Background

Neratinib (N), an irreversible pan-HER TKI, is approved in the EU for extended adjuvant treatment of early-stage HR+ HER2+ breast cancer (BC) after adjuvant trastuzumab (T)-based therapy. The CONTROL trial (NCT02400476) investigated pre-emptive antidiarrheal prophylaxis or dose escalation (DE) for prevention of diarrhea, the most frequent side effect of N.

Methods

CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients (pts) ≥18y with stage I–IIIc HER2+ BC received oral N (240 mg/d for 1y) after T-based adjuvant therapy. Pts were enrolled sequentially into separate cohorts: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) DE + loperamide PRN (2 cohorts). DE1 schedule: N 120 mg/d x w1, 160 mg/d x w2, then 240 mg/d from w3 to 12m. DE2 schedule: N 160 mg/d x w1&2, 200 mg/d x w3&4, then 240 mg/d from w5 to 12m. Primary endpoint: incidence of grade ≥3 diarrhea.

Results

563 pts were enrolled. All preventive strategies reduced grade 3 diarrhea vs ExteNET (historical control: 39%). Median cumulative duration of grade 3 diarrhea ranged from 2–3.5d in CONTROL (vs 5.0d for ExteNET). The proportion of pts discontinuing N because of diarrhea was decreased in CONTROL vs ExteNET. Key diarrhea outcomes in all CONTROL cohorts are presented in the table and will be fully detailed during the congress. Table: 73P

Patient disposition and diarrhea characteristics: All CONTROL cohorts

Conclusions

These final findings from CONTROL show improved tolerability of N with all diarrhea prophylaxis strategies and suggest that DE1 with loperamide PRN allows pts to stay on treatm.ent longer and receive full benefit from N.

Clinical trial identification

NCT02400476.

Editorial acknowledgement

Editorial/writing assistance for this abstract was provided by Lee Miller (Miller Medical Communications Ltd.). This work was funded by the study sponsor (Puma Biotechnology Inc.).

Legal entity responsible for the study

Puma Biotechnology Inc.

Funding

Puma Biotechnology Inc.

Disclosure

A. Brufsky: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc. A.J. Chien, R. Bose: Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. B. Pistilli: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc.; Financial Interests, Personal, Advisory Role, Consulting fees: Pierre Fabre; Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. D. Diprimeo, N. Foruzan, L.M. McCulloch: Financial Interests, Personal, Full or part-time Employment: Puma Biotechnology Inc.; Financial Interests, Personal, Stocks/Shares: Puma Biotechnology Inc. All other authors have declared no conflicts of interest.

Background

The intrinsic subtype classification provides prognostic information on the outcome of patients with hormone receptor-positive/HER2-negative (HR+/HER2-) early breast cancer. The nCOUNTER PAM-50 test is the mRNA-based technique approved for the identification of Luminal (Lum) A and LumB tumors, to select candidates for additional adjuvant chemotherapy, mainly those with LumB tumors. Since genomic tests are expensive and not widely available, some IHC-based surrogated classifiers have been proposed based on HR, HER2 and Ki67 expression. In this real-world data analysis, we determine the ability of three different surrogate classifiers to predict the real nCOUNTER PAM-50 subtype.

Methods

Tumor samples centralized to perform the nCOUNTER PAM-50 assay in the Laboratory of Traslational Oncology at the Hospital General Universitario Gregorio Marañon between 2014 and 2020 were included in the analysis. HR and Ki67 status were determined at local laboratories. All tumors were HER2 negative by local standards. Correlation among nCOUNTER PAM-50 test and three classifiers are analysed (Cheang M et al., J Natl Cancer Inst 2009; Prat A et al., J Clin Oncol 2013; Maisonneuve P et al., Breast Cancer Res. 2014).

Results

A total of 1105 samples were analysed. 55 out of them did not have Ki67 value reported, being excluded from the analysis. From the remaining 1050 samples, 679 (64.6%) were classified as LumA and 351 (33.4%) as LumB. Concordance among these molecular subtypes by nCOUNTER PAM-50 assay and the IHC surrogated are summarized in the table. The classification based on Maisonneuve et al. 2014 showed the best correlation, although the correlation was only fair. Table: 85P

Conclusions

In this study, the concordance between Lum subtypes determined by 3 different IHC-based classifiers and nCOUNTER PAM-50 assay is clearly suboptimal. Between 13 - 19% of nCOUNTER PAM-50 LumB tumors were classified as LumA by IHC and could be undertreated. Conversely, between 38-54% of nCOUNTER PAM-50 LumA tumors were classified as LumB by IHC and could receive unnecessary chemotherapy.

Legal entity responsible for the study

Miguel Martín Jiménez.

Funding

Has not received any funding.

Disclosure

M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Astrazeneca; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech; Financial Interests, Personal, Invited Speaker: Roche/Genentech; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Puma; Non-Financial Interests, Invited Speaker: Trio; Non-Financial Interests, Leadership Role: GEICAM. Y. Jerez: Financial Interests, Personal, Advisory Role: Novartis, Pfizer, Roche and AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche, Novartis and AstraZeneca; Financial Interests, Personal, Training: Roche, Novertis, Pfizer and Teva. I. Echavarria Diaz-Guardamino: Financial Interests, Personal, Invited Speaker: Eli Lilly, Pfizer, Roche, Novartis and Teva; Financial Interests, Personal, Advisory Role: Eli Lilly, Pfizer, Roche, Novartis and Teva. I. Marquez-Rodas: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Regeneron; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Advisory Board: Highligth Therapeutics; Financial Interests, Personal, Advisory Board: Bioline Rx; Financial Interests, Personal and Institutional, Invited Speaker, GEM1802 clinical trial: Pierre Fabre; Financial Interests, Institutional, Invited Speaker, GEM1801 clinical study: Novartis; Financial Interests, Institutional, Invited Speaker, GEM1801 clinical study: BMS; Financial Interests, Institutional, Invited Speaker, GEM1801 clinical study: Roche; Financial Interests, Institutional, Invited Speaker, GEM1801 clinical study: Pierre Fabre; Financial Interests, Institutional, Invited Speaker, GEM1801 clinical study: Incyte; Financial Interests, Institutional, Invited Speaker, GEM1801 clinical study: MSD; Financial Interests, Institutional, Invited Speaker, National coordinator of Spotlight 203 clinical trial: Highlight Therapeutics; Non-Financial Interests, Invited Speaker: Spanish Melanoma Group. T. Massarrah: Financial Interests, Personal, Advisory Role: AstraZeneca, Novartis, Roche; Financial Interests, Personal, Training: Novartis, AstraZeneca. J.Á. García Saenz: Financial Interests, Personal, Advisory Role: Seagen, Gilead, Sanofi; Financial Interests, Personal, Invited Speaker: Novartis, Celgene, Eli Lilly, Eisai, AstraZeneca, Daiichi Sankyo, MSD. F. Moreno Anton: Financial Interests, Personal, Invited Speaker: Novartis, Roche, Pfizer, AstraZeneca, Diachi-Sankyo, Exact Sciences, Fresenius Kabi Institution research from Pfizer; Financial Interests, Personal, Training: Novartis, Roche, Pfizer. C. Olier Garate: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer; Financial Interests, Personal, Advisory Role: Novartis, Pfizer. D. Moreno Muñoz: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer; Financial Interests, Personal, Advisory Role: Novartis, Pfizer. T. Merina: Financial Interests, Personal, Other: Oncogenomics. S. Lopez-Tarruella Cobo: Financial Interests, Personal, Advisory Role: Novartis, Pierre Fabre, Pfizer, Roche, AstraZeneca, Daiichi Sankyo, MSD, Seagen, GlaxoSmithKline, Gilead, Veracyte and Lilly; Financial Interests, Personal, Invited Speaker: Novartis, Roche, Lilly. All other authors have declared no conflicts of interest.

Background

Preclinical and pharmacological data of the three approved cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) suggest differences among them. Abemaciclib inhibits other targets (CDK2/Cyclin A/E and CDK1/Cyclin B) causing cell cycle arrest in phases G1 and G2. In preclinical models, both senescence and apoptosis occurred earlier and at lower concentrations of Abemaciclib, compared to treatment with either palbociclib or ribociclib. Abemaciclib monotherapy or combined with tamoxifen has demonstrated activity in endocrine refractory metastatic breast cancer (MBC) who had received prior treatment with chemotherapy. There are limited clinical data of abemaciclib after a prior CDK4/6i exposure.

Methods

To assess the safety profile and clinical outcomes of a consecutive cohort of HR+/HER2- MBC patients treated with abemaciclib beyond a previous progression on palbociclib or ribociclib at our institution.

Results

From April, 2020 until February, 2022, 11 women met inclusion criteria and were included. 9 out 11 received abemaciclib combined with tamoxifen. 8 patients had visceral involvement, none had brain metastasis. Median age was 69 years (range 42-84 years). Median time to abemaciclib from the end of previous CDK4/6i was 17.5 months (range 3-41 months). Median number of therapies until rechallenge was 3 (range 1-7) including chemotherapy in 54.5% of patients. Median time of follow-up was 6 months (range 1-22 months). The median progression-free survival (PFS) was 6 months (95%CI 3.5 – 10). 5 patients still continue on abemaciclib. Of these, 1 patient with hepatic metastases achieved complete response. Clinical benefit rate (CBR) at 24 weeks was seen in 5 patients out of 8 evaluable patients. Most common adverse events (AEs) were diarrhea (72.7%, no grade ≥ 3) and asthenia (27.3%, no grade ≥3). Neutropenia grade 4 was seen in a heavily treated patient with previous episodes on other therapies.

Conclusions

Abemaciclib may result an effective and safe treatment option in MBC patients previously treated with palbociclib or ribociclib. Further prospective studies to confirm this hypothesis are required.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.