical Products Administration for this patient population.