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March 6, 2024
Clinical Relevance: Rybrevant offers a novel treatment option for NSCLC patients with EGFR exon 20 insertion mutations, reiterating the need for genetic testing to tailor therapies effectively target specific tumor types.
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Oncologists should now consider Rybrevant for first-line treatment of NSCLC with EGFR exon 20 insertion mutations, following its full FDA approval. This targeted therapy marks a significant advancement for patients with locally advanced or metastatic non-small cell lung cancer, enhancing treatment options and potentially improving outcomes.
The agency also granted traditional approval to the drug for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations that has been detected by an FDA-approved test and whose disease has progressed on or after platinum-based chemotherapy. This second approval provides an option for patients who have already undergone and not responded well to platinum-based chemotherapy.
Dr. Roy S. Herbst, the chief of medical oncology at the Yale Cancer Center, Yale School of Medicine, told SurvivorNet that this cutting-edge medication offers a novel approach for a challenging subset of lung cancer known for its limited response to conventional therapies.
“Not every mutation is the same,” he says. “And now, depending on the mutation, we can have a specific drug so this is exciting.”
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Trial Results
Approval was based on results from the PAPILLON study which involved 308 NSCLC patients with the EGFR exon 20 insertion mutation.
Subjects were divided into two groups: one received Rybrevant with chemotherapy, and the other received just chemotherapy. Those treated with Rybrevant and chemotherapy saw significant improvement, living an average of 11.4 months without cancer progression compared to 6.7 months for the chemotherapy-only group. While final survival benefits are still under review, early results show no negative trends.
Common side effects included rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, COVID-19, diarrhea and vomiting.
Dr. Herbst explains why he thinks Rybrevant is an improvement upon chemotherapy:
“Chemotherapy is like a cluster bomb that kills a lot of tumor cells maybe, but it also kills a lot of normal cells. And the response rates used to be 20 or 30%. Now you’re using something that’s more laser guided and then your chance of response can go up to 60, 70 or 80%.”
However, Herbst does note that drugs like Rybrevant are not a cure.
“Resistance will often develop.That’s a problem,” he says. “We want to figure out why the tumor is resisting and what to do next. So that’s the next challenge.”
Scientific Mechanism
Rybrevant functions through a dual-targeting mechanism, engaging both the epidermal growth factor receptor (EGFR) and the MET receptor.
These receptors are pivotal in the signaling pathways that promote cancer cell proliferation and survival.
The drug’s bi-specific monoclonal antibody structure allows it to bind simultaneously to EGFR and MET receptors on the surface of cancer cells. This binding inhibits the activation of these receptors, effectively blocking the downstream signaling pathways that lead to tumor growth and progression.
The dual inhibition strategy of Rybrevant not only hampers tumor cell growth but also helps in overcoming resistance mechanisms that may develop against single-target therapies.
Related: Why Tagrisso May be Practice Changing In Lung Cancer With An EGFR Mutation
Targeted Cancer Type and Mutation
Dr. Herbst stresses the importance of Next-Generation Sequence (NGS) testing to pin down the exact nature of a patient’s tumor.
“When a patient comes in, we immediately sequence the tumor. We are doing panels that might include three or four or 500 genes, the ones that are most likely. Some sort of next generation approach is the best standard of care these days – it has to be done,” he says.
Once NGS determines the specific genetic mutation, physicians can select the target drug most likely to benefit each patient.
NSCLC with EGFR exon 20 insertion mutations, for example, is a specific and challenging subset of lung cancer patients.
These mutations occur in the exon 20 region of the EGFR gene, leading to abnormal receptor activation and contributing to the cancer’s growth and development. EGFR exon 20 insertions are less common than other EGFR mutations, such as those found in exon 19 deletions or exon 21 L858R substitutions, but they are particularly resistant to first-generation EGFR tyrosine kinase inhibitors (TKIs), making them a difficult-to-treat population.
This mutation is found in approximately 2% to 3% of NSCLC patients, meaning it is a relatively rare genetic alteration.
This represents a tiny proportion of lung cancer patients, but Dr. Herbst says having a targeted option is very significant to them.
“What if it is you or your wife or daughter or uncle? There’s obviously a market for this,” he says.”Certainly the presence or absence now of having a mutation in the gene is big and we’re ratcheting down to a specific level of personalization.”
Watch: Tagrisso May Reduce Risk of Death by Half in Some Early-Stage Lung Cancer Patients