Background

Neoadjuvant atezolizumab plus docetaxel, trastuzumab and pertuzumab therapy showed favorable efficacy and safety profiles in HER2-positive early breast cancer (EBC) in NEO-PATH phase 2 study, which provided evidence of combining immunotherapy and anti-HER2 treatment as a potential new therapeutic option. We evaluated potential genomic biomarkers in NEO-PATH trial.

Methods

Tumor tissue were collected before neoadjuvant chemotherapy from all enrolled patients and at surgery in patients who did not achieve pathologic complete response (pCR). Targeted sequencing using FoundationOne CDx^TM and whole transcriptome sequencing (WTS) were performed. The association between genomic features and pCR achievement was analyzed by Fisher's exact test for the enrichment test by mutations and by differential gene expression analysis using edgeR package. A p-value or false discovery rate (FDR) less than 0.05 were considered as statistically significant.

Results

Targeted sequencing result were obtained from 63 patients(T1) and 15 patients(T3), respectively. Pre-treatment RAD21 amplification (p=0.0002), MYC amplification (p=0.0095) and MYC pathway mutations (p=0.0095) were more frequently detected in non-pCR group (n=23) compared to pCR group (n=40), and co-amplification of ERBB2 and MYC were enriched in non-pCR group (p=0.01687). When genomic mutations were compared before and after neoadjuvant chemotherapy, ERBB2 amplification (p= 0.0026) and CDK12 amplification (p=0.0006) were enriched in pre-treatment tumors and PTPRO mutation (p=0.0229) was enriched in residual tumor tissue. WTS result were obtained from 62 patients(T1) and 10 patients(T3), respectively. Luminal subtypes were enriched in non-pCR group (p = 0.0558). In patients with non-pCR, LRP1B (FDR=4.04e-04), ESR1 (FDR=1.07e-4) and RAD21 (FDR=2.05e-03) were highly expressed and ESR1, luminal and MYC related genesets showed higher expression (FDR<0.05).

Conclusions

Luminal subtype and MYC amplification were associated with non-pCR in patients with HER2-positive EBC who were treated with immunotherapy and anti-HER2 treatment combination. Further evaluation of the predictive role of these mutations are warranted.

Clinical trial identification

NCT03881878.

Legal entity responsible for the study

Yeon Hee Park.

Funding

This work was supported by a grant from the Ministry of Health and Welfare, Republic of Korea (HA17C0055) and by the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). The study drugs were provided by Roche (trastuzumab, pertuzumab, and atezolizumab), Sanofi (docetaxel), and Dong-A ST (tripegfilgrastim).

Disclosure

H.K. Ahn: Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca, Roche, Boehringer Ingelheim, MSD, Pfizer, Eli Lilly; Financial Interests, Personal, Invited Speaker: MSD Boehringer Ingelheim. S. Im: Financial Interests, Personal, Invited Speaker: Merck, AstraZeneca, Eisai, GSK, Hanmi, Eli Lilly, MSD, Pfizer, Novartis; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Pfizer, Dae Woong; K.H. Jung: Non-Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Novartis, BiXink, Takeda. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Roche, Novartis, MSD; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pfizer, Roche, MSD; Non-Financial Interests, Principal Investigator: AstraZeneca, Pfizer, Novartis, MSD, Lilly, Roche, Daiichi Sankyo. All other authors have declared no conflicts of interest.

Background

Patients (pts) with a/mTNBC have limited treatment options and poor prognosis. Combining checkpoint inhibitors with 1L chemotherapy improves outcomes but only in PD-L1+ve a/mTNBC, emphasizing a critical need. Dato-DXd, a TROP2 antibody-drug conjugate (ADC) with potent topoisomerase (TOPO) I inhibitor payload, elicited a 34% objective response rate (ORR) in heavily pretreated a/mTNBC and 52% ORR in a subset naïve to TOPO I-based ADCs. In BEGONIA, an ongoing 2-part, open-label platform study, D (an anti-PD-L1 antibody) combined with other therapies, including ADCs, is being evaluated in 1L a/mTNBC (NCT03742102). Here, we report preliminary results of Dato-DXd + D.

