Danny Nguyen, MD

Danny Nguyen, MD, assistant clinical professor at the department of medical oncology & therapeutics research at City of Hope, discusses next steps for research of mobocertinib (Exkivity) in patients with 

-positive non–small cell lung cancer (NSCLC).

Mobocertinib was investigated in a phase 1/2 study (NCT02716116), which showed efficacy and a tolerable safety profile for patients with an 

 exon 20 mutation, leading to accelerated FDA approval. It was only approved following disease progression on platinum-based chemotherapy, but according to Nguyen, an ongoing phase 3 study (NCT04129502) is comparing mobocertinib with carboplatin and pemetrexed in the first line.

Another area of investigation is sequencing mobocertinib and amivantamab (Rybrevant), which is also an 

 exon 20-targeted agent approved following platinum-based chemotherapy. Nguyen says that it is likely that patients with this mutation will likely receive both agents, but sequencing studies could discover which sequence offers superior efficacy and tolerability.

In addition, he suggests future studies could investigate mobocertinib in combination with other agents such as chemotherapy or targeted therapies to improve efficacy.

 Next steps for the development of mobocertinib is their ongoing phase 3 study in the first line studying comparing it to carboplatin and pemetrexed. That's ongoing to further characterize the benefit in that setting.

In addition, trying maybe [to sequence] it with the other approved 

 exon 20 medication amivantamab is a hot topic as well. So one question that gets asked of me a lot is, "Well, which one do we do first?" At this point, there [are] not much data to suggest one over the other [in the] first line, because they both have the same approval, which is post-platinum chemotherapy. I think at this point it is kind of like a moot point where most patients will probably be on both medications at some point anyways, but I think that's going to be a question that people try to answer in the future as well.

 Other pathways moving forward would probably also include novel combinations as well, so combining mobocertinib with other active agents, such as chemotherapy, or potentially other targeted inhibitors as well.

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Danny Nguyen, MD, discusses next steps for research of mobocertinib in patients with EGFR-positive non–small cell lung cancer.

Next Steps for Investigation of Mobocertinib for EGFR Exon 20+ NSCLC

Danny Nguyen, MD, assistant clinical professor at the department of medical oncology & therapeutics research at City of Hope, discusses an analysis of efficacy and adverse events (AEs) of mobocertinib (Exkivity) in patients with EGFR-positive non–small cell lung cancer (NSCLC) that was presented at the European Society for Medical Oncology 2021 Congress.

The phase 1/2 study (NCT02716116) administered 160 mg daily of mobocertinib, an oral EGFR/HER2 inhibitor, to patients who were pretreated with platinum-based chemotherapy. Dose reductions due to AEs were required in 29 of 114 patients, and 21 of these 29 needed a lower dose due to gastrointestinal (GI) toxicity. According to Nguyen, investigators reported diarrhea in 91% of patients and grade 3 or 4 diarrhea in 21%. Nausea was observed in 34% and vomiting in 30%.

Nguyen says that the exposure-safety analysis showed that the overall response rate (ORR) was 21% (95% CI, 8.0-39.7) in patients who needed dose reductions due to AEs, compared with 31% (95% CI, 21.1-41.5) in those who did not require dose reductions. The duration of response (DOR) was 5.7 months (95% CI, 3.7-not reached [NR]) compared with 17.5 months (95% CI, 7.4-NR), and progression-free survival (PFS) was 5.9 months (95% CI, 3.7-11.0) compared with 7.3 months (95% CI, 5.5-10.8) in patients who did not need dose reductions. The efficacy of mobocertinib was demonstrated to be linked to the level of exposure, leading to reduced efficacy in dose reductions.

 What we found was that most of the GI toxicities were low grade in severity; diarrhea was the most common GI toxicity in 93% of patients, all-grade diarrhea was observed in 91% of patients, with grade 3 or 4 diarrhea observed in 21% of patients. Thirty-four percent of patients experienced nausea and 30% of patients experienced vomiting. The median time to onset of diarrhea was approximately 5 days, all-grade diarrhea typically resolved in about 2 days, with grade 3 diarrhea resolving in about 6 and a half days or a week. Almost three-quarters of patients were on some form of anti-diarrheal medication: more commonly, loperamide.

So what we found when analyzing all the patients who experienced diarrhea and dose modifications was that the ORR of mobocertinib was approximately 21% of patients who experienced AEs leading to dose reductions. Whereas compared that to an ORR of 31% in those patients without AEs leading to dose reductions. We also found that PFS was lower in these patients: 5.9 months versus 7.3 months. And the DOR was also lower: about 6 months compared to 17.5 months.

Danny Nguyen, MD, discusses an analysis of efficacy and adverse events of mobocertinib in patients with EGFR-positive non–small cell lung cancer that was presented at the European Society for Medical Oncology 2021 Congress. 

Danny Nguyen, MD | Authors

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