Background

We assumed that a strategy with dual blockade of T+P without chemotherapy followed by T-DM1 at progression might be similarly effective in terms of overall survival (OS), but less toxic resulting in better Quality of Life (QoL) in pts with HER2+ MBC. Updated efficacy results by hormone receptor (HR) status and QoL data are given.

Methods

Pts with centrally confirmed HER2+ MBC were randomized 1:1 to receive either P+T alone (arm A) or P+T combined with weekly paclitaxel or vinorelbine (arm B), followed by maintenance treatment with T+P until progression. After progression, T-DM1 was given as 2nd line therapy in both arms. The primary endpoint was OS at 24 months (mo), among secondary endpoints progression free survival (PFS) was included. QoL was assessed every 3 mo up to 24 mo during 1st line by the NFBSI-16 (summary score and subscale scores for disease-related symptoms, treatment side-effects, function/well-being). Two single items assessed treatment burden and coping.

Results

Between 05/13 and 01/16, 210 pts were enrolled. Median age was 58 years, 63% of pts had lung or liver metastases, 36% of tumors were HR-, paclitaxel/vinorelbine was given in 46/59 pts. Efficacy results are shown in table. No difference in OS was observed. HR status did not affect PFS for 1st line. During 1st line, changes from baseline showed small improvements in QoL (NFBSI-16 summary scores) in arm A, while QoL scores remained stable in arm B. Patients in arm B reported more treatment burden during the first 6 months, but not thereafter, while coping improved clinically relevant in both arms.

Table: 150O

Efficacy results

Conclusions

Despite shorter 1st line PFS, OS at 2 years was not affected for P+T alone followed by T-DM1. Side-effects were less frequently seen in the chemotherapy-free arm, although QoL was similar during 1st line in both arms.

Legal entity responsible for the study

SAKK.

Funding

Roche Pharma.

Disclosure

J. Huober: Honorary: Roche, Novartis, Lilly, Pfizer, Celgene; Advisory boards: Roche, Novartis, Lilly, Pfizer, Celgene, AstraZeneca. B. Thürlimann: Consulting or advisory role: Roche. H. Bonnefoi: Travel grants, lecture fee: Roche. All other authors have declared no conflicts of interest.

Background

Human epidermal growth factor receptor 3 (HER3) is overexpressed in a variety of solid tumors, including breast cancer. U3-1402 is a HER3-targeted antibody drug conjugate with a novel peptide-based cleavable linker and a potent topoisomerase I inhibitor payload. The ongoing, phase 1/2 study (NCT02980341) is evaluating the safety, tolerability, and efficacy of U3-1402 in HER3-overexpressing metastatic breast cancer (MBC). Here, we report updated results from Dose Escalation and Dose Finding.

Methods

In Dose Escalation, the U3-1402 dose was escalated between 1.6 and 8.0 mg/kg based on dose-limiting toxicity (DLT) data and guided by the modified Continuous Reassessment Method. In Dose Finding, patients received 1 of 2 doses (4.8 or 6.4 mg/kg). The primary objectives were to determine the safety/tolerability, the maximum tolerated dose (MTD), and the recommended dose for expansion. Efficacy assessments included investigator-assessed objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Pharmacokinetics and the anti-drug antibodies were also assessed.

Results

As of 6 Nov 2018, 42 patients received U3-1402 across Dose Escalation and Dose Finding (34 and 8, respectively). Overall, 21 patients have discontinued treatment. The median age was 54.5, and the median prior anticancer regimens was 6. ORR was 42.9% (18/42) and the DCR was 90.5% (38/42). With a 7.6-month median exposure, 14 (33.3%) patients had serious treatment-emergent adverse events (TEAEs) regardless of causality; 7 (16.7%) were drug-related. One patient discontinued treatment due to TEAEs; no TEAEs led to death. Grade ≥3 TEAEs (≥15%) regardless of causality included thrombocytopenia (35.7%), neutropenia (28.6%), leukopenia (21.4%) and anemia (16.7%). MTD was not reached; DLTs included events of decreased platelet count and increases in AST or ALT.

Conclusions

In a preliminary analysis of this ongoing phase 1/2 clinical trial, U3-1402 demonstrated antitumor activity in a substantial number of heavily pretreated HER3-expressing MBC patients, and U3-1402 treatment was associated with a manageable safety profile. (Encore from SABCS2018).

Editorial acknowledgement

Nicole Seneca, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC, King of Prussia, PA, USA.

