Abstract C46: NSABP FC-7: A phase Ib study evaluating neratinib (N) and cetuximab (Cmab) in patients (pts) with quadruple wild-type (quad wt) (KRAS/NRAS/BRAF/PI3KCA wt) metastatic colorectal cancer (mCRC) resistant to Cmab

Autor: Ashok Srinivasan, James L. Wade, Thomas J. George, Marc Buyse, Jodi A. Kanyuch, Ashwin Reddy Sama, Norman Wolmark, S. Rim Kim, Ding Wang, Kay L. Pogue-Geile, James J. Lee, Samuel A. Jacobs, Philip J. Stella, Carmen J. Allegra
Rok vydání: 2015
Předmět:
Zdroj: Molecular Cancer Therapeutics. 14:C46-C46
ISSN: 1538-8514
1535-7163
Popis: Background Multiple mechanisms may account for de novo and acquired resistance to Cmab. One mechanism, HER2 amplification, promotes heterodimer formation with HER3, bypassing EGFR blockade and resulting in downstream signaling. Bertotti reported HER2 amplification rates of 2.7% in unselected CRC pts (n = 2349), 13.6% in KRAS wt, Cmab-resistant pts (n = 44), and 36.4% in quad wt, Cmab-resistant xenopts (n = 11), suggesting that HER2 amplification is selected for by prior Cmab exposure. To test the hypothesis that dual ERBB blockade could overcome resistance to Cmab in quad wt mCRC pts, as suggested by preclinical data, we combined N, an oral small molecule tyrosine kinase inhibitor that irreversibly binds to pan ERBB receptor tyrosine kinases, with Cmab in mCRC pts who progressed on previous anti-EGFR therapy (tx). Methods In this phase Ib study, 15 anti-EGFR tx (Cmab or panitumumab [Pmab])-resistant pts with quad wt mCRC have been enrolled. Clinical endpoints included determination of safety and efficacy of the combination of Cmab, fixed dose 250 mg/m2 iv weekly, and N at escalating doses of 120, 160, 200, and 240 mg/d continuously using 3+3 design. Each cycle was 28 d. All eligible pts must have had prior tx with at least oxaliplatin, irinotecan, and Cmab or Pmab, are required to have archived tumor available before initial anti-EGFR tx with quad wt profile, and agree to a research biopsy at time of enrollment (after anti-EGFR progression), ECOG PS < 2, measurable disease, and adequate hematologic and liver parameters; HER2 amplification is not required. Primary diarrhea prophylaxis with intensive loperamide is required at all dose levels for the initial 2 wks followed by titration. HER2 status is determined by IHC using image analysis-assisted microscopy to score tissues. We consider a sum of 3+ and 2+ in 40% of tumor cells as positive (pos). Findings The MTD of N in combination with Cmab has not been reached. Accrual to the final cohort 240 mg/d is ongoing. Of 14 pts evaluable for toxicity, 1 pt on N 240 mg/d experienced DLT of grade 3 diarrhea for ≥48h. One had grade 3 diarrhea at N 200 mg/d in cycle 3 for < 24 h. Grade 1-2 rash was the most common AE occurring in nearly all pts; only 1 pt had grade 3 rash. Other toxicities were mild and expected. Thus far, best response data is available on 9 pts. Using RECIST 1.1, 5 pts had stable disease (SD) occurring at N doses of 120, 160, and 200 mg/d. Three of 4 pts who were HER2 pos in their post anti-EGFR biopsy sample had SD lasting 105, 138, and 168 d; the 4th HER2-amplified pt was not evaluable. Two pts with HER2-neg tumors had SD for 42 and 97 d. Two of 4 pts with best response of progressive disease (PD) were HER2 neg, and in 2, tumor was insufficient for analysis. Of 11 paired pt samples with an adequate number of tumor cells for HER2 analysis in pre- and post-Cmab samples, 3 pts converted from HER2 neg to HER2 pos, and 1 was HER2 pos in both pre- and post Cmab samples. Conclusion Dual anti-ERBB therapy with Cmab and N was safe and well tolerated. Despite multiple prior therapies, SD was seen in 5 of 9 evaluable pts including 1 pt at N 120 mg/d. A trend toward longer duration of SD was observed in the pts who were HER2 pos. Four of 11 post-Cmab tissues (36%) were HER2 pos, including 3 who converted from HER2 neg to pos and 1 was pos pre-and post-Cmab. Support: Puma Biotechnology, Inc. Citation Format: Samuel A. Jacobs, James J. Lee, Thomas J. George, Jr., James L. Wade, III, Philip J. Stella, Ding Wang, Ashwin R. Sama, Marc E. Buyse, Jodi A. Kanyuch, Ashok Srinivasan, Kay L. Pogue-Geile, S. Rim Kim, Norman Wolmark, Carmen J. Allegra. NSABP FC-7: A phase Ib study evaluating neratinib (N) and cetuximab (Cmab) in patients (pts) with quadruple wild-type (quad wt) (KRAS/NRAS/BRAF/PI3KCA wt) metastatic colorectal cancer (mCRC) resistant to Cmab. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C46.
Databáze: OpenAIRE
Externí odkaz: