Alison M. Schram, MD, of Memorial Sloan Kettering Cancer Center, discusses initial results from the pivotal Phase 2 PYNNACLE trial evaluating rezatapopt, a first-in-class p53 reactivator, in patients with advanced solid tumors harboring a TP53 Y220C mutation.

Rezatapopt For Locally Advanced or Metastatic Solid Tumors With a  TP53 Y220C Mutation: Initial Analysis of the Pivotal PYNNACLE Phase 2 Trial

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, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, supported by Merus, we had the pleasure of speaking with Alison Schram, MD, about the FDA approval of zenocutuzumab-zbco (Bizengri) for patients with previously treated advanced pancreatic adenocarcinoma or non–small cell lung cancer (NSCLC) harboring 

 gene fusions. Dr Schram is an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York. 

the FDA granted accelerated approval to zenocutuzumab

 for the treatment of adult patients with advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring an 

 gene fusion who have disease progression on or after prior systemic therapy; and adult patients with advanced, unresectable, or metastatic NSCLC harboring an 

 gene fusion who have disease progression on or after prior systemic therapy. This regulatory decision was based on findings from the phase 2 eNRGy trial (NCT02912949), in which patients with pancreatic adenocarcinoma (n = 30) achieved an overall response rate (ORR) of 40% (95% CI, 23%-59%), and a duration of response (DOR) that ranged from 3.7 months to 16.6 months. In the NSCLC cohort (n = 64), the (ORR) of 33% (95% CI, 22%-46%), and the median DOR was 7.4 months (95% CI, 4.0-16.6). 

In our exclusive interview, Dr Schram discussed the significance of this approval, key efficacy data from the pancreatic cancer and NSCLC cohorts of eNRGy, and the importance of using RNA-based testing to identify patients with 

That’s all we have for today! Thank you for listening to this episode of 

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Dr Schram discusses the significance of the FDA approval of zenocutuzumab for NRG1 fusion–positive NSCLC and pancreatic adenocarcinoma.

FDA Approval Insights: Zenocutuzumab for NRG1+ Pancreatic Adenocarcinoma and NSCLC: With Alison Schram, MD 

Dr Schram on the FDA Approval of Zenocutuzumab in NRG1+ NSCLC and Pancreatic Cancer

Alison Schram, MD, medical oncologist, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses 

 (Bizengri, formerly MCLA-128) for the treatment of adult patients with advanced, unresectable, or metastatic non–small cell lung cancer (NSCLC) or pancreatic cancer harboring an 

 fusion with disease progression on or after prior systemic therapy.

The approval was supported by data from the phase 1/2 eNRGy trial (NCT02912949). 

Schram notes the significance of this regulatory decisions as the first targeted therapy approved for patients with 

 fusion–positive cancers, explaining that this agent represents a much-needed treatment option for this group. Patients with 

 fusion–positive NSCLC have a poor prognosis and generally have worse outcomes with standard-of-care to chemotherapy and immunotherapy, she says. Schram adds that patients with pancreatic cancer have limited treatment options following first- and second-line chemotherapy.

 demonstrated that in a cohort of patients with pancreatic ductal adenocarcinoma (n = 33), zenocutuzumab elicited an investigator-assessed overall response rate (ORR) of 42.4% (95% CI, 25.5%-60.8%) per RECIST 1.1 criteria. Patients with NSCLC (n = 79) achieved an investigator-assessed ORR of 37.2% (95% CI, 26.5%-48.9%) per RECIST 1.1 criteria.

In the PDAC cohort, patients experienced a median time to response (TTR) of 1.8 months (range, 1.6-5.4) and a median duration of response (DOR) of 9.1 months (95% CI, 5.5-12.0) per investigator assessment and RECIST 1.1 criteria. The estimated 6-month DOR rate was 71% (95% CI, 41%-88%).

Patients with NSCLC achieved a clinical benefit rate of 61.5% (95% CI, 49.8%-72.3%). The median TTR was 1.8 months (range, 1.5-13.0), and the median DOR was 14.9 months (95% CI, 7.4-20.4). The estimated 6- and 12-month DOR rates were 81% (95% CI, 60%-92%) and 57% (95% CI, 34%-75%), respectively.

 fusion–positive solid tumors who received the zenocutuzumab at 750 mg once every 2 weeks (n = 179), treatment-emergent adverse effects (TEAE) occurred in 61% of patients, including 6% of patients who had grade 3/4 TEAEs.

