Newer Targeted Agents in NSCLC: TAK-788, an EGFR and HER2 Inhibitor


Robert Doebele discusses TAK-788, a first-in-class inhibitor of both EGFR and HER2 shown in an early-phase study to be active in NSCLC.

As part of our coverage of the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago, we spoke with medical oncologist and lung cancer specialist Robert C. Doebele, MD, PhD, about the results of an early-phase trial of a first-in-class oral agent, TAK-788. Dr. Doebele is an associate professor of medicine at the University of Colorado, Denver, where he heads a translational research laboratory that is investigating oncogenes relevant to lung cancer.

Cancer Network: Can you tell us about TAK-788? What does this oral drug target, and what is the rationale for testing it in advanced non–small-cell lung cancer?

Dr. Doebele: Sure. TAK-788 is a small, oral inhibitor of EGFR [epidermal growth factor receptor] and HER2 [human epidermal growth factor receptor 2]. It was specifically designed to meet an unmet need in nonsmall-cell lung cancer, which is that patients currently with certain types of EGFR and HER2 mutations do not have effective FDA [US Food and Drug Administration]-approved therapies. Specifically, these are patients who have EGFR exon 20 insertion mutations or patients with HER2 mutations. So, although we’ve had a plethora of EGFR inhibitors for nonsmall-cell lung cancer, drugs like erlotinib, gefitinib, alectinib, and osimertinib have not been shown to be efficacious in patients with EGFR exon 20 insertions or HER2 insertion mutations. So this drug is a third-generation covalent inhibitor of EGFR that was meant to achieve efficacy in this subpopulation of patients. The difficulty that has occurred in this setting is that EGFR exon 20 binding molecules are very similar in appearance and drug binding to wild-type EGFR binding molecules, and that has made getting appropriate doses into patients difficult. [TAK-788] has been shown to be selective for EGFR exon 20 insertion and HER2, so we could achieve the right dose to obtain tumor shrinkage.

Cancer Network: Can you tell us the design of the trial and the types of patients that were enrolled?

Dr. Doebele: This particular trial is a phase I dose-escalation trial, so this is the first time that the drug is being tested in humans. It’s a dose-escalation trial, so we are reporting on the dose escalation and the various cohorts. This was a mix of multiple different doses that were tested. Some of the patients reported in this cohort we presented received lower doses than the dose that we will go forward with in the next part of the trial.

Cancer Network: Can you highlight the important safety results first, since this is a phase I trial?

Dr. Doebele: To highlight the safety aspects of the trial, this drug’s main side effects are typical EGFR-related side effects. So, there have been some gastrointestinal toxicity [events], such as diarrhea, nausea, and vomiting. There have also been some skin and rash toxicities. All of these are well-described toxicities that occur with many of the EGFR inhibitors that we use for non–small-cell lung cancer.

Cancer Network: Did the trial provide any hints as to the efficacy of this drug in this patient population? And could you give us more details on how many patients were analyzed?

Dr. Doebele: In terms of efficacy, there were patient responses. We don’t necessarily want to [report] an objective response rate [at this time], because there were so many doses tested that there was not a significant number of patients tested at the recommended phase II dose of 160 milligrams. However, there was activity seen at several other doses in patients with EGFR exon 20 and HER2 [mutation]-positive lung cancer. [It] is very encouraging that, as we expand the trial using the 160-milligram dose, we can better assess the true rate of tumor response for each cohort.

Cancer Network: What are the next steps for this drug? Are additional trials being planned?

Dr. Doebele: This trial is now moving into an expansion cohort, so now that we have identified the correct dose for this medication, four specific cohorts of patients will be studied. The first cohort will be patients with EGFR exon 20 insertion mutations. The second will be patients with HER2 mutations, and the third will be patients who have either of those mutations [plus] brain metastases, to specifically test whether this drug has activity on brain metastases. And the fourth cohort will test the drug’s activity on patients with non–small-cell lung cancer [who] have other atypical mutations that were not described by the first two cohorts. So there will be four specific patient populations to address these specific questions: patients with EGFR exon 20 [mutations], HER2 [mutations], brain metastases, and [a variety of] uncommon mutations.

Related Videos
Tailoring neoadjuvant therapy regimens for patients with mismatch repair deficient gastroesophageal cancer represents a future step in terms of research.
Not much is currently known about the factors that may predict pathologic responses to neoadjuvant immunotherapy in this population, says Adrienne Bruce Shannon, MD.
Data highlight that patients who are in Black and poor majority areas are less likely to receive liver ablation or colorectal liver metastasis in surgical cancer care.
Findings highlight how systemic issues may impact disparities in outcomes following surgery for patients with cancer, according to Muhammad Talha Waheed, MD.
Pegulicianine-guided breast cancer surgery may allow practices to de-escalate subsequent radiotherapy, says Barbara Smith, MD, PhD.
Adrienne Bruce Shannon, MD, discussed ways to improve treatment and surgical outcomes for patients with dMMR gastroesophageal cancer.
Barbara Smith, MD, PhD, spoke about the potential use of pegulicianine-guided breast cancer surgery based on reports from the phase 3 INSITE trial.
Patient-reported symptoms following surgery appear to improve with the use of perioperative telemonitoring, says Kelly M. Mahuron, MD.
Treatment options in the refractory setting must improve for patients with resected colorectal cancer peritoneal metastasis, says Muhammad Talha Waheed, MD.
Although immature, overall survival data from the KEYNOTE-868 trial may support the use of pembrolizumab plus chemotherapy in patients with endometrial cancer.
Related Content