Encouraging results of nivolumab + bevacizumab + FOLFOXIRI in patients with RAS/BRAF mutations as a 1st Line treatment option

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Encouraging results of nivolumab + bevacizumab + FOLFOXIRI in patients with RAS/BRAF mutations as a 1st Line treatment option, Opportunity for BMS for further expanding its blockbuster label for CRC patients.

Encouraging results of nivolumab + bevacizumab + FOLFOXIRI in patients with RAS/BRAF mutations

The Phase II study single-centre study, evaluating the triplet combination of FOLFOXIRI + bevacizumab + nivolumab in patients with advanced colorectal cancer RAS/BRAF mutated (mut): NIVACOR trial.

Nivolumab Mechanism of Action: Antibody-dependent cell cytotoxicity; Programmed cell death-1 receptor antagonists; T lymphocyte stimulants

In 2017, USFDA gave accelerated approval to OPDIVO drug to treat patients with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer that has progressed following treatment with FOLFOXIRI. Currently, nivolumab is being evaluated with chemotherapy and bevacizumab to treat first-line patients with RAS/BRAF mutation, where bevacizumab + chemotherapy is the current standard of care (SOC).

At the data cutoff in December 2021, 73 patients were enrolled in 9 Italian centres. The mDOR was 8.4 months. The mPFS was 10.1 months, and 12-months PFS was 53.4%.

In subgroups analysis of MSS patients, the ORR was 78.9% with an mDOR of 7.59 months, DCR of 96.2%, and mPFS of 9.8 months. The ORR has been achieved in 100% patients dMMR patients and in only 29% of the pMMR patients. The main grade (G) 3 -4 toxicities were: neutropenia (G3 21.9%, G4 15.1%), diarrhea (G3 17.8%, G4 1.4%), hypertension G3 (6.8%), fatigue G3 (6.8%), and febrile neutropenia G4 (4.1%).

KOL insights

“The safety run-in results of the NIVACOR trial do not raise concerns regarding the co-administration of chemotherapy (FOLFOXIRI) / bevacizumab), and nivolumab.”–Expert Opinion.

Conclusion

Despite recent advancements in cancer management, colorectal cancer (CRC) remains the top cause of cancer-related deaths in the United States and globally. Like many other cancers, CRC is a diverse illness with many subtypes defined by genetic differences. The BRAF gene is mutated frequently in CRC (most commonly V600E substitution). Despite a rapidly increasing therapeutic arsenal, the overall survival (OS) for metastatic colorectal cancer (mCRC) patients did not routinely exceed 18–20 months until a few years ago. These outcomes have been transformed by targeted medicines, which have resulted in a significant rise in response rate (RR), progression-free survival (PFS), and overall survival (OS).

The FDA has only approved anti-PD-1 monoclonal antibodies for DNA mismatch repair-deficient/microsatellite instability-high (MMRd/MSI-H) mCRC, accounting for a small percentage of all mCRC. The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab and FOLFOXIRI + bevacizumab in patients with good performance status. The current trial is evaluating the efficacy of anti-PD1 therapy with current SOC proven to be beneficial and efficacious for first-line RAS/BRAF patients who previously had an unmet need of lack of any targeted therapy. Further evaluation of this regimen, if proved efficacious, can become a new SOC.

The primary endpoint Overall response rate (ORR) was met in the ITT population (BRAF and RAS mutated), and the response rate endpoint was met in the MSS group.

2. Merus’ Zenocutuzumab, a HER2-HER3 Bispecific Antibody, Successfully Targets NRG1 Fusions in Lung and Pancreatic Cancer

ASCO 2022: Merus’ Zenocutuzumab Updates

Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers

Zenocutuzumab Mechanism of Action: Antibody-dependent cell cytotoxicity; ERBB 2 receptor antagonists; ERBB-3 receptor antagonists; Immunomodulators

Merus’ Zenocutuzumab is a bispecific antibody containing 2 different Fab arms directed against HER2 and HER3. The agent purportedly docks on HER2 and then binds to HER3, blocking its binding site for NRG1. The reported data are from the Phase I/II eNRGy trial and EAP, which are assessing the safety and anti-tumor activity of zenocutuzumab monotherapy in NRG1+ cancer.

