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SUMMIT trial ‘guides development’ of pan-HER inhibitor in various cancers
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Clinical response to neratinib varied by tumor and HER-2 mutation type, according to results from the global, multicenter phase 2 SUMMIT trial presented at the American Association for Cancer Research Annual Meeting.
Neratinib (PB272, Puma Biotechnology) is an oral, irreversible pan-HER tyrosine kinase inhibitor that blocks signal transduction through epidermal growth factor receptors and has demonstrated activity in HER-2– and HER-3–mutant tumors in preclinical models.
“Mutations in the HER-2 and HER-3 genes are found at relatively low frequency in a variety of types of cancer,” David M. Hyman, MD, director of developmental therapeutics at Memorial Sloan Kettering Cancer Center, said in a press release. “We designed a clinical trial to validate whether these mutations are rational therapeutic targets and whether the investigational therapeutic neratinib, which targets members of the HER family, has anticancer activity.”
Researchers of the multihistology phase 2 basket trial evaluated neratinib in patients with advanced solid tumors and locally documented HER-2/HER-3 mutations.
Patients received 240 mg neratinib with high-dose loperamide prophylaxis during cycle 1.
Of the 21 unique cancer types enrolled, the most common included lung (n = 26), breast (n = 25), bladder (n = 16) and colorectal (n = 12) cancers.
Patients harbored 30 variants of the HER-2 mutation — the most common of which were S310, L755, A755_G776insYVMA and V777 — and 12 HER-3 mutation variants.
“By enrolling patients with a wide variety of cancer types harboring many different mutations, we have assembled a data set large enough to unravel the complex relationship between cancer type, mutation identity and susceptibility to pan-HER inhibition,” Hyman said. “It appears that there is not a binary relationship and that both cancer type and mutation identity are important.”
Overall response rate at week 8 served as the primary endpoint.
In total, 141 patients (HER-2 = 125; HER-3 = 16) received the neratinib regimen, including 125 patients with data evaluable for efficacy (HER-2 = 110; HER-3 = 15).
Clinical responses occurred in tumors with HER-2 S310, L755, V777, P780_Y781insGSP and A775_G776insYVMA mutations. No activity occurred in the HER-3–mutant cohort.
ORR at week 8 was highest in patients with breast cancer (ORR, 32%; 95% CI, 15.9-53.5), whereas biliary tract (ORR, 22.2%; 95% CI, 2.8-60) and cervical cancer (ORR, 20%; 95% CI, 0.5-71.6) had intermediate response rates. There were no responses observed for patients with colorectal cancer. These data led to indication-specific cohort expansions.
Researchers centrally sequenced 116 patients’ tumor or cell-free DNA. Based on this analysis, the locally reported HER-2/HER-3 mutation was confirmed in 108 patients. A discordant HER-2/HER-3 mutation was detected in five patients and not detected in three patients.
The safety profile of neratinib appeared consistent with previous reports.
“The take-home message at this point is that there are areas of promise, but we will likely need to combine pan-HER inhibition with other treatment modalities, such as chemotherapy or antihormone therapy, in order to obtain practice-changing response rates and durability of response,” Hyman said. “This is not surprising given that the FDA–approved HER-2–targeted therapeutics trastuzumab (Herceptin, Genentech), pertuzumab (Perjeta, Genentech), and lapatinib (Tykerb, Novartis) are used in combination with chemotherapy for the treatment of breast cancer.”
Co-mutation patterns in different tumor types and their association with neratinib sensitivity/resistance also are under review.
“Despite this, we have learned a huge amount from the trial,” Hyman said. “There have been reports on the responsiveness of HER-2–mutant cancers to off-label use of FDA–approved HER-2–targeted therapeutics, but this study provides a rigorous analysis of the many variables that are involved and will provide the most definitive data to guide the clinical development of HER family–targeted therapeutics in HER-2/HER-3–mutant tumors.” – by Kristie L. Kahl
Reference:
Hyman D, et al. Neratinib in HER-2 or HER-3 mutant solid tumors: SUMMIT, a global, multi-histology, open-label, phase 2 ‘basket’ study. Presented at: American Association for Cancer Research Annual Meeting; April 1-5, 2017; Washington, D.C.
Disclosure: Hyman is a consultant for Atara Biotherapeutics, Chugai, CytomX and Boehringer; and receives research funding from AstraZeneca and Puma Biotechnology.
Perspective
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Edward S. Kim, MD
Precision medicine was once believed to be difficult to achieve in the practice of medicine. Clinical acumen has always been the staple of medical treatment, with technologies complementing the clinician. However, more and more, the integration of assessment of a patient’s tumor genes is leading treatment decisions. The extreme end of the spectrum would entail treating a patient’s tumor not based on histology or phenotype, but purely on the genotype (ie, primary organ agnostic). We have learned over the years that it is a combination of genotypic information and clinical assessment that leads to the best outcomes.
The SUMMIT trial represents a paradigm focusing on specific mutations in the HER family, and not on organ type. The other variable involved is the drug utilized, in this case, neratinib (PB272, Puma Biotechnology). Hyman and colleagues report these results of their phase 2 study. The rigor involved with conducting these types biomarker-directed basket trials is high, but will add to a better understanding of drug effectiveness and serve as a rich source of tissue and biomarker information. The ability to mine this important information from the patients — to study their individual molecular information — will only enhance and accelerate the drug development process and deserves strong consideration for support and enrollment.
Perspective
Back to TopHoward A. Burris, III, MD
The basket trials are a source of great learning. They inform us on where to go in future trials, and helps us understand the biology of subtypes, areas of opportunity and places to reach a go or no-go early decision. Participation in a basket trial is far more impactful than the anecdotal, compassionate use stories that we often hear. This setting is certainly the place where participation in a clinical trial is the best thing we can do for our patients. Incorporating the complete molecular profile will provide much more information and give us better insights.
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