It's World Cancer Research Day! Did you know that thanks to cancer research, survival trends are generally increasing, even in some of the most lethal cancers. At MEDSIR we're motivated by our mission to accelerate the path of bringing promising treatments to patients like in our PATHFINDER trial which evaluates an AKT inhibitor for treatment of triple negative breast cancer (TNBC).
Approximately 1 in every 8 women will be diagnosed with invasive breast cancer in their lifetime and 1 in 39 will die from it. While the five-year survival rate is 99% for patients diagnosed with localized disease, it is only 27% for metastatic patients. Furthermore, not all subtypes have the same prognosis. TNBC, meaning the patient’s tumor does not express hormone receptors (ER and PgR) or human epidermal growth factor receptor (HER2), has the worst five-year survival rate of 77% for all stages (localized, regional, and distal). (1)
Chemotherapy is still considered the standard of frontline care for most cases of metastatic TNBC despite low rates of antitumor response and short median progression-free survival. (2-4) Because of this, numerous strategies have been explored to create more effective therapy options. These include antiangiogenics, PARP inhibitors, antibody drug conjugates, and immunotherapy.
The PI3K-AKT-mTOR signaling pathway is a particularly promising target for cancer therapies given that activation of the pathway is associated with proliferation, cell cycle progression, and survival. Specifically, inhibition of AKT is highly attractive because AKT is hyperactivated in many cancer types and plays a role in cancer development, progression, and therapeutic resistance. (5)
In breast cancer, the PI3K-AKT-mTOR signaling pathway is often activated by genetic alterations in key genes that regulate the pathway’s activity, which can include mutations of the AKT gene, activating mutations of PIK3CA, loss-of-function alterations of the tumor suppressor PTEN, deregulation of receptor tyrosine kinase signaling, and amplification and mutations of receptor tyrosine kinases (6,7). Approximately 35% of patients with TNBC and 50% of luminal breast cancers have PIK3CA/AKT1/PTEN-altered tumors (6).
Considering all this, MEDSIR developed the PATHFINDER trial which aims to evaluate the efficacy, safety and tolerability of ipatasertib, a selective small-molecule inhibitor of all three isoforms of the AKT gene, in combination with chemotherapy (capecitabine, eribulin or carboplatin plus gemcitabine) in patients with taxane-pretreated unresectable locally advanced or metastatic TNBC.
There will be two stages for the trial. The first phase will be a safety run-in, followed by a non-randomized phase IIA expansion study. Patients must be female with taxane-pretreated unresectable metastatic or locally advanced TNBC, have had at least 1 but no more than 2 prior chemotherapy regimens in the metastatic setting and measurable or evaluable disease according to RECIST v 1.1, and cannot have been previously treated with PI3K, mTOR, and/or AKT inhibitors.
The primary endpoint is incidence of adverse events, with secondary endpoints of progression-free survival, time to response, objective response rate, duration of response, clinical benefit rate, overall survival, and depth of response. Additionally, the study will explore efficacy in terms of subsets of patients with PIK3CA/AKT1/PTEN-altered tumors. The study will evaluate predictive or prognostic biomarkers associated with baseline clinical features or response to treatment and will assess mechanisms of resistance to study treatments.
Recruitment is ongoing in Spain and Portugal and we just presented the clinical trial design of PATHFINDER at ESMO! Contact us to learn more!
References:
1. American Cancer Society. Breast Cancer Facts & Figures 2019-2020. Atlanta: American Cancer Society, Inc. 2019.
2. Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. The Lancet [Internet]. 2011 Mar 12 [cited 2019 Feb 5];377(9769):914–23. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60070-6/abstract
3. Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, et al. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat [Internet]. 2017 [cited 2019 Feb 5];161(1):63–72. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222915/
4. Rugo HS, Roche H, Thomas E, Chung HC, Lerzo GL, Vasyutin I, et al. Efficacy and Safety of Ixabepilone and Capecitabine in Patients With Advanced Triple-negative Breast Cancer: a Pooled Analysis From Two Large Phase III, Randomized Clinical Trials. Clin Breast Cancer. 2018 Dec;18(6):489–97.
5. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005 Nov 14;24(50):7455–64.
6. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;490(7418):61–70.
7. Millis SZ, Gatalica Z, Winkler J, Vranic S, Kimbrough J, Reddy S, et al. Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications. Clin Breast Cancer. 2015 Dec;15(6):473-481.e3.