Methods

Unresectable a/mTNBC pts eligible for 1L treatment, regardless of PD-L1/TROP2 status, received intravenous Dato-DXd 6 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. Primary endpoints are safety and tolerability. Secondary endpoints include investigator-assessed ORR (RECIST v1.1) and response duration. Data cutoff was Nov 2021.

Results

29 pts received Dato-DXd + D (24 ongoing), 27 had the opportunity to have 2 postbaseline scans. Median (range) follow-up was 3.9 (2–6) months. Confirmed ORR was 20/27 (74%; 95% CI, 54–89); 2 (7%) pts had complete and 18 (67%) had partial responses, all were in response at data cutoff. No dose-limiting toxicities were observed. 4 pts (14%) underwent 1 Dato-DXd dose reduction due to stomatitis, 4 (14%) had 1 Dato-DXd dose delay, and 4 (14%) had 1 D dose delay. No dose modifications were required due to diarrhea. Table: 166MO

Summary of adverse events (AEs), n (%)

Conclusions

Combination of Dato-DXd + D in 1L a/mTNBC demonstrated robust response rates with a manageable safety profile in this preliminary analysis, warranting further investigation. Additional enrollment and analysis of translational data is ongoing. Funding: AstraZeneca/Daiichi Sankyo.

Clinical trial identification

NCT03742102.

Editorial acknowledgement

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Nicole Seneca, PhD, of Parexel (Hackensack, NJ) and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca/Daiichi Sankyo.

Funding

AstraZeneca/Daiichi Sankyo.

Disclosure

P. Schmid: Financial Interests, Personal and Institutional, Other, Employment, consulting or advisory role and research funding: Genentech; Financial Interests, Personal and Institutional, Other, Employment, Honoraria, consulting or advisory role and research funding: Roche; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: AstraZeneca; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Novartis; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Pfizer; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Bayer; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Celgene; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Eisai; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Merck; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Puma Biotechnology; Financial Interests, Institutional, Funding, Research Funding: Astellas Pharma; Financial Interests, Institutional, Funding, Research funding: OncoGenex. K.H. Jung: Financial Interests, Personal, Advisory Role, Consulting or advisory role: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Celgene; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Eisai; Financial Interests, Personal, Advisory Role, Consulting or advisory role: MSD; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Novartis; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Roche; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Takeda. P.J. Wysocki: Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: AstraZeneca; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Astellas; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Amgen; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: BMS; Financial Interests, Institutional, Other, Honoraria: Gilead; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: IPSEN; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Immunicom; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Janssen; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: MSD; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Merck; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Pierre Fabre; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Pfizer; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Roche; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Sanofi. J. Jassem: Financial Interests, Personal, Other, Personal fees: AstraZeneca; Financial Interests, Personal, Other, Personal fees: Pfizer; Financial Interests, Personal, Other, Personal fees: Roche; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: Pfizer; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: Exact Sciences; Financial Interests, Personal, Other, Conference registration fee: Boehringer Ingelheim. C.X. Ma: Financial Interests, Personal and Institutional, Funding, Funding: Puma; Financial Interests, Personal and Institutional, Funding, Funding: Pfizer; Financial Interests, Personal, Advisory Role, Consulting Fees: Gilead; Financial Interests, Personal, Advisory Role, Consulting Fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting Fees: Athenex; Financial Interests, Personal, Advisory Role, Consulting Fees: Jacobio; Financial Interests, Personal, Advisory Role, Consulting Fees: Natera; Financial Interests, Personal, Advisory Role, Consulting Fees: Bayer Healthcare; Financial Interests, Personal, Advisory Role, Consulting Fees: Biovica; Financial Interests, Personal, Advisory Role, Consulting Fees: Eisai; Financial Interests, Personal, Advisory Role, Consulting Fees: Eli Lilly; Financial Interests, Personal, Advisory Role, Consulting Fees: Novartis; Financial Interests, Personal, Advisory Role, Consulting Fees: Phillips Electronics; Financial Interests, Personal, Advisory Role, Consulting Fees: Sanofi; Financial Interests, Personal, Advisory Role, Consulting Fees: Seattle Genetics; Financial Interests, Personal, Advisory Role, Consulting Fees: Pfizer. R. Fernandes: Financial Interests, Personal, Advisory Role, Consulting fees: Canadian Agency for Drugs and Technologies in Health (CADTH); Financial Interests, Institutional, Other, Honoraria: Bayer; Financial Interests, Institutional, Other, Honoraria: Pfizer; Financial Interests, Institutional, Other, Honoraria: Ipsen; Financial Interests, Institutional, Other, Honoraria: BMS; Financial Interests, Institutional, Other, Honoraria: Merck; Financial Interests, Institutional, Other, Honoraria: Novartis; Financial Interests, Institutional, Other, Honoraria: Janssen. R. Huisden: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. R. Stewart: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca, during the conduct of the study and outside the submitted work: AstraZeneca; Financial Interests, Personal, Other, Personal fees from Pfizer, outside the submitted work: Pfizer. P. Vukovic: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. A. Tablante Nunes: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. Z. Nowecki: Financial Interests, Institutional, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Other, Honoraria: Sanofi Aventis; Financial Interests, Institutional, Other, Honoraria: MSD; Financial Interests, Institutional, Other, Honoraria: Roche.