Clinical trial identification

NCT02980341, release date December 2, 2016; Clinicaltrials.jp: JapicCTI-163401, release date October 12, 2016.

Legal entity responsible for the study

Daiichi Sankyo Co., Ltd., and Daiichi Sankyo, Inc.

Funding

Daiichi Sankyo Co., Ltd.

Disclosure

N. Masuda: Personal fees in the form of honoraria, research funding paid to the institution: Chugai, AstraZeneca, Pfizer, Eli Lilly, Eisai, Takeda, Kyowa-Kirin, Novartis, Daiichi Sankyo; Research funding paid to the institution: MSD. S. Takahashi: Personal fees for non-CME services: Eisai, BMS; Research funding: Novartis, AstraZeneca, Daiichi Sankyo, MSD, Taiho, Bayer, Chugai. T. Kogawa: Personal fees for non-CME services: Taiho, AstraZeneca, Daiichi Sankyo Co., Ltd; Research funding: Daiichi Sankyo Co. Y. Yamamoto: Personal fees: Chugai, AstraZeneca, Novartis, Pfizer, Kyowa Hakko-Kirin, Eisai, Daiichi-Sankyo, Lilly, Sysmex, Taiho, Takeda. T. Toyama: Personal fees for non-CME services: Daiichi Sankyo. T. Saeki: Grants, personal fees: Eisai, Daiichi Sankyo, Chugai, Taiho, Ono Pharma. H. Iwata: Research funds (Inst), consulting, personal fee: AstraZeneca, Chugai, Daiichi Sankyo, Pfizer; Research funds (Inst), consulting: Kyowa Hakko Kirin, Lilly Japan; Personal fee: Eisai; Research funds (Inst): Bayer, Eisai, GSK, MSD, Nihonkayaku, Novartis. All other authors have declared no conflicts of interest.

Background

MBC remains an incurable disease and the second cause of cancer mortality for women worldwide. While evidence supports molecular evolution of the disease during its life cycle, few molecular profiling studies provide comprehensive longitudinal molecular and clinical data.

Methods

AURORA is a European multicenter program enrolling MBC pts at first diagnosis or after 1 line of therapy for MBC. Central targeted gene sequencing (TGS) is performed on DNA extracted from primary tumor, a metastatic biopsy, whole blood and circulating tumor DNA (ctDNA) extracted from baseline plasma. From the paired tissue samples, RNA-seq and copy number variation analysis (CNV) are performed in batches. Fresh frozen metastatic biopsies, baseline and sequential plasma and serum samples are biobanked for future research. Up to 100 pts with “bone-only” disease are allowed without a bone biopsy. Pathology, clinical and follow-up data are collected, and pathology slides are scanned at high resolution. A report with the TGS data is annotated by a molecular advisory board (MAB) and provided to the treating physician.

Results

Curated molecular results are available for 381 pts recruited up to November 2017. Pathological subtype distribution is: 232 HR+/HER2-, 69 HER2+, 77 triple-negative (TNBC), 3 N/A. In addition to the whole MBC population, analysis has focused on relevant categories of clinical interest: de novo and bone-only MBC, endocrine resistance, pts treated with targeted agents (mTOR, CDK4/6, HER2 inhibitors), chemo-resistant TNBC and BC with late relapse. Clinically-relevant molecular categories were defined based on annotated aberrations: putative mechanisms of resistance alterations (ESR1, FGFR1, RB1), activating drivers (ERBB2, PIK3CA, AKT1), somatic and germline alterations in DNA damage repair genes (homologous recombination, mismatch repair). We report on subtype switching from primary BC to MBC, on molecular signatures, on genes and pathways disrupted in several of these categories, and on the added value of ctDNA profiling.

Conclusions

Analysis of data from the AURORA program sheds light on the molecular makeup of several clinically-relevant MBC categories.

Clinical trial identification

NCT02102165.

Legal entity responsible for the study

Breast International Group (BIG).

Funding

BCRF - Breast Cancer Research Foundation.

