Seribantumab Elicits Deep, Durable Responses in Solid Tumors Harboring NRG1 Fusions

Supplements And Featured Publications, Updates in NRG1+ Tumors,

Seribantumab was found to produce encouraging overall response rates with acceptable tolerability when used as a monotherapy in patients with solid tumors harboring NRG1 fusions.

The human anti–HER3 IgG2 monoclonal antibody seribantumab was found to produce encouraging overall response rates (ORRs) with acceptable tolerability when used as a monotherapy in patients with solid tumors harboring NRG1 fusions, according to initial findings from the phase 2 CRESTONE trial (NCT04383210) presented at the 2022 ASCO Annual Meeting.1

In the primary efficacy population of cohort 1 (n = 12), seribantumab induced an ORR of 33%, with a complete response (CR) rate of 17% and a partial response rate of 17%. Additionally, 58% of patients achieved stable disease, and 8% experienced disease progression. In this population, the disease control rate (DCR) with the agent was 92%.

In patients in cohort 1 who specifically had non–small cell lung cancer (NSCLC; n = 11), the ORR achieved with seribantumab was 36%, with 18% of patients achieving a CR and 18% experiencing a PR. Fifty-five percent of these patients had stable disease, and 9% experienced progressive disease. In this group, the DCR with the agent was 91%.

“[These findings are] consistent with prior data [observed] in other studies that [examined] seribantumab in a non–NRG1 fusion population,” lead study author Daniel R. Carrizosa, MD, MS, a medical oncologist and associate professor at the Levine Cancer Institute, of Atrium Health, said in a presentation on the data.

NRG1 fusions are rare alterations found in 0.2% of all solid tumors, and NRG1 fusion proteins bind to and activate HER3. Patients with NRG1 fusions have been known to experience poor clinical outcomes with standard therapeutic options, including chemotherapy and immunotherapy, and no targeted therapies are currently approved for this population.

Data on preclinical models have shown that seribantumab can inhibit tumor growth and induce tumor regression at clinically achievable concentrations.2 To further explore the agent, investigators launched the global, multicenter, open-label CRESTONE trial.

To be eligible for enrollment, patients had to have locally advanced or metastatic solid tumors harboring NRG1 fusions per local testing and have received at least 1 prior systemic therapy. Patients could not have tumors harboring any other oncogenic alterations, with the exception of those enrolled to the exploratory cohort 3.

Patients in cohort 1 could not have previously received pan-ERBB–, HER2-, or HER3-targeted therapy. In the exploratory cohort 2, patients needed to have relapsed/refractory disease following pan-ERBB–, HER2-, or HER3-targeted therapy. Lastly, in the exploratory cohort 3, patients were required to have a NRG1 fusion without an EGF-like domain, or a NRG1 fusion with other molecular alterations or insufficient tissue for confirmatory testing for NRG1 fusions.

All patients enrolled to the trial received intravenous seribantumab at 3 g weekly.

The primary end point for those in cohort 1 was ORR by independent central radiologic review and per RECIST v1.1 criteria. Secondary end points included safety, investigator-assessed ORR, duration of response (DOR), progression-free survival, overall survival, and clinical benefit rate.

Patients from cohort 1 were included in the primary efficacy population, and patients from all 3 cohorts were assessed for safety.

In cohort 1, the median age was 61 years (range, 44-76), 67% of patients were female, and 67% were White. Patients had an ECOG performance status of 0 (33%) or 1 (67%). Notably, 14 of 15 patients in cohort 1 had NSCLC, and 1 patient had pancreatic cancer. NRG1 fusion partners detected in cohort 1 included ATP1B1 (7%), CD74 (40%), SDC4 (13%), SLC3A2 (33%), and other (1%). The median number of prior systemic therapies received was 1 (range, 1-5), and 93% of patients had a confirmed NRG1 fusion (93%). One patient had an unknown NRG1 fusion status.

Additional efficacy data showed that 92% of patients with tumors harboring NRG1 fusions experienced tumor reduction from baseline per RECIST v1.1 criteria. The median DOR was not yet reached (range, 1.4-11.5). Moreover, 75% of responses occurred had occurred by the time of the first tumor assessment, which was done at 6 weeks (± 2 weeks). Notably, 75% of responding patients and 53% of all patients remained on treatment at the time of data cutoff.

