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Treatment with Tucatinib in addition to Pertuzumab and Trastuzumab in patients with HER2-positive metastatic breast cancer (HER2+ MBC) after local therapy of isolated brain progression: InTTercePT, a UCBG/GINECO study. Background HER2+ MBC patient on first line treatment with pertuzumab and trastuzumab have a 13% risk of developing brain metastasis (BM) as the first site of progression. For such patient with isolated brain progression, guidelines recommend to use central nervous system (CNS) directed therapy whenever possible (stereotactic radiosurgery or surgery or both). These patients will have a higher risk of subsequent brain and systemic progression after local treatment. Therefore, whether systemic treatment should be continued or changed remains an open question. The tyrosine kinase inhibitor tucatinib is an orally bioavailable HER2 inhibitor with validated antineoplastic activity and the ability to cross the blood brain barrier. The randomized HER2CLIMB study, demonstrated that adding tucatinib to trastuzumab/capecitabine improved both progression-free survival (PFS) and overall survival (OS) among HER2+ MBC patients previously treated with trastuzumab, pertuzumab and T-DM1. Particularly, this regimen demonstrated improved antitumor activity in patients with BM, in terms of CNS-PFS and OS. Exploratory analysis of HER2CLIMB and in a phase 1b study, showed patients who continued systemic treatment with tucatinib (in combination either with trastuzumab/capecitabine or TDM-1) after CNS-directed treatment had a better outcome compared with those that discontinued systemic tucatinib-based treatment. These results suggest that for patient in the first line metastatic setting who experience isolated brain progression, adding tucatinib to the trastuzumab/pertuzumab regimen could help control BM, improve PFS, OS and patients’ quality of life. Trial design InTTercePT is an open-label, single-arm, national, multicentric, phase II trial assessing the combination of tucatinib, pertuzumab and trastuzumab. Tucatinib will be administered orally twice daily at 300 mg. Pertuzumab and trastuzumab will be administered at the initial dose of 840 mg and 8 mg/kg respectively following by a maintenance dose of 420 mg and 6mg/kg respectively, 3-weekly. If indicated, hormone therapy is allowed in combination with HER2-directed therapy. Eligibility criteria include HER2+ MBC with isolated brain progression (new or progressive BM with stable or responding systemic disease) under pertuzumab/trastuzumab treatment (± taxane) after complete local treatment (surgery and/or radiation therapy). There is no limit to the number and size of BM. Specific aims To evaluate the efficacy, in terms of PFS rate (RECIST v1.1) of tucatinib in combination with pertuzumab/trastuzumab. Secondary endpoints include OS, brain PFS (RECIST v1.1) and BM response in patient not in complete remission at the brain level after local treatment and safety (NCI-CTCAE v5.0). Statistical methods Given the lack of safety data from this association, two interim safety analysis are planned: after 10 and 20 patients having received at least one dose of the treatments combination during at least one cycle. The number of patients to be included was calculated using Fleming’s single-stage procedure for phase II trials. The sample size calculation was based on a minimum success (non-progression rate at 6 months) considered of interest of p1 = 75% and an uninteresting rate of p0 = 60%. Assuming a unilateral type I error alpha of 10% and a power of 85%, 52 patients are needed. Considering 5% of the patients may be non-evaluable, 55 patients will be included. At the time of analysis, if at least 37 successes are observed, the treatment will be considered as interesting for further investigation. The study is recruiting. By July 1, 2022, 10 patients have been screened and 8 treated (NCT05041842). Funding SeaGen Contact information thomas.bachelot@lyon.unicancer.fr Citation Format: Thomas Bachelot, Christelle Jouannaud, Benjamin Verret, Sylvie Chabaud, Camille Petrau, Laetitia Stefani, Mony Ung, Isabelle Desmoulins, William Jacot, Caroline Bailleux, Sandrine Marques, Jérôme Lemonnier, Anne-Claire Hardy-Bessard. Treatment with Tucatinib in addition to Pertuzumab and Trastuzumab in patients with HER2-positive metastatic breast cancer (HER2+ MBC) after local therapy of isolated brain progression: InTTercePT, a UCBG/GINECO study [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 OT1-10-01.