Background

The phase II trial of the pan-HER inhibitor poziotinib (NCT02418689) demonstrated the clinical effectiveness of poziotinib 12 mg p.o. once daily (QD) in patients with HER2-positive metastatic breast cancer (mBC) in a heavily pretreated setting with median progression free survival (PFS) of 4 months from the primary analysis. Diarrhea and stomatitis were the major toxicities. We now report the results from the final planned analysis of overall survival (OS).

Methods

Eligible patients have received anticancer chemotherapy including taxane and ≥2 prior HER2-directed regimens including trastuzumab. PFS was the primary endpoint. Secondary endpoints included OS and objective response rate (ORR), and safety was evaluated. The database was locked on October 1, 2021 including data from the last patient who received poziotinib for 104 cycles (72.7 months) and transferred to the early access program. The final OS analysis was planned when ≥ 54 deaths occurred. The final OS analysis occurred after 68 deaths.

Results

From April 2015 to February 2016, 106 patients were enrolled at seven sites in Korea. At data cut off on 1 October 2021, the full analysis set included 102 patients. Median age was 51.0 (range 30–76) years. Median number of treatment regimens before poziotinib was 4 (2-16). At the data cut-off, median PFS (95% CI) was 4.0 (3.0–4.4) months. Median OS (95% CI) was 17.7 (95% CI 12.4–20.8) months (68/102 events; 66.7%). OS rate (95% CI) at 36 and 60 months was 18 (10-28)% and 14 (7-24)%, respectively. Most frequent all-grade adverse events (AEs) considered to be treatment related were: diarrhea (96.2%), stomatitis (92.5%), pruritus (63.2%), rash (63.2%), dry skin (38.7%), dermatitis acneiform (32.1%), and decreased appetite (26.4%). Grade ≥3 AEs and serious AEs occurred in 45.3% and 8.5% of patients, respectively.

Conclusions

Poziotinib showed clinically meaningful OS benefit for patients with HER2-positive mBC and the safety profile was as expected for tyrosine kinase inhibitors(TKIs). This encouraging result provide an important update on the clinical effectiveness and safety of poziotinib in HER2-positive mBC patients who were previously heavily treated.

Clinical trial identification

NCT02418689.

Legal entity responsible for the study

The authors.

Funding

Hanmi.

Disclosure

Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Other, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Research Grant: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Other, Research Grant: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator: Pfizer; Non-Financial Interests, Principal Investigator: Novartis; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Principal Investigator: Lilly; Non-Financial Interests, Principal Investigator: Roche; Non-Financial Interests, Principal Investigator: Daiichi Sankyo. J. Sohn: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. K.S. Lee: Financial Interests, Institutional, Research Grant: Ono. J.H. Kim: Financial Interests, Institutional, Research Grant: Ono. E. Baek: Financial Interests, Personal and Institutional, Other, Employee: Hanmi. H. Han: Financial Interests, Personal and Institutional, Other, Employee: Hanmi. S. Im: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Prizer; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Research Grant: Hanmi; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Institutional, Principal Investigator: Lilly; Financial Interests, Institutional, Principal Investigator: Novartis. All other authors have declared no conflicts of interest.