Novel Tyrosine Kinase Inhibitor Shows Promise for Metastatic Non-Small Cell Lung Cancer With Specific Genetic Mutation

Mobocertinib performed well and had a favorable safety profile in patients with platinum-pretreated EGFR exon 20 insertion–positive metastatic non-small cell lung cancer and could serve as a possible treatment in this patient population, according to findings presented at the virtual 2021 ASCO Annual Meeting.

In the platinum-pretreated patient cohort (114 patients), the confirmed overall response rate (the rate of a measurable response to treatment) assessed by an independent review committee was 28%, and all responses were partial responses. By investigator assessment, the confirmed overall response rate was 35%; the complete response rate was less than 1%, and the partial response rate was 34%.

The median duration of response (length of time a tumor continues to respond to treatment without growing or spreading) was 17.5 months by independent review committee and 11.2 months by investigator assessment. The confirmed disease control rate (percentage of patients who have achieved complete response, partial response and stable disease) was 78% by independent review committee and investigator assessment.

The median overall survival (time from diagnosis or treatment start when patients are alive) was 24 months, and the median progression-free survival (time during and after treatment when the patient lives without disease progression) was 7.3 months.

“Based on these data, we believe that mobocertinib is a potential treatment option for patients with EGFR 20 insertion mutations,” said lead study author Dr. Suresh S. Ramalingam, a professor in the Department of Hematology and Medical Oncology and director of the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine, during a virtual presentation of the data.

“Mobocertinib is an orally administered tyrosine kinase inhibitor that is specifically being developed for the treatment of (patients with) EGFR (exon) 20 insertion mutations,” added Ramalingam, who is also deputy director and director of the Lung Cancer Program of Winship Cancer Institute of Emory University. “Among EGFR mutations, the insertion 20 mutations account for approximately 10%.”

In this study, researchers assessed the effects of a 160-mg dose of mobocertinib once per day on two groups:

• patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy and no active or measurable central nervous system metastases (114 patients; median age, 60 years; 66% women; 59% received two or more prior systemic anticancer lines)
• patients with EGFR exon 20 insertion–positive metastatic non-small cell lung cancer (96 patients, of whom 86 received prior platinum-based chemotherapy; median age, 59 years; 65% women).

The median follow-up time was 14.2 months in the platinum-pretreated patient group and 13 months in the EGFR exon 20 insertion–positive metastatic group.

For patients without measurable central nervous system metastases, the majority of patients were never smokers (71%). The median number of prior anticancer regimens was two; 100% of patients received prior platinum-based chemotherapy, 43% received prior immunotherapy, and 25% received prior EGFR tyrosine kinase inhibitors. Finally, 35% of patients had brain metastases at the start of the study.

For those with EGFR exon 20 insertion-positive metastatic disease, most patients were never smokers (73%). The median number of prior lines of anticancer therapy in this group was one; 90% of patients received prior platinum-based chemotherapy, 34% received prior immunotherapy, and 31% received prior EGFR TKIs. Finally, 34% of patients had brain metastases at the beginning of the study.

In this cohort, the confirmed overall response rate by the independent review committee was 25%, and all responses were partial responses. The confirmed overall response rate by investigator assessment was 32%; 1% of patients achieved a complete response and 31% achieved partial responses.

The median duration of response was not evaluable by independent review committee and 11.2 months by investigator assessment. The confirmed disease control rates were 76% and 75%, respectively.

In the EGFR exon 20 insertion–positive group, 60% of patients experienced progressive disease by investigator assessment. The brain was the first site of progressive disease in 38% of patients. Of these patients, 23% continued on mobocertinib for at least three months after initial progressive disease. The median time on treatment beyond initial progressive disease was 1.6 months.

Additionally, in the remaining 62% of patients who experienced progressive disease in initial sites other than the brain, 6% continued on mobocertinib for at least three months after initial progressive disease. The median time on treatment beyond initial progressive disease was 0.1 months.

In the EGFR exon 20 insertion–positive group, 33 patients had brain metastases at the beginning of the study. Of these patients, 76% developed progressive disease, 68% of which reported the brain as the first site of progressive disease.

Additional results indicated that 23% of patients in the platinum-pretreated patient group and 26% of patients in the EGFR exon 20 insertion–positive group remained on mobocertinib at the time of the data cut-off. The median time on treatment was 7.4 months and 6.8 months, respectively.

“Nearly 85% of patients in this study had some level of tumor shrinkage (with mobocertinib) … and nearly 50% of patients with an objective response still have an ongoing response at the time of data cut-off for this presentation,” said Ramalingam.

Notably, in the platinum-pretreated patient cohort, responses were observed in all evaluated subgroups irrespective of prior EGFR tyrosine kinase inhibitor treatment, prior immunotherapy, or EGFR exon 20 insertion mutation variant.

Additionally, the safety profile observed with mobocertinib was consistent with the known profiles of EGFR tyrosine kinase inhibitors.

Regarding safety in the platinum-pretreated patient cohort, all patients reported any-grade side effects, and 99% of patients reported any-grade treatment-related side effects. Of these, any severe or worse side effects were observed in 69% of patients and any severe or worse side effects related to the treatment were observed in 47% of patients.

Serious side effects were noted in 49% of patients; 46% of these were severe or worse. A quarter of patients (25%) experienced a side effect that led to dose reduction and 17% experienced a side effect that led to treatment discontinuation.

The most commonly reported side effects that led to treatment discontinuation in this cohort included diarrhea (4%), nausea (4%), vomiting (2%), decreased appetite (2%), and inflammation of the mouth and lips (2%). Other common any-grade side effects included rash, inflammation of skin around the nails, dry skin, increased creatinine and itchy skin.

In the EGFR exon 20 insertion–positive group, side effects of any severity were reported in 100% of patients, 66% of which were severe or worse. Nearly all patients (99%) reported any-grade treatment-related side effects, 42% of which were severe or worse. Serious side effects were observed in 47% of patients, of which 44% were severe or worse. Additionally, 22% of patients experienced a side effect that required dose reduction, and 10% of patients experienced a side effect that required treatment discontinuation.

Nausea and diarrhea were the most frequently reported side effects that required treatment discontinuation in the EGFR exon 20 insertion–positive group. Other side effects included rash, skin infection around fingernails and toenails, decreased appetite, dry skin, increased creatinine, inflammation of the mount and lips, vomiting, acne-like bumps on certain areas of the body, itchy skin and increased amylase (which potentially indicates pancreatitis).

Of note, one treatment-related death from cardiac failure occurred in the EGFR exon 20 insertion–positive group in a platinum-pretreated patient.

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