Niravath, Polly Ann

Abstract Purpose: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR. Patients and Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR. Results: Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1–2 diarrhea and acneiform rash being the most common toxicities. Conclusions: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.

PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m 2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B). Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

1005 Background: Evidence-based treatments (tx) for metastatic, HER2+ BCBM are limited. We previously found a central nervous system (CNS) objective response rate (ORR) of 8% (95% CI 2-22%) for the irreversible, EGFR/HER2-targeted kinase inhibitor, neratinib. To enhance CNS activity, we evaluated the combination of neratinib + capecitabine in a subsequent cohort, and report results here. Methods: Pts with measurable BCBM (≥ 1 cm in longest dimension) and no prior lapatinib or capecitabine were eligible. All but 3 had CNS progression after local CNS tx. During 21 day cycles, pts received capecitabine 750 mg/m2 twice daily x 14 days followed by 7 days off + neratinib 240 mg orally once daily. Loperamide prophylaxis (16 mg total daily) was recommended during cycle 1. Brain MRI and non-CNS imaging were repeated every 2 cycles until 18 wks, then every 3 cycles. The primary endpoint was composite CNS ORR, requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions (central review, VORR), no progression of non-target or non-CNS lesions, no new lesions, no escalating steroids, and no progressive neurologic signs/symptoms. We used a two-stage design with hypotheses ORR 15% and 35% (error rates 5% and 20%), responses in ≥5/19 pts to enter 2ndstage; responses in ≥9/35 [26%] pts to be promising. Results: 39 pts enrolled between 4/2014-11/2016 (2 withdrew before tx, 37 analyzed); median age 51, median prior metastatic lines 2 (range 0-6), 65% had prior WBRT. As of 11/15/16, 23 (62%) patients are alive and 7 remain on protocol tx; median number of cycles initiated = 5 (range 1-26). 18 women (49%) had a VORR (95% CI 32-66%, neurologic exams not yet available on all pts). Overall 12-month survival is 63% (95% CI 43%-77%); 4/7 pts still on protocol therapy have not yet reached 6 cycles. No pts had grade 4 toxicity; 18 (49%) had grade 3 toxicity, with diarrhea most common (32%), and 6 pts discontinued tx for toxicity. Conclusions: The combination of neratinib and capecitabine is active for BCBM with VORR in nearly half of pts, supporting further development of the regimen for BCBM. Updated results will be presented at the meeting. Clinical trial information: NCT01494662.

Abstract Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

Abstract Background: We have previously shown in animal models that combination anti-HER2 therapy leads to complete tumor regression of HER2+ breast cancer (BC). We translated these findings in a neoadjuvant trial of 12 weeks (wks) of L+T (TBCRC006) that demonstrated a meaningful pathologic complete response (pCR) and near pCR (in ER+ tumors) in patients with locally advanced HER2+ BC. In the present trial, we sought to determine whether longer treatment would lead to a higher rate of pCR without the use of chemotherapy by converting near pCR to pCR especially in the ER+ subset. Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon Phase 2 design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2+ BC measuring 2 cm or larger were eligible and were randomized in a 1:2 ratio to 12 vs. 24 wks of L+T. Letrozole (along with ovarian suppression if premenopausal) was also administered in patients whose tumors were also ER+. Serial tumor biopsies were obtained at baseline, wk 1, wk 12, and at the time of surgery. All evaluable patients were assessed for pCR, defined as no residual invasive carcinoma in the breast. Patients did not undergo surgery, withdrew consent, or received additional neoadjuvant therapy were counted as non-responders. Results: Ninety-seven patients were enrolled (33 in 12-wk arm and 64 in 24-wk arm), of whom 95 were evaluable. Seventy seven percent of patients were white and 18% were black. Twenty percent were of Hispanic ethnicity. Median age was 51 and 55% were postmenopausal. Median tumor size was 5 cm and 65% were ER+. Study treatment was well tolerated with grade 1-2 diarrhea (24% in 12-wk arm, 31% in 24-wk arm) and grade 1-2 acneform rash (12% in 12-wk arm, 19% in 24-wk arm) being the most common toxicities. Grade 3 toxicities were uncommon and were mostly in the 24-wk arm (elevated liver function test: 9%, diarrhea 2%, mucositis 2%), while the 12-wk arm had one grade 3 anemia and the study’s only serious adverse event (acute kidney injury). There were no grade 4 toxicities. The experimental arm completed stage 2 accrual and pCR rate was numerically superior to control, entirely due to better results in ER+ (Table 1), but lower than the expected pCR rate of 36% needed in the planned analysis to conclude in favor of enhanced efficacy with extended therapy. pCR rates were also lower in the control arm than in the previous study. Table 1. pCR rates 12-week arm % (n)24-week arm % (n)ER-positive8.7% (2/23)33.2% (13/39)ER-negative20% (2/10)8.7% (2/23)Overall pCR12.2% (4/33)24.2% (15/62) Conclusions: Treatment with L+T (with endocrine therapy in ER+ tumors) for 24 weeks leads to doubling of the pCR rate in women with HER2+ breast cancer without using cytotoxic chemotherapy. This approach is effective and well tolerated and warrants study as part of a de-escalation strategy that may spare some patients the cost and toxicity of chemotherapy. Tissue obtained on this trial will provide a valuable resource to validate correlative findings from our prior studies and discover new biomarkers to help guide proper patient selection for treatment. Citation Format: Mothaffar F Rimawi, Polly A Niravath, Tao Wang, Brent Rexer, Andres Forero, Antonio C Wolff, Rita Nanda, Anna M Storniolo, Ian Krop, Matthew P Goetz, Julie R Nangia, Sao Jiralerspong, Anne C Pavlick, Carolina Gutierrez, Rachel Schiff, Susan G Hilsenbeck, C Kent Osborne. TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-02.