Disclosure

P.G. Aftimos: Personal fees: Boehringer Ingelheim, Macrogenics, Synthon, Amgen, Novartis, Roche, Amcure, and non-financial support: MSD, Roche, Pfizer, Amgen, outside the submitted work. A.M. Antunes De Melo e Oliveira: Grant/research support (Institution): AstraZeneca, Boehringer Ingelheim, Cascadian Therapeutics, Celldex, Genentech, GlaxoSmithKline, Immunomedics, Novartis, Seattle Genetics, Philips Healthcare, Piqur, Puma Biotechnology, Roche, Sanofi; Consultant fees: GSK, Puma Biotechnology, Roche; Honoraria: Roche; Travel grants: GP Pharma, Grünenthal, Novartis, Pierre-Fabre, Roche. M. Piccart: Board member (Scientific board): Radius; Consultant (Honoraria): AstraZeneca, Lilly, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Camel-IDS, Crescendo Biologics, Periphagen, Huya, Debiopharm, PharmaMar, G1 Therapeutics, Menarini, Seattle Genetics, Immunomedics, Oncolytics; Research grants to my Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, Servier; Speakers bureau/stock ownership: none. All other authors have declared no conflicts of interest.

Background

Activating mutations in PIK3CA, the gene coding for the catalytic subunit (p110α) of phosphoinositide-3-kinase (PI3K), are the most frequent oncogenic alterations in oestrogen receptor-positive (ER+) breast cancer and are also prevalent in other tumour types. PI3Kα inhibitors have recently been shown to be clinically active in ER+ breast cancers harbouring PIK3CA mutations. In early clinical trials we had observed that there was also a population of patients that displayed deep and prolonged clinical benefit. In one such patient, whose tumour we had fully genomically characterized, we detected the presence of double PIK3CA mutations in all metastatic sites and at different times over tumour evolution (Juric, Castel, and Scaltriti Nature 2015).

Methods

This finding, together with our anecdotal observations of recurrent double PIK3CA mutations in a number of breast cancer genomes, prompted us to undertake a comprehensive analysis of the prevalence of these mutations and to investigate their potential biological relevance and correlation with sensitivity to PI3Kα inhibitors.

Results

We observed the presence of double PIK3CA mutations in 12-15% of breast cancer and other tumour types. These double PIK3CA mutations are clonal, located in cis on the same allele, and are composed of a single hotspot mutation combined with a recurrent second-site mutation. Double PIK3CA mutations in cis result in increased PI3K activity and downstream signalling together with enhanced cell proliferation and tumour growth compared to single hotspot mutations. The biochemical mechanisms underlying this increased oncogenicity include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased membrane lipid binding. Finally, these double PIK3CA mutations predict for increased sensitivity to PI3Kα inhibitors compared to single hotspot mutations in experimental models and in patients with breast cancer.

Conclusions

These findings implicate double PIK3CA mutations in cis as a hypermorphic oncogene relative to single hotspot mutations, providing a rationale to develop PI3Kα inhibitors for the therapy of double PIK3CA mutant breast cancer and other cancers.

Legal entity responsible for the study

Memorial Sloan Kettering Cancer Center.

Funding

Grants from the NIH, including awards P30 CA008748, R01 CA190642 (M.S. and J.B.), R21 CA223789 (M.S.), and R35 CA197588 (L.C.C.). Grants from Stand Up to Cancer (Cancer Drug Combination Convergence Team), the V Foundation and the National Science Foundation (G.X., R.R., and M.S.). N.V. is supported by the Conquer Cancer Foundation of ASCO/Breast Cancer Research Foundation YIA and by a grant from the Society of MSK. N.V. and E.R. are supported by the Fund for Innovation in Cancer Informatics. N.V., E.T., G.X., and M.S. are supported by a kind gift from Mrs. Barbara Smith and her husband.

Disclosure

N. Vasan: Advisory board activities: Novartis. P. Razavi: Advisory board activities: Novartis; Research support: Illumina, Grail. R. Sebra: Vice president of Sema4, a Mount Sinai Venture. L.C. Cantley: Founder and member of the board of directors and scientific advisory board: Agios Pharmaceuticals; Co-founder, member of the scientific advisory board, shareholder, laboratory funding: Petra Pharmaceuticals. M. Scaltriti: Research funds: Puma Biotechnology, Daiichi-Sankio, Immunomedics, Menarini Ricerche; Co-founder: Medendi Medical Travel. J. Baselga: Employee: AstraZeneca; Board of directors: Foghorn; Past board member: Varian Medical Systems, Bristol‐Myers Squibb, Grail, Aura Biosciences, Infinity Pharmaceuticals; Consulting and/or advisory work: Grail, PMV Pharma, ApoGen, Juno, Lilly, Seragon, Novartis, Northern Biologics; Stock or other ownership interests: PMV Pharma, Grail, Juno, Varian, Foghorn, Aura, Infinity Pharmaceuticals, ApoGen, Tango, Venthera, for which is a co‐founder; Honoraria or travel expenses: Roche, Novartis, Eli Lilly. All other authors have declared no conflicts of interest.