Third-Line GEN-002/Avelumab Elicits Clinical Activity in PD-L1+ Gastric Cancer


Manufacturers believe that GEN-002/avelumab holds promise as a third-line option for patients with gastric cancer and PD-L1 expression.

Jeeyun Lee, MD

Jeeyun Lee, MD

Patients with pretreated advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma derived clinical benefit from third-line GEN-002 and avelumab (Bavenzio), according to findings from an interim analysis of a phase 2 trial (NCT05419362).1

The overall response rate observed with the doublet was found to meet predetermined criteria for the trial, according to Genome & Company. Moreover, no safety concerns were noted. As such, an independent data monitoring committee has recommended that the trial continue into its second stage without any modifications and that 21 additional patients be enrolled.

Detailed findings from the trial are anticipated to be presented in the second half of 2023.

“There is a strong unmet need to establish third line of therapy for [patients with] gastric cancer/GEJ adenocarcinoma compared with the [established] first and second lines of therapy,” Jeeyun Lee, MD, principal investigator of clinical trials from the Hematology and Oncology Division at Samsung Medical Center in Seoul, South Korea, stated in a press release. “Hence, the preplanned interim result of this trial is quite interesting. We continue to enroll patients and look forward to seeing the final analysis of the trial soon.”

GEN-001 is a microbiome-based therapy that is comprised of a single-strain bacterium isolated from healthy individuals.2 When developing the agent, investigators utilized stool samples from patients on a clinical trial and performed 16S ribosomal RNA profiling of the gut microbiome. They examined the bacterial composition in those with lung cancer and compared it with healthy controls, both responders and nonresponders to immunotherapy, and identified immune-related microbiome species, extracting more than 100 bacterial strains.

To determine if the bacteria had activity or a synergistic effect when paired with immunotherapy, investigators conducted in vivo studies. Data indicated that several bacteria had favorable antitumor activity. Preclinical data showed that when GEN-001 was used in a syngeneic mouse model, it was able to inhibit growth of PD-1–sensitive cancers; when the agent was paired with a PD-1 agent, this activity was bolstered. The agent was also found to have activity in mouse models that were resistant to PD-L1 inhibition.

In April 2020, the FDA accepted an investigational new drug application for GEN-001 plus avelumab in patients with solid cancers.3 The clearance permitted the launch of a first-in-human phase 1 trial (NCT04601402) of the combination, which was comprised of dose-escalation and -expansion cohorts.

In the escalation phase, patients with advanced or metastatic solid tumors who received at least 2 prior lines of therapy, including PD-1/PD-L1 inhibitors, and progressed. Oral GEN-001 was administered once daily and each capsule contained at least 1 x 1011 colony-forming units (CFU), and avelumab was given intravenously at 800 mg once every 2 weeks.4 The expansion cohort included those with non–small cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial cancer who progressed on 2 or more prior lines, including checkpoint inhibition.

The multicenter, open-label, phase 2 trial enrolled patients with histologically confirmed, unresectable, recurrent, locally advanced, or metastatic gastric cancer or GEJ adenocarcinoma who had an ECOG performance status of 0 or 1 and acceptable organ function.5 They were required to have progressed following 2 or more lines of standard treatment, to have PD-L1 positivity, measurable disease by RECIST v1.1 criteria, and an estimated life expectancy of at least 3 months.

They could not have received prior T-cell coregulatory protein inhibitors, nor could they have ascites that were clinically significant or known prior severe hypersensitivity reactions to monoclonal antibodies or any component of the study drug. Other exclusion criteria included active infection in need of antibiotics, known history or evidence of pneumonitis, active autoimmune disease in need of systemic therapy, or current immunosuppressive treatment, among others.

Study participants received oral GEN-001 capsules once daily, with each capsule containing at least 3 x 1011 CFU, in combination with 800 mg of intravenous avelumab once every 2 weeks.

The primary outcome measure of the trial is to evaluate the antitumor activity achieved with the combination in the form of objective response rate by RECIST v1.1 criteria. Key secondary end points comprise incidence of toxicities and laboratory abnormalities, duration of response, progression-free survival, and overall survival. Investigators will also collect fecal samples to assess the microbiota.

“On the basis of these results and in accordance with the predetermined hypothesis of the interim analysis, Genome & Company highly expect that the evidence for treatment with GEN-001 plus avelumab as a third line of therapy for gastric cancer/GEJ [adenocarcinoma] will be strongly established,” according to the press release.1

Another phase 2 trial, slated to begin in the second half of 2023, will evaluate GEN-001 in combination with pembrolizumab (Keytruda) as a potential therapeutic option in patients with advanced biliary tract cancer. The company shared that they recently requested approval to amend the trial protocol from South Korea’s Ministry of Food and Drug Safety.


  1. Positive results from interim analysis of ‘GEN-001’ plus avelumab (Bavencio) phase II trial. News release. Genome & Company. May 19, 2023. Accessed May 22, 2023.
  2. New immuno-oncology personalized therapy approaches. Genome Company. Biopharm Deal. Accessed May 22, 2023.
  3. Genome & Company receives FDA IND clearance for GEN-001, its first anti-cancer microbiome therapeutic. News release. Genome & Company. April 20, 2020. Accessed May 22, 2023.
  4. GEN-001 (live biotherapeutic product) and avelumab combination study for patients with solid tumors who have progressed on anti-PD-(L)1 therapy. Updated August 3, 2022. Accessed May 22, 2023.
  5. GEN-001 in combination with avelumab for patients with PD-L1 positive gastric cancer. Updated June 16, 2022. Accessed May 22, 2023.
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