In those with tumors harboring NRG1 fusions, irrespective of fusion partner, the confirmed investigator-assessed ORR achieved with seribantumab was 33% in the overall population (n = 4/12). In those with NSCLC, the ORR per investigator assessment was 36% (n = 4/11). Ninety-two percent of patients experienced tumor reduction from baseline per RECIST v1.1 criteria.

Among all patients evaluable for safety (n = 35), the median age was 65 (range, 19-78), 69% were female, and 66% were White. ECOG performance statuses included 0 (51%) and 1 (49%), and primary tumor types included biliary tract/cholangiocarcinoma (6%), breast cancer (11%), NSCLC (57%), pancreatic cancer (14%), and other (11%). NRG1 fusion partners among the safety population included ATP1B1 (6%), CD74 (31%), SDC4 (6%), SLC3A2 (17%), AGRN (6%), APP (6%), and other (29%). The median number of prior systemic therapies was 2 (range, 1-6).

Carrizosa also shared a couple of case studies to illustrate the benefit derived with seribantumab. One male who was 70 years of age and who had NSCLC adenocarcinoma previously received 3 lines of therapy, which included platinum-based chemotherapy, immunotherapy, and investigational treatment in the form of immunotherapy plus a targeted agent.

At week 12 of treatment with seribantumab, the patient achieved a PR, with a 35% tumor reduction. At maximum, the patient’s tumor was reduced by 42% with treatment. In this patient, the DOR with the agent was 11.5 months and the response was ongoing. The patient started treatment with the agent under safety run-in and transitioned to receive the agent at a weekly dose of 3 g following induction/consolidation treatment. The patient has been on treatment for 16.0 months.

Another female patient who is 60 years of age and who has NSCLC adenocarcinoma and previously received 3 lines of treatment, including platinum-based chemotherapy and immunotherapy, experienced at PR with seribantumab at week 6 of treatment, with a tumor reduction of 68%. By week 24, investigators noted that the response deepened to a CR. The DOR was 9.7 months in this patient, with a CR that has been ongoing for 5.6 months. The patient has been on treatment for 11.7 months.

Regarding safety, all patients experienced at least 1 treatment-emergent adverse effect (TEAE) with seribantumab, and 49% had at least 1 TEAE that was grade 3 or higher. The most common TEAEs of any grade were diarrhea (49%), fatigue (40%), rash (31%), hypokalemia (29%), nausea (29%), abdominal pain (23%), decrease appetite (23%), hypomagnesemia (23%), cough (20%), anemia (17%), and dysuria (17%). Grade 3 or higher TEAEs included diarrhea (6%), nausea (6%), abdominal pain (6%), hypokalemia (3%), and anemia (3%).

Additionally, 86% of patients experienced at least 1 treatment-related AE (TRAE) of any grade, though only 6% had a TRAE of grade 3 or higher. The most common TRAEs of any grade were diarrhea (40%), fatigue (29%), rash (26%), and nausea (17%).

One dose-limiting toxicity, grade 2 fatigue, was reported, and resulted in a dose reduction during the safety run-in. Seventy-seven percent of patients received the optimized phase 2 dose of 3 g of seribantumab every week. Two patients received dose reductions due to AEs per investigator discretion, including 1 patient who experienced grade 1 alanine aminotransferase increase, and 1 patient who had grade 2 fatigue. Notably, no patients discontinued seribantumab due to AEs.

CRESTONE will continue to investigate seribantumab as a potential new standard of care for patients with solid tumors harboring NRG1 fusions.

“Importantly, comprehensive genomic profiling with RNA-based sequencing is vital, so we can find patients like these to provide personalized medicine and help them with the treatment of their tumors,” Carrizosa concluded.

References

  1. Carrizosa DR, Burkard ME, Elamin YY, et al. CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions. J Clin Oncol. 2022;40(suppl 16):3006. doi:10.1200/JCO.2022.40.16_suppl.3006
  2. Odintsov I, Lui AJW, Sisso WJ, et al. The anti-HER3 mAb seribantumab effectively inhibits growth of patient-derived and isogenic cell line and xenograft models with oncogenic NRG1 fusions. Clin Cancer Res. 2021;27(11):3154-3166. doi:10.1158/1078-0432.CCR-20-3605