As of April 12, 2022, 110 patients were treated with zenocutuzumab. Efficacy was assessed in 79 evaluable patients with the measurable disease having the opportunity for 6 months or more follow-up and who met the criteria for the primary analysis population. 57% of patients had NSCLC, 23% had Pancreatic ductal adenocarcinoma, 8% had Breast cancer. The median age was 59 years; 59% were female. The median number of prior lines of systemic therapy was 2 . Qualifying NRG1 fusions included 26 distinct fusion partners.

Key findings of the results are:

● ORR per RECIST criteria as assessed by the investigator was 34% across multiple tumor types

I. PDAC ORR 42% (8/19)

II. NSCLC ORR 35% (16/46)

● Tumor shrinkage was observed in 70% of patients.

● The median time to response was 1.8 months, and the median duration of exposure was 6.3 months.

● The median duration of response was 9.1 months, and 20/83 patients were continuing treatment as of the cutoff date.

● Strong safety profile with a low incidence of Grade 3 or higher treatment-related adverse events

“Zenocutuzumab has led to durable responses in previously treated NRG1 fusion-positive cancer, with a median duration of response greater than 9 months and more than 25% of those responding continuing at 12 months. Additionally, Zenocutuzumab has an extremely well-tolerated safety profile. There are currently no approved therapies targeting NRG1 fusion-positive cancer, and Zenocutuzumab offers an important, potential new standard of care.” – Expert Opinion.

“Zenocutuzumab has the potential to be the first drug approved for NRG1 fusion-positive cancers and likely provides a more effective and tolerable option for patients who have progressed on or failed to respond to standard therapy” – Expert Opinion.

CONCLUSION

NRG1 fusions arising from chromosomal rearrangements occur at low frequencies (< 1%) across solid tumors but are enriched in certain cancer types, including KRAS wild-type pancreatic cancer, driver-negative non–small cell lung cancer (NSCLC), and the invasive mucinous adenocarcinoma subtype of lung cancer. Merus currently estimates that 0.5-1.5% of pancreatic cancer and 0.3-3% of lung cancer patients have NRG1 fusions. The head start provided by zenocutuzumab could make a difference in NRG1 fusion tumors.

The FDA has granted Fast-Track designation to zenocutuzumab for NRG1+ cancer and Orphan designation for pancreatic cancer. No targeted therapies are currently approved for tumors harboring NRG1 fusions, but that may soon change based on the results of the pivotal eNRGy study. Given acceptable evidence of anticancer effectiveness across several NRG1 fusion-positive tumor types, the present eNRGy data bolster support for zenocutuzumab, especially when patients had already undergone a median of two prior regimens. Another advantage of zenocutuzumab is its tolerability profile, which is superior to that of regular chemotherapy.

NRG1 fusion cancers are a niche, and there are some Her3-targeting projects with potential in NRG1 fusion cancers. Hummingbird Bioscience’s HMBD-001 recently went into the clinic in HER3-positive solid tumours, including NRG1 fusion-driven cancers. Meanwhile, Aveo Oncology is developing a Her3-targeting antibody radio-conjugate. GSK's GSK2849330 has also shown promise in NRG1 fusion tumours, albeit it is not currently in the company's pipeline. At ASCO 2022, Daiichi Sankyo's patritumab deruxtecan, a Her3-targeting antibody-drug combination, showed promising results in breast and lung malignancies; however, the company does not seems to be focused on NRG1 fusions

Companies- Gilead, Daiichi Sankyo, Merus, Sanofi, AstraZeneca, Eli Lilly, Radius Health, Sermonix Pharmaceuticals, Roche, Veru Pharma, and others.