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ExteNET showed that neratinib, an irreversible pan-HER tyrosine ki- nase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved inva- sive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET.

Background: In the SUMMIT trial, original cohorts of patients with HR+, HER2-negative (locally assessed), HER2-mutant MBC received N alone or N+F, with promising clinical response rates but abbreviated duration. Clinical progression coincided with emergence of additional HER2 mutations and/or amplification of the mutant allele [Smyth et al. Cancer Discov 2020;10:198–213]. Addition of T to the combination was postulated to prolong response; the combination of N+F+T in heavily pretreated patients with HR+, HER2-mutant MBC who had received CDK4/6 inhibitors (n=51) yielded a confirmed overall response rate (ORR) of 35.3%, median duration of response (DOR) of 14.3 months, clinical benefit rate (CBR) of 47.1%, and median progression-free survival (PFS) of 8.2 months [Jhaveri et al. J Clin Oncol 2022;40:1028]. Seven of these 51 patients were part of a randomized (1:1:1) cohort who received N+F+T, F+T, or F alone. Patients randomized to F+T or F could crossover to N+F+T upon progression. No patients responded to F or F+T; however, one of four patients who crossed over to N+F+T upon progression on F+T responded to the triplet, as did two of six who crossed over upon progression on F. We undertook ctDNA sequencing in patients who responded to N+F+T upfront and after crossover. Methods: Patients with HR+, HER2-negative MBC with activating HER2 mutation(s) and prior CDK4/6i received N+F+T (oral N 240 mg/d with loperamide prophylaxis, im F 500 mg d1, d15, and d29 of cycle 1 then q4w, iv T 8 mg/kg initially then 6 mg/kg q3w) or F+T or F alone. Efficacy endpoints included investigator-assessed ORR and CBR (RECIST v1.1), DOR, and best overall response. ctDNA was collected at baseline, every third cycle during treatment, and at the end of treatment and analyzed by next-generation sequencing. Samples were analyzed using the TEMPUS xF assay. Results: Sequencing results from ctDNA analysis are pending at the time of this abstract submission. Baseline HER2 mutations and co-alterations will be reported and compared with those found in tissue samples. Genomic spectrum and variant allele frequencies in samples taken at baseline, on treatment, and at the end of treatment from patients who experienced complete or partial response to N+F+T and then progressed (n=25) will be sequenced and mechanisms of acquired resistance will be posited. ctDNA genomic profiles of serial time points from patients randomized to F or F+T before and after crossover to N+F+T (n=10) will also be evaluated. Conclusions: Similarities and differences between the mechanisms of acquired resistance to N+F+T, and those previously reported to be associated with progression on N or N+F, will be discussed. Citation Format: Cynthia Ma, James Waisman, Adam M. Brufsky, Eddy S. Yang, Hans Wildiers, John P. Crown, Sarina A. Piha-Paul, Jennifer M. Suga, José Ángel García-Sáenz, Valentina Gambardella, Angel Guerrero, Salomon Stemmer, Ron Bose, Tonya Novara-Demgen, Daniel DiPrimeo, Lisa D. Eli, Komal Jhaveri. Genomic analysis of circulating tumor DNA (ctDNA) from patients with HR+, HER2-mutant metastatic breast cancer (MBC) enrolled in SUMMIT: mechanisms of acquired resistance to neratinib + fulvestrant + trastuzumab (N+F+T) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-01.

HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (NCT01953926). The primary objective of the BTC cohort was objective response rate (ORR). Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR was 16%. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appeared worse for ampullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one responder. Neratinib demonstrated anti-tumour activity in patients with refractory BTC harbouring HER2 mutations. Future studies of rational combinations are warranted.

4079 Background: HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs) and are associated with poor overall survival (OS) in patients with metastatic disease. HER2 overexpression is associated with an increased risk of disease recurrence in patients with resected BTC. There is limited data on targeting HER2 in BTC harboring activating somatic HER2 mutations. Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has demonstrated activity in several HER2-mutant solid tumors. Methods: SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumors harboring oncogenic HER2 somatic mutations. The primary objective of the BTC cohort was to estimate objective response rate (ORR). Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), OS, response duration, safety, and tolerability. Retrospective central confirmation of locally reported HER2 mutation (next-generation sequencing on archival or fresh tumor tissue using MSK-IMPACT or in cfDNA extracted from plasma by MSK-ACCESS) and association with outcome was an exploratory endpoint. This trial is registered with ClinicalTrials.gov (NCT01953926). Results: 25 treatment-refractory patients with metastatic BTC were enrolled (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers). ORR was 16% (95% CI 4.5–36.1%) and CBR was 28% (95% CI 12.1–49.4%). Median PFS and OS were 2.8 (95% CI 1.1–3.7) and 5.4 (95% CI 3.7–11.7) months, respectively. Median PFS for the gallbladder, cholangiocarcinoma and ampulla cohorts was 3.7 (95% CI 0.8–6.4), 1.4 (95% CI 0.5–9.1), and 1.1 (95% CI 1.1–3.8) months, respectively. Corresponding median OS values in these cohorts were 9.8 (95% CI 2.4–NE), 5.4 (95% CI 0.8–16.2), and 5.0 (95% CI 3.7–10.2) months, respectively. Central mutation confirmation was feasible for 23 of 25 patients; 22 were concordant with enrolment assays. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Exploratory analyses suggested worse outcomes for HER2-mutant tumors with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one of four responders. Diarrhea (56% any grade) was the most common toxicity. Conclusions: Neratinib is tolerable with modest antitumor activity in patients with BTC harboring HER2 mutations. Although the primary endpoint was met, future studies should evaluate rational combinations to augment and/or prolong responses. Clinical trial information: NCT01953926.

Aims To evaluate the effect of lansoprazole, a proton-pump inhibitor, on the absorption, pharmacokinetics, and safety of neratinib, a pan-HER tyrosine kinase inhibitor, in healthy subjects. Methods This was an open-label, two-period, fixed-sequence study. Fifteen healthy adult subjects received a single oral dose of neratinib 240 mg (Period 1), followed by a washout period, then oral lansoprazole 30 mg once daily for 7 days and a single dose of neratinib 240 mg on Day 5 (Period 2). Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Plasma neratinib concentration–time data were analysed using noncompartmental methods. Geometric mean ratios for AUC0–t, AUC0–inf, and peak plasma concentrations (Cmax) for neratinib plus lansoprazole vs. neratinib were used to assess the magnitude of the drug–drug interaction if the 90% confidence intervals were outside 80.00–125.00%. Results Neratinib geometric least-squares mean (LSM) Cmax was reduced from 84.5 ng ml−1 with neratinib alone to 24.5 ng ml−1 with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC0–t was 1478 ng ml−1 h with neratinib vs. 426 ng ml−1 h with neratinib plus lansoprazole, and geometric LSM AUC0–inf was 1557 ng ml−1 h vs. 542 ng ml−1 h, respectively. Mean t½ was similar with both treatments (approximately 14 h). Geometric mean ratios 90% confidence intervals for AUC0–t, AUC0–inf and Cmax fell outside the prespecified equivalence range (80.0–125.0%). Treatment-emergent adverse events, all mild, were reported by five (33%) subjects. Conclusions Coadministration of lansoprazole with neratinib reduced the rate and extent of neratinib exposure in healthy subjects.