Background: Mutations of ESR1 (ESR1mut), the gene encoding for Estrogen Receptor (ER) alpha, have been functionally characterized as driving resistance to aromatase inhibitors (AI) given to in ER+ HER2- metastatic breast cancer (mBC). In the randomized multicenter phase 3 PADA-1 trial (NCT03079011), ER+ HER2- mBC patients treated with first line AI+Palbociclib were screened every two months for ESR1mut in blood (bESR1mut), by subjecting cell-free circulating DNA (cfcDNA) to a droplet digital PCR (ddPCR) assay. Upon the onset of a rising (i.e., increasing or appearing) bESR1mut, patients with no concomitant disease progression were randomized between keeping the same regimen (AI-Palbociclib) or switching to Fulvestrant-Palbociclib. We report herein the sample flow of this first-in-its-class trial, from April 2017 to March 2021, and the cross-validation of ddPCR results with NGS. Methods: At each time point, 20 mL of blood were drawn into BCT Streck® tubes. cfcDNA was extracted from 4 mL of plasma. bESR1mut testing was centralized in 2 platforms using the same ddPCR assay, which combines a drop-off ddPCR, targeting the clustered hotspot L536, Y537 and D538 mutations found in exon 8, with an unconventional ddPCR interrogating specifically the E380Q mutation, located in exon 5 (Jeannot et al, Oncogene 2020). Results were expressed as the number of ESR1mut copies detected per mL of plasma together with the Mutant Allele Frequency (MAF). As a control, we submitted 200 ESR1mut+ (by ddPCR) left-over samples to an amplicon-based Next Generation Sequencing (NGS) assay covering all ESR1 exons - with a nominal sensitivity of >0.5% MAF. Results: From 03/2017 to 03/2021, 1,017 MBC patients have been included in 83 centers and 12,552 blood samples have been collected. The median time of delivery to central platforms was 1 day (range: [0-11]). A median volume of 9.5 mL [2-20] of plasma was obtained after 2 centrifugations. bESR1mut results were notified to investigators with a median turnaround time of 13 days [1-813] (32 days in 2017, 9 days in 2019, 8 days in 2021). Among the 12,525 available ddPCR results: N=77 ( Citation Format: Céline Callens, François-Clément Bidard, Anais Curto-Taribo, Olfa Trabelsi-Grati, Samia Melaabi, Suzette Delaloge, Anne-Claire Hardy-Bessard, Thomas Bachelot, Florian Clatot, Thibault De La Motte Rouge, Jean-Luc Canon, Laurent Arnould, Fabrice André, Sandrine Marques, Marc-Henri Stern, Jean-Yves Pierga, Anne-Vincent Salomon, Emmanuelle Jeannot, Frederique Berger, Ivan Bieche, Anne Pradines. Real time detection of ESR1 mutation in blood by droplet digital PCR in the PADA-1 trial: Feasibility and cross-validation with NGS [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-01.

Background: Aromatase inhibitors (AI) in combination with a CDK 4/6 inhibitor have been established as the standard first line treatment of non AI-resistant hormone receptor-positive (HR+) HER2- metastatic breast cancer (mBC) patients (pts). ESR1 mutations are known drivers of resistance to AIs in the metastatic setting but their actionability remains unknown. The phase 3 PADA-1 trial aimed both at refining the global safety of palbociclib combined to any AI as first line treatment of HR+ HER2- mBC pts, and at evaluating the clinical benefit associated with a switch to fulvestrant-palbociclib upon detection of a rising ESR1 mutation in blood (bESR1mut). Methods: PADA-1 (NCT03079011), a multicenter, randomized, open-label, phase 3 trial, enrolled HR+ HER2- mBC pts with no prior therapy for mBC, in the absence of AI-resistance. In the first step, pts received a combination of any AI and palbociclib at standard recommended doses and underwent centralized bESR1mut screening every two months. In the second step, bESR1mut+ pts with no clinical/imaging concomitant disease progression were randomized between continuing the same therapy (standard arm) or switching to fulvestrant-palbociclib (experimental arm). The third step consisted in an optional cross-over after tumor progression for patients randomized in the standard arm. PADA-1 co-primary endpoints were global safety of the combination of palbociclib + endocrine therapy in the whole population of patients, throughout the study, with focus on hematological toxicities; and PFS in the second step. We present here the results of the global safety co-primary endpoint. Results: From 3/2017 to 01/2019, 1017 pts were accrued in 83 sites. As per 05/2021, 272 pts were still in step 1, 35 in step 2, and 8 in step 3. The overall follow-up was 33.7 months. 