New approaches show promise for treatment of gastroesophageal cancers
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Key takeaways:
- Domvanalimab plus zimberelimab and FOLFOX showed encouraging results.
- Novel CMG901 conferred an objective response in nearly one-third of CLDN18.2-positive patients.
Two different treatment regimens showed efficacy among patients with gastroesophageal cancers, according to study results presented during an ASCO Plenary Series session.
The findings from both studies showed no new adverse events associated with the investigational approaches, researchers noted.
EDGE-Gastric study
“The combination of anti-PD-1 inhibitors with chemotherapy improves OS in first-line gastroesophageal cancers and is now the current standard of care. However, we know that long-term outcomes remain poor in this disease,” Yelena Y. Janjigian, MD, chief of gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center, said during a virtual presentation. “Combination of anti-PD-1 and anti-T-cell immunoglobulin and ITM domain [TIGIT] increase tumor antigen-specific CD8-poisitive T cell expansion with potent preclinical antitumor activity.”
Arm A1 of the phase 2 international EDGE-Gastric study included 41 patients (mean age, 61 years; 59% men) with previously untreated gastric, gastroesophageal junction or esophageal adenocarcinoma assigned domvanalimab (Arcus Biosciences, Gilead Sciences) dosed at 1,600 mg once IV every 4 weeks, plus 480 mg zimberelimab (Arcus Biosciences, Gilead Sciences) once IV every 4 weeks combined with standard-dose FOLFOX once every 2 weeks.
Safety and investigator-assessed objective response rate served as primary outcomes. Secondary endpoints included efficacy by PD-L1 status.
At a median time on treatment of 33 weeks, 59% of patients remained on study treatment with no observed adverse event-related deaths.
Researchers observed an ORR of 80% among those with a tumor area positivity score for PD-L1 of 5% or higher and an ORR of 46% among those with a tumor area positivity score for PD-L1 of less than 5%.
In addition, results showed an overall 6-month PFS rate of 77% among all patients and a 93% PFS rate among those with a PD-L1 score of 5% or higher.
Grade 3 or higher adverse events occurred in 68% of the study population and serious treatment-related adverse events occurred in 24%. However, researchers observed no new safety concerns associated with domvanalimab or zimberelimab and no treatment-associated deaths occurred.
“The addition of domvanalimab and zimberelimab to FOLFOX shows encouraging ORR and 6-month PFS in the first-line cohort of patients with advanced gastroesophageal adenocarcinoma — irrespective of PD-L1 expression,” Janjigian said. “We now have the randomized, phase 3 STAR-221 trial underway comparing domvanalimab and zimberelimab plus chemotherapy vs. standard nivolumab [Opdivo, Bristol Myers Squibb] plus chemotherapy among patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma.”
China study
In the second study, Rui-Hua Xu, MD, PhD, researcher at Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues sought to assess the safety and efficacy of CMG901 — a novel first-in-class CLDN18.2-specific antibody-drug conjugate — among patients with advanced gastric or gastroesophageal junction cancer.
“Gastric cancer has substantial disease burden globally, particularly in Asia,” Xu said during the virtual presentation. “CLDN18.2 is a clinically validated target for the treatment of gastric cancer, and its expression represents the largest subgroup of gastric cancer. Our initial results from a dose-escalation phase 1 trial of CMG901 showed a manageable safety profile and preliminary efficacy in patients with advanced gastric, gastroesophageal junction cancer. Here, we present updated findings of CMG901 from the dose-expansion trial.”
Researchers assigned patients (n = 113) to a dose-escalation phase (part A, n = 6; dose range, 0.3-3.4 mg/kg CMG901) and a dose-expansion phase (part B, n = 107; CMG901 dosed at 2.2 mg/kg, 2.6 mg/kg and 3 mg/kg). They evaluated the safety, tolerability and antitumor activity of the novel therapy.
Results showed that the maximum tolerated dose was not reached during the dose-escalation phase.
Researchers observed an objective response rate of 32.6% among 89 CLDN18.2-positive patients with at least one post-treatment scan.
At median follow-up of 5.98 months, results showed a median PFS of 4.76 months among all 93 CLDN18.2-positive patients.
All 113 patients experienced at least one treatment-associated adverse event, with 64% reporting grade 3 or higher events. One death occurred due to a treatment-associated adverse event.
“CMG901 demonstrated promising efficacy in patients with CLDN18.2-positive gastric and gastroesophageal junction cancers,” Xu said. “Clinical benefit was observed across all subgroups and the safety profile was manageable. These results provide a strong rationale to further explore CMG901 as an antibody-drug conjugate in patients with CLDN18.2-positive gastric and gastroesophageal junction cancers.”
References:
- Janjigian YY, et al. Abstract 433228. Presented at: ASCO Plenary Series; Nov. 7, 2023.
- Xu R, et al. Abstract 434420. Presented at: ASCO Plenary Series; Nov. 7, 2023.
Perspective
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Elizabeth C. Smyth, MD
CLDN18.2 is a young target and we do not yet fully understand its interaction with other biomarkers. However, it is a bystander in carcinogenesis and nonprognostic.
This year, two phase 2/phase 3 randomized trials are evaluating CLDN18.2, a therapeutic targeted at gastroesophageal cancer, including the results from the phase 1 trial of CMG901 in patients with advanced gastric and gastroesophageal junction cancer. There are no preclinical development publications available for this molecule, so I look forward to seeing those in due course to understand target-binding and drug diffusion characteristics.
The study by Xu and colleagues is an Asia-only analysis, which means that most of the patients had gastric cancer. In addition, most patients enrolled had CLDN18.2 expression of good intensity on at least 20% of cells. It is a reasonably chemorefractory population, with most patients already having received taxane-based therapy. I am surprised that previously treated patients were permitted to enter the study. I would have liked to confirm target expression with a pretreatment biopsy in those patients.
Overall, the researchers reported good radiologic response rates. One in three patients had a response according to RESIST criteria, and I do not see a major difference across dose levels. These results are much better than what has been seen with second-line and third-line standard-of-care options. Unlike new checkpoint inhibitors, doses do not appear to be muted in the liver, nor does there appear to be as much cross-resistance with taxanes.
The spider plots show a nice median duration of response that could be improved at higher doses, but I would take that with a pinch of salt due to the small number of patients involved. There are reasons to be cheerful about CMG901, but there are also reasons why this deserves further evaluation. Again, this is an Asia-only trial, and what we frequently see with gastric cancer drugs is that they sometimes work differently outside of Asia. There is more work to do.
In the second study presented by Dr. Janjigian, we know that immune checkpoint inhibitors have changed the face of gastroesophageal cancer in the first-line setting. We have tried in the past to improve outcomes by adding additional immune checkpoint inhibitors, but this was unsuccessful in Checkmate-649.
The EDGE-Gastric study is a small phase 2 trial that is in very early-phase data. However, this is acceptable for the response endpoint and a preliminary look at safety. When examining the PFS data presented, we should acknowledge these are very early results. We are literally still on the first quarter of the survival curve. Results still seem to be in line with what might be expected from earlier trials of chemotherapy plus PD-L1 inhibitors and are encouraging in patients who express high levels of PD-L1, but it’s a small data set.
It is important to reflect on safety for any new combination. The investigators reported no surprises in terms of toxicity. The results of this study showed that the treatment combination may have added benefit for these patients. However, much more research is necessary to understand the disease-specific context of TIGIT before this becomes standard of care.
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Janjigian YY, et al. Abstract 433228. Presented at: ASCO Plenary Series; Nov. 7, 2023.
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