On April 1, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported the initial results from a Phase Ib study evaluating the efficacy and safety for the combination of ipatasertib, Tecentriq (atezolizumab) and chemotherapy (paclitaxel or nab-paclitaxel (Abraxane [paclitaxel albumin-bound particles for injectable suspension]) as a first-line treatment option for people with advanced triple-negative breast cancer (TNBC) (Press release, Hoffmann-La Roche, APR 1, 2019, View Source [SID1234534809]). Combination treatment demonstrated a confirmed objective response rate (ORR) of 73% (95% CI 53-88%), irrespective of tumour biomarker status. The median duration of follow-up was 6.1 months (range 3.1–10.6). Grade ≥3 adverse events occurred in 14 people (54%); the most common all-grade adverse events were diarrhea (88%; grade ≥3 19%) and rash (69%; grade ≥3 27%).

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"We are enthusiastic about the potential of this combination in triple-negative breast cancer, an aggressive type of breast cancer," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "These early results support the contribution of ipatasertib to our combination treatment approach in TNBC and reinforce our vision to develop medicines that may benefit patients with this challenging disease."

Preliminary efficacy data for the first 26 patients (18 paclitaxel, 8 nab-paclitaxel) show confirmed responses in 19/26 patients, giving a confirmed ORR of 73%. Responses were seen irrespective of PD-L1 status (9/11 [82%] PD-L1+; 6/8 [75%] PD-L1–; 4/7 [57%] PD-L1 unknown) or PIK3CA/AKT1/PTEN alteration status (5/7 [71%] Dx+, 9/11 [82%] Dx–; 5/8 [63%] Dx unknown).

Activation of the PI3K/AKT pathway has been implicated in resistance to chemotherapies and hormonal therapies in multiple tumour types and loss of PTEN, a negative regulator of AKT, has emerged as a potential mechanism for resistance to checkpoint inhibitor therapy. By inhibiting the PI3K/AKT pathway, ipatasertib may contribute to reversal of T-cell-mediated immunotherapy resistance. These results and the potential benefit that ipatasertib plus the Tecentriq/taxane combination may bring to patients are encouraging and add to the Roche development program in triple-negative breast cancer following the approval of the Tecentriq combination.

Trial enrolment for the Phase 1b study is ongoing. Later this year, Roche will initiate a pivotal multi-center, randomised, double-blind Phase III study investigating the combination of ipatasertib, atezolizumab and paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer.

About the study
The Phase Ib study is an open-label, multicentre study evaluating the safety and efficacy of ipatasertib in combination with atezolizumab and paclitaxel or nab-paclitaxel for patients with locally advanced or metastatic triple-negative breast cancer who have not previously received chemotherapy in the advanced setting. Two triplets: ipatasertib in combination with atezolizumab and paclitaxel (Paclitaxel arm) and ipatasertib in combination with atezolizumab and nab-paclitaxel (nab-Paclitaxel arm) are being evaluated for first-line treatment for advanced TNBC. A second cohort, which is enrolling now, will allow collection of tumour biopsies to assess treatment-related biomarker changes in TNBC patients who have progressed after at least one line of chemotherapy in the advanced setting.

About ipatasertib
Ipatasertib is an oral, highly specific, investigational medicine designed to target and bind to all three isoforms of AKT, which blocks the PI3K/AKT signaling pathway and may prevent cancer cell growth and survival.

Ipatasertib is being studied in tumours that are frequently found to have activation of the PI3K/AKT pathway, including breast and prostate cancers. Pivotal studies are ongoing to evaluate the efficacy and safety of ipatasertib and the opportunity it may provide to address significant unmet needs for patients with these diseases. Ipatasertib has demonstrated clinically meaningful activity in both breast and prostate cancers, with a manageable safety profile.

Ipatasertib was discovered at Genentech in partnership with Array BioPharma Inc.

About Triple-Negative breast cancer
Breast cancer is the most common cancer among women with more than 2 million diagnosed worldwide each year.[1] TNBC represents 15% of all breast cancers and is more common in women under the age of 50, compared with other forms of breast cancer.[2;3;4] It is defined by the lack of expression and/or amplification of the targetable receptors for oestrogen, progesterone and HER2 amplification.[5] Patients with metastatic TNBC generally experience rapid progression and shorter overall survival (OS) compared to other subtypes of breast cancer.[3]

About Roche in breast cancer
Roche has been advancing breast cancer research for more than 30 years with the goal of helping as many people with the disease as possible. Our medicines, along with companion diagnostic tests, have contributed to bringing breakthrough innovations in the HER2 -positive breast cancer. As our understanding of breast cancer biology rapidly improves, we are working to identify new biomarkers and approaches to treatment for all forms of early and advanced breast cancer, including triple-negative and hormone receptor-positive.

Our targeted medicines Herceptin, Perjeta and Kadcyla are continuing to transform the treatment of early and advanced HER2-postive breast cancer and, through our Tecentriq and ipatasertib clinical programmes, we hope to bring new treatment combinations to people with breast cancer, ultimately improving outcomes.

In the United States Tecentriq in combination with nab-paclitaxel is approved for treatment of PD-L1-positive metastatic triple-negative breast cancer. Roche currently has seven phase III studies in TNBC.