In findings presented at the recent American Society of Clinical Oncology (ASCO) Annual Meeting, Takeda presented results of recent Phase I/II research exploring the viability of using mobocertinib in treating certain non-small cell lung cancer (NSCLC) patients. Minal Mehta, senior medical director/global clinical lead for mobocertinib with Takeda, spoke with Outsourcing-Pharma about the findings, and what they might mean for NSCLC patients.
OSP: Could you please tell us a bit about NSCLC—the nature of the disease, typical prognosis for a diagnosed patient up until now, and what treatment options have been available?
MM: NSCLC is the most common form of lung cancer, accounting for approximately 85% of the estimated 2.2m new cases of lung cancer diagnosed each year worldwide. Metastatic means the NSCLC has spread from its source in the lungs to other parts of the body. The most common sites of lung cancer metastasis are the liver, bone, and brain.
The prognosis and treatment options for NSCLC vary depending on the type of NSCLC. Certain types, such as epidermal growth factor receptor (EGFR) Exon20 insertion+ mNSCLC, have a less optimal prognosis due in part to a lack of effective treatment options. Fortunately, research in this field is rapidly evolving and introducing targeted therapies that may result in improved outcomes.
OSP: Please describe EGFR Exon20 insertion+ mNSCLC, and how its presence impacts patients with that particular characteristic.
MM: EGFR is a protein found on the surface of some cells and is what binds epidermal growth factor, causing the cells to divide. EGFR mutations can be found within lung cancer cells, including NSCLC, which causes over-activation of the protein that drives tumorigenesis. The exon refers to the location of the EGFR mutations in the EGFR gene, which can be found on exon 18, 19, 20, or 21.
Patients with EGFR Exon20 insertion+ mNSCLC make up only about 1-2% of patients with NSCLC. The disease is not as well-known as other lung cancer types and requires comprehensive genomic profiling (CGP) in order to be diagnosed properly.
OSP: Could you please tell us about the recent Phase I/II trial—how many patients, location of trial sites, how much if any of the study could be considered decentralized, etc?
MM: The Phase I/II trial is a global, single-arm, open-label trial that evaluated the safety and efficacy of mobocertinib in patients with mNSCLC. The trial is comprised of a Phase 1 dose-escalation, which evaluated mobocertinib as a monotherapy and in combination with chemotherapy, several expansion cohorts, and an extension cohort investigating mobocertinib as a monotherapy in patients with EGFR Exon20 insertion+ mNSCLC.
Takeda’s New Drug Application (NDA) for mobocertinib, which is currently being reviewed by the US Food and Drug Administration (FDA) on a priority six-month review cycle, is primarily based on results from an analysis of the platinum-pretreated population in the Phase 1/2 trial. The platinum-pretreated patient population investigated 114 patients with EGFR Exon20 insertion+ mNSCLC from the Phase 1/2 trial who received prior platinum-based therapy. All patients were treated at the 160 mg once-daily oral dose and shared similar eligibility for study participation.
The trial was conducted at 69 sites across the globe, with locations in the U.S., China, Germany, Italy, Japan, the Republic of Korea, Spain, Taiwan, and the United Kingdom. Decentralization was not applicable for this study.
OSP: I understand the results of that study indicated “demonstrate clinically meaningful benefit” in patient participants—could you offer a little more detail about that designation and anything you can share that’s making Takeda feel optimistic about the drug’s odds of eventual approval?
MM: Updated data from the Phase I/II trial of mobocertinib showed the oral, targeted therapy continues to demonstrate robust and durable responses in patients with EGFR Exon20 insertion+ mNSCLC who have received prior platinum-based chemotherapy, after over a year of follow up.
Building on the findings presented in January at the 2020 World Conference on Lung Cancer (WCLC), results showed a median overall survival (OS) of 24 months with a median follow-up of 14 months, and responses were observed across diverse EGFR Exon20 insertion variants.
Other key data points remained consistent with the previously reported data, including a confirmed objective response rate (ORR) of 28% per independent review committee (IRC) and 35% per investigator, a median duration of response (DoR) of 17.5 months, a median progression-free survival (PFS) of 7.3 months and a disease control rate (DCR) of 78% per IRC.
The updated Phase I/II data, coupled with mobocertinib’s oral administration, reinforce its potential in patients with EGFR Exon20 insertion+ mNSCLC, who are in critical need of targeted treatment options. If approved, mobocertinib, a first-in-class tyrosine kinase inhibitor (TKI), will be the first oral therapy available that was specifically designed to selectively target EGFR Exon20 insertion mutations.
OSP: In your announcement about the Phase I/II trial you mention that (if approved) mobocertinib will be the first oral therapy available specifically designed to selectively target EGFR Exon20 insertion mutations. Why is that significant?
MM: Mobocertinib is the first small-molecule TKI specifically designed to selectively target EGFR Exon20 insertions in patients with mNSCLC and demonstrated clinical proof-of-concept in these patients. The development of mobocertinib was guided by an iterative, structure-guided design strategy that was used to optimize affinity and selectivity for EGFR with Exon20 insertion mutations over wild-type (WT) EGFR in order to differentiate it from available EGFR TKIs that have proven ineffective for this patient population.
Additionally, mobocertinib’s administration will be an important advancement for patients, as an oral therapy may have a less significant impact on a patient’s daily routine compared to other regimens. Considering its unique design and administration, if approved, we believe mobocertinib will serve as a novel, first-in-class offering to this patient population.
OSP: Do you have anything to add?
MM: At Takeda, we are committed to research and development in EGFR Exon20 insertion+ mNSCLC. With the current NDA for mobocertinib under review by the FDA, we are encouraged by the potential to introduce the first oral targeted treatment option for the over 35,000 patients diagnosed with the disease worldwide each year.
We look forward to continuing to work with the FDA and regulatory authorities around the world to bring mobocertinib to patients.