Second-Line RGX-202-01 Plus FOLFIRI/Bevacizumab Shows Early Efficacy, Safety in KRAS-Mutant CRC

Andrew Hendifar, MD

A second-line combination regimen comprised of RGX-202-01, FOLFIRI (leucovorin, 5-fluouracil [5-FU], and irinotecan), and bevacizumab (Avastin) demonstrated an encouraging efficacy signal and a favorable toxicity profile in patients with KRAS-mutant colorectal cancer (CRC), according to data from an ongoing phase 1b study (NCT03597581).¹

Findings, which were shared via a poster during the 2022 ESMO World Congress on Gastrointestinal Cancer, indicated that the regimen elicited an objective response rate (ORR) of 50% among evaluable patients with KRAS-mutated disease (n = 10). All responders experienced a confirmed partial response (PR), and the stable disease rate was 50%. In this subset, the preliminary progression-free survival (PFS) experienced with the combination was 11.8 months.

“These clinical data continue to demonstrate the clear potential of RGX-202-01 to improve on the standard of care [SOC] for patients with advanced or metastatic CRC, especially for those whose tumors harbor KRAS mutations,” Andrew Hendifar, MD, assistant professor at Cedars-Sinai Medical Center and principal investigator of the study, stated in a press release.²

Approximately 40% to 45% of patients with CRC have tumors that harbor KRAS mutations. It is known that KRAS-mutated tumors become dependent on various altered metabolic pathways downstream of active RAS signaling that are directly affected by SLC6a8 inhibition; this is thought to make these pathways highly sensitive to treatment with RGX-202-01.

“RGX-202-01 employs a novel mechanism by inhibiting the creatinine transporter SLC6a8, which enables cells to generate ATP as well as other nucleotides by importing phosphor-creatine,” Hendifar explained. “These results also show that KRAS-mutant tumors are highly sensitive to the effects of SLC6a8 inhibition by RGX-202-01.”

Previously, RGX-202-01 monotherapy was found to have clinical activity and an acceptable safety profile in patients with refractory KRAS-mutated CRC, according to data from a completed phase 1a dose-escalation trial. Preclinical data have shown that the agent also has synergistic efficacy when paired with 5-fluouracil. This information supported the rationale to combine RGX-202-01 with chemotherapy regimens that contain 5-FU, like FOLFIRI.

In the ongoing phase 1b trial, investigators set out to examine the safety, pharmacokinetics, pharmacodynamics, and efficacy of RGX-202-01 with standard of care as a second-line option for patients with CRC.

To be eligible for enrollment, patients were required to have advanced or metastatic disease and have received only 1 prior line of therapy—except for those with microsatellite instability–high tumors; the latter group of patients were permitted to received checkpoint inhibitors. Patients also needed to have experienced disease progression on a frontline oxaliplatin-based regimen for metastatic CRC, have measurable disease per RECIST v1.1 criteria, and acceptable organ function or an ECOG performance status of 0 or 1.

Those enrolled to dose-escalation cohort 1 (n = 4) received RGX-202-01 at a twice-daily dose of 2400 mg in combination with bevacizumab at 5 mg/kg followed by irinotecan at 180 mg/m² concurrently with folinic acid at 400 mg/m², followed by 5-FU at 2400 mg/m² over the course of 46 hours on days 1 and 15 of each 28-day treatment cycle.

Those included in dose-escalation cohort 2 (n = 4) received RGX-202-01 at a twice-daily dose of 3000 mg in combination with FOLFIRI and bevacizumab. The expansion cohort, which is still enrolling but is estimated to enroll 11 patients, will receive RGX-202-01 at a twice-daily dose of 3000 mg in combination with FOLFIRI and bevacizumab.

At a data cutoff of April 28, 2022, 8 patients comprised the dose-escalation portion of the trial, and 11 patients were enrolled to the dose-expansion cohort. Among these 19 patients, the median age was 60 years (range, 32-78), 74% were White, 68% were male, and 53% had an ECOG performance status of 1.

Regarding KRAS status, 63% had mutated disease and 37% had wild-type disease. Ninety-five percent of patients had at least 2 metastatic sites. All patients previously received oxaliplatin and 5-FU, and 74% previously received bevacizumab.

Additional data showed that in the KRAS wild-type subset (n = 7), the combination resulted in an unconfirmed PR rate of 14% and a stable disease rate of 71%; 14% of patients experienced disease progression.

Tumor regressions were found to deepen over time in those with KRAS-mutated tumors, with first radiographic evidence of PR appearing as late as 40 weeks following the initiation of treatment.

Since the April 28, 2022 data cutoff date, through June 10, 2022, 2 patients with KRAS-mutated tumors have undergone follow-up imaging; 1 patient continues to experience a PR and 1 now has stable disease. Two patients with KRAS wild-type disease also had follow-up imaging; 1 of these patients continues to have stable disease and the other patient maintained stable disease. Moreover, the ORR data remain unchanged in both subsets.

A maximum tolerated dose was not yet identified in the dose-escalation phase of the research, and no dose-limiting toxicities were reported at either of the RGX-202-01 doses evaluated.

Toxicities reported among all 19 patients included nausea (grade ≤2, 58%), diarrhea (grade ≤2, 53%), neutropenia (grade ≤2, 32%; grade ≥3, 11%), abdominal pain (grade ≤2, 26%; grade ≥3, 11%), fatigue (grade ≤2, 26%; grade ≥3, 11%), constipation (grade ≤2, 32%), vomiting (grade ≤2, 16%; grade ≥3, 5%), hypertension (grade ≤2, 5%; grade ≥3, 11%), rectal pain (grade ≤2, 5%; grade ≥3, 11%), dehydration (grade ≤2, 11%; grade ≥3, 5%), intestinal obstruction (grade ≥3, 11%), anemia (grade ≤2, 5%; grade ≥3, 5%), hyponatremia (grade ≤2, 5%; grade ≥3, 5%), pulmonary embolism (grade ≤2, 5%; grade ≥3, 5%), arthralgia (grade ≤2, 11%), decreased appetite (grade ≤2, 11%), face oedema (grade ≤2, 11%), hemorrhoids (grade ≤2, 11%), hyperglycemia (grade ≤2, 11%), and muscular weakness (grade ≤2, 11%).

One patient each experienced grade 3 or higher abdominal abscess, increased aspartate aminotransferase, back pain, increased blood bilirubin, colitis, device-related infection, gastrointestinal fistula, sepsis, upper respiratory tract infection, urinary tract infection, and urinary tract obstruction.

The incidence of gastrointestinal and neutropenia treatment-emergent adverse effects in both stages of the research were noted to be consistent with second-line, SOC FOLFIRI/bevacizumab regimens in CRC.

“The drug is also very well tolerated, enabling a safe and effective combination therapy with FOLFIRI/bevacizumab to provide further optionality for patients,” Hendifar concluded.

References

1. Hendifar AE, Rosen LS, Cercek A, et al. Phase 1b study of RGX-202-01, a first-in-class oral inhibitor of the SLC6a8/CKB pathway, in combination with FOLFIRI and bevacizumab (BEV) in second-lien advanced colorectal cancer (CRC). Presented at: 2022 ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022; Barcelona, Spain. Abstract 291. https://bit.ly/3QQtjDM
2. Inspirna to present phase 1b RGX-202-01 clinical trial data at the 2022 ESMO World Congress on Gastrointestinal Cancer. News release. Inspirna, Inc. June 28, 2022. Accessed June 29, 2022. https://bit.ly/3R8oztw