Targeted therapies in triple negative breast cancer

Missed the previous three parts?

Part 1: An introduction to the different subtypes of breast cancer can be found here.

Part 2: Targeted therapies in HER2 positive breast cancer can be found here.

Part 3: Targeted therapies in HER2 negative breast cancer can be found here.

Triple negative breast cancer

About 15% of breast cancers are TNBC, characterized by aggressive behaviour, distinct patterns of metastasis, and lack of targeted therapies. Chemotherapy has been the mainstay of treatment with TNBC – one therapy used is FEC-T, a chemotherapy combination that includes fluorouracil, epirubicin, cyclophosphamide and Taxotere (docetaxel) but this standard-of-care is suboptimal and there is no compelling evidence that combination therapies are superior to single-agent chemo regimens. Preferred single-agent therapies include anthracyclines, antimetabolites, taxanes, and other microtubule inhibitors. Triple-negative breast cancer is more likely to recur than the other 2 subtypes, with 85% 5-year breast cancer–specific survival for stage I triple-negative tumours vs 94% to 99% for HR positive and HER2 positive cancer.

Tecentriq + Abraxane (atezolizumab + nab-paclitaxel)

In March 2019 the FDA gave accelerated approval Tecentriq + Abraxane (atezolizumab + nab-paclitaxel)from Genentech/Roche for the initial treatment of some women with advanced triple-negative breast cancer. FDA’s approval was based on results from the phase III IMpassion130 clinical trial, which compared atezolizumab plus nab-paclitaxel with placebo plus nab-paclitaxel as the initial, or first-line, treatment for patients with triple-negative breast cancer. Among the 369 patients in the trial with PD-L1–positive tumours, the median progression-free survival was 7.4 months for patients treated with atezolizumab plus chemotherapy and 4.8 months for those who received placebo plus chemotherapy. The objective response rate was 53% in the atezolizumab group versus 33% for the placebo group. The combination therapy is the first FDA-approved regimen for breast cancer to include immunotherapy and has now been CHMP-recommended in the EU.

Next generation treatments

There are a variety of immunotherapy drugs in trial both alone and as combinations. Genentech currently has seven ongoing Phase III studies investigating the monoclonal antibody Tecentriq in TNBC, including early and advanced stages of the disease. But given that a positive overall survival outcome was achieved only in a subset of PD-L1+ TNBC patients, this suggests further genetic selection for treatment is the path to follow [Ref 3]. Other trials involve Tecentriq in combination with capecitabine, pegylated liposomal doxorubicin plus cyclophosphamide, and carboplatin plus gemcitabine or capecitabine.

Another promising immunotherapy is BriaCell Therapeutic’s Bria-IMT . In early studies in advanced TNBC, in combination with Merck Inc’s PD-1 inhibitor Keytruda (pembrolizumab), results suggest rapid additive or synergistic anti-tumour activity including examples of tumour reduction at multiple sites and disease stabilization.

IMMU 132 is an anti-TROP-2 antibody from Immunomedics which was filed in the US in 2018, but received a complete response letter from the FDA in early 2019. Phase II data shows sacituzumab govitecan resulted in an overall response rate of 33.3 % in patients with TNBC, and a median progression-free survival of 5.5 months, and still shows benefits in pre-treated patients. The company remains hopeful it will receive approval in 2020.

Meanwhile AstraZeneca’s Lynparza (olaparib) is also in small scale phase II trials for TNBC combined with Imfinzi (durvalumab). 

Imfinzi itself is in early phase II trials with Nab-paclitaxel, and Paclitaxel plus carboplatin. The use of combinations including PARP inhibitors or specific chemotherapies could eventually offer a highly successful strategy [Ref 4].

Also notable is the PARP inhibitor Zejula (niraparib) + Keytruda combination which is in the TOPACIO phase I/II trial. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations.

Trials using Keytruda alone in TNBC have not met primary endpoints, but it is also in early stage trials in combination with carboplatin plus docetaxel, cyclophosphamide, and Carboplatin plus nab-paclitaxel, amongst others. 

Cancer vaccines are also under investigation. For instance, AE37 is presently the object of a Phase II clinical study involving more than 200 patients with node-positive or high-risk node-negative breast cancer. The trial aims to show a reduction in cancer relapse after two years compared with patients not given the vaccine. In August, the company reported that "at a median of 17 months follow-up, the relapse rate in patients with low levels of HER2 expression treated with AE37 is half that of the same patient population in the control arm." This Phase II trial will test whether the AE37 vaccine may trigger immunity in triple negative breast cancer patients, priming them for clinical benefit from immune checkpoint blockade.

A HER2-derived peptide vaccine, NeuVax, from Sellas, in combination with Herceptin (trastuzumab) is more advanced, having entered phase III trials. Phase II studies show disease free survival of patients treated with Neuvax + Herceptin was 92.6% compared to 70.2% for those treated with trastuzumab alone and represented a clinically meaningful and a statistically significant improvement with the combination therapy. This was associated with a statistically significant reduction by 71.9% in the frequency of clinically detected recurrences - the TNBC cohort with the combination of trastuzumab + NPS showed a significantly reduced relapse rate (7.5%) vs. trastuzumab alone (27.3%). Contrary to expectations, the phase III PRESENT trial of NeuVax alone has been halted early after disappointing response rates.

Other therapies in early development include AVID 100 from Forbius, a potent EGFR-targeting antibody-drug conjugate (ADC) engineered to achieve enhanced anti-tumour efficacy. In preclinical studies, AVID100 demonstrated significant anti-cancer activity in EGFR-overexpressing tumour models resistant to marketed EGFR inhibitors.

Thank you for joining us over the past few weeks. To revisit the previous three parts of this four-part series on targeted treatments for breast cancer, see below:

Part 1: An introduction to the different subtypes of breast cancer can be found here.

Part 2: Targeted therapies in HER2 positive breast cancer can be found here.

Part 3: Targeted therapies in HER2 negative breast cancer can be found here.

Ref 3-“Recent advances in triple negative breast cancer: the immunotherapy era” Antonio Marra et al. BMC Medicine 201917:90 https://doi.org/10.1186/s12916-019-1326-5.

Ref 4-“The clinical promise of immunotherapy in triple-negative breast cancer” Vikas P et al. Cancer Management and Research 10 December 2018 Volume 2018:10 Pages 6823—6833 DOI https://doi.org/10.2147/CMAR.S185176