232 pts have deceased. 333 SAEs have been reported, including 21 grade 5, 35 grade 4, 183 grade 3, 53 grade 2, 26 grade 1 and 15 unknown grade. Among the grade 5 cases, 2 have been declared as potentially related to the underlying treatment (Death of unknown cause, pulmonary embolism). No pt died of SARS-CoV2 infection. The main hematological toxicities encountered, as well as selected non-hematological events are described in Table 1. Permanent discontinuation of the treatment due to toxicity occurred in 39 pts/1017 (3.8%). Palbociclib dose decreases occurred in 419 (41.2%) pts. Conclusion: By the number of included patients, PADA-1 is the largest prospective trial with 1st line AI and palbociclib. Data confirm the favorable safety profile of palbociclib when combined to any AI +/- switch to fulvestrant. Hematological toxicity appears limited and is mostly restricted to non-clinically significant neutropenia. Permanent discontinuation was exceptional. Detailed per-step analyses will be presented. Table 1.Adverse events (% pts)Grade 3, N (%)Grade 4, N (%)Neutropenia628 (61.8%)83 (8.2%)Febrile neutropenia4 (0.4%)0Thrombocytopenia18 (1.8%)3 (0.3%)Anemia24 (2.4%)0Lymphocytopenia58 (5.7%)5 (0.5%)Insterstitial lung disease4 (0.4%)0Liver enzymes increase (AST/ALT)5 (0.5%)0Mucositis10 (1%)0 Citation Format: Suzette Delaloge, Anne-Claire Hardy-Bessard, Thomas Bachelot, Jean-Yves Pierga, Jean-Luc Canon, Florian Clatot, Fabrice André, Thibault De La Motte Rouge, Barbara Pistilli, Florence Dalenc, Nadine Dohollou, Olivier Arsene, Thierry Petit, Cecilia Riedl, François Morvan, Adina Marti, Emma Lachaier, Mihaela Achille, Michel Gozy, Anne Escande, Dominique Mille, Fanny Trouboul, Sandrine Marques, Jerome Lemonnier, Frederique Berger, François-Clément Bidard. First line aromatase inhibitor (AI) + palbociclib with randomized switch to fulvestrant + palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Global safety results of PADA-1, a UCBG-GINECO phase III trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-16.

1070 Background: In PADA-1 (NCT03079011), a phase III trial testing the clinical utility of ESR1mut detection, ER+ HER2- advanced breast patients (ABC pts) received Aromatase Inhibitor (AI) and Palbociclib (Pal) +/- LHRH agonist as first line therapy. PADA-1 was open to “AI-sensitive” pts, including those with de novo stage IV disease or metastatic relapse after adjuvant endocrine therapy but also pts with metastatic relapses during adjuvant tamoxifen (TAM). In this subsidiary analysis, we report the efficacy of AI+PAL as first line therapy in patients relapsing on adjuvant TAM. Methods: Main inclusion criteria in PADA-1 are: pre- or post-menopausal pts with ER+ HER2- ABC, who did not receive any prior therapy for ABC and who had no adjuvant AI or completed adjuvant AI for > 12 months or who had disease recurrence while on adjuvant TAM. Results: From 04/2017 to 01/2019, 1017 ABC pts have been included in PADA-1, of which 115 (11.3%) had a metastatic relapse while on adjuvant TAM (TAM only (N = 112) or TAM+GnRH agonist (N = 3)). Median age at inclusion was 46 years (range 25-81), and 58 (50.4%) patients had visceral disease. The median PFS under AI+PAL was 20.4 months (95%CI16.1;27.8) in patients relapsing during adjuvant TAM. In contrast, median PFS in patients with de novo metastatic disease and metastatic relapses after the completion of adjuvant endocrine therapy were 30.6 months (95%CI26.7;Not reached) and 27.8 months (95%CI24.1;30.)], respectively. A subgroup analysis among patients relapsing on adjuvant TAM showed that those relapsing during the first two years of adjuvant TAM had a shorter PFS (11.4 months 95%CI[8.7;20.7]) than those relapsing after 2 years of adjuvant TAM (23.8 months 95%CI[20.2;Not reached]). Conclusions: To our knowledge, these are the first data on first line AI+CDK4/6 inhibitor in patients relapsing on adjuvant TAM. While PFS on AI + PAL appears primarily driven by endocrine resistance status, our data show that AI+PAL is a valuable option also in patients relapsing during adjuvant TAM. Clinical trial information: NCT03079011 .