The most common TEAEs reported in at least 10% of patients included diarrhea (any-grade, 17%; grade 3/4, 2%), infusion-related reactions (12%; 0%), fatigue (10%; 0%), nausea (8%; 1%), vomiting (6%; 1%), anemia (4%; 1%), constipation (3%; 0%), increased alanine aminotransferase levels (3%; 1%), increased aspartate aminotransferase levels (3%; 1%), decreased appetite (3%; 1%), and abdominal pain (2%; 1%).

Alison Schram, MD, discusses the FDA approval of zenocutuzumab in non–small cell lung cancer and pancreatic cancer harboring NRG1 fusions.

Alison Schram, MD, medical oncologist, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the efficacy and safety of RLY-4008 in patients with cholangiocarcinoma harboring an 

In the phase 1/2 ReFocus trial (NCT04526106), investigators are examining the safety and preliminary efficacy of the next-generation FGFR2 inhibitor, RLY-4008, in patients with 

-positive, unresectable or metastatic cholangiocarcinoma.

Data presented at the 2022 ESMO Congress focused on patients with 

 fusion–positive, FGFR inhibitor–naïve cholangiocarcinoma, Schram says. Among patients treated across all dose levels (n = 38), the confirmed objective response rate (ORR) with RLY-4008 was 57.9% by RECIST v1.1 criteria. When administered at the recommended phase 2 dose (RP2D) of 70 mg daily (n = 17), the agent produced a confirmed ORR of 82.4%, Schram explains. In the all-dose population, 92% of patients experienced tumor reduction.

The safety profile with RLY-4008 was consistent with the preclinical data previously reported with the FGFR2 inhibitor, Schram adds. Notably, RLY-4008 spares 

. As a result, hyperphosphatemia and diarrhea were uncommon, according to Schram. FGFR2-mediated toxicities reported with the agent included stomatitis, nail toxicity, and hand-foot syndrome, although most of these effects were low grade, Schram says. Additionally, 27% of patients who were given RLY-4008 at the RP2D required dose reductions, Schram concludes.

Alison Schram, MD, discusses the efficacy and safety of RLY-4008 in patients with cholangiocarcinoma harboring an FGFR2 fusion or rearrangement.


Dr. Schram on the Efficacy of RLY-4008 in FGFR2+ Cholangiocarcinoma

Alison Schram, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the results of the phase 1/2 eNRGy trial (NCT02912949), which were presented during the 2021 ASCO Annual Meeting, in 

Findings from the eNRGy trial demonstrated a 29% overall response rate (ORR) with zenocutuzumab, an investigational bispecific antibody, in patients with locally advanced, unresectable or metastatic, 

Confirmed partial responses (PRs) were observed in 42% of the 12 patients with 

 fusion–positive pancreatic ductal adenocarcinoma treated with the novel agent. An additional 50% of these patients derived stable disease from zenocutuzumab, Schram says. In this cohort, 100% of patients with elevated CA 19-9 measurements experienced a decline of more than 50%, Schram explains. 

The ORR was 25% in the non–small cell lung cancer cohort (n = 24) and responses were observed irrespective of prior afatinib (Gilotrif) treatment, Schram says. In the basket cohort, one patient each with breast cancer and cholangiocarcinoma derived a PR, yielding a confirmed ORR of 22% in this cohort (n = 9), Schram says.

Notably, 40% of patients had treatment ongoing at the time of the data cut-off, Schram says. As such, zenocutuzumab could offer patients with heavily pretreated 

 fusion–positive solid tumors an effective treatment option, concludes Schram. 

Alison Schram, MD, discusses the results of the phase 1/2 eNRGy trial, which were presented during the 2021 ASCO Annual Meeting, in NRG1 fusion–positive solid tumors.  



Alison Schram, MD

Articles

Rezatapopt For Locally Advanced or Metastatic Solid Tumors With a TP53 Y220C Mutation: Initial Analysis of the Pivotal PYNNACLE Phase 2 Trial

FDA Approval Insights: Zenocutuzumab for NRG1+ Pancreatic Adenocarcinoma and NSCLC: With Alison Schram, MD

Dr Schram on the FDA Approval of Zenocutuzumab in NRG1+ NSCLC and Pancreatic Cancer

Dr. Schram on the Efficacy of RLY-4008 in FGFR2+ Cholangiocarcinoma

Dr. Schram on the Results of the Phase 1/2 eNRGy Trial in NRG1+ Solid Tumors