Disease Analysis: Triple-Negative Breast Cancer

Latest key takeaways

• Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen and progesterone receptors, and does not involve the overexpression of human epidermal growth factor 2 (HER2). Datamonitor Healthcare estimates that in 2018, there were 2.1 million incident cases and 8.6 million five-year prevalent cases of breast cancer worldwide. By 2027, incident and five-year prevalent cases of breast cancer are expected to increase to 2.3 million and 9.3 million cases, respectively.
• The TNBC market will experience rapid growth over the next 10 years across the US, Japan, and five major European markets (France, Germany, Italy, Spain, and the UK). The primary drivers for this growth will be the approval and subsequent uptake of new targeted therapies and immunotherapies. The market for TNBC is also becoming increasingly segmented by biomarker status, creating fierce competition among both approved and pipeline therapies for small patient populations.
• There will likely be reimbursement issues as payers may initially hesitate to reimburse new treatments based on novel biomarkers. Additionally, payers may be unwilling to reimburse expensive therapies with only incremental improvements in patient outcomes.
• Avastin’s relatively poor risk-to-benefit profile has led to its removal from the US market and difficulties with reimbursement in the UK, where it was also removed from the Cancer Drugs Fund. Additionally, Avastin faces biosimilar competition following its 2019 patent expiry.
• Abraxane is a preferred treatment regimen in cases of hypersensitivity to paclitaxel, and has demonstrated efficacy as a first- and second-line monotherapy treatment. Approval in combination with Tecentriq has boosted Abraxane’s clinical and commercial potential, although it is forecast to steadily lose market share after the introduction of generics in the EU in 2019 and in the US in 2022.
• Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1)-targeted monoclonal antibodies for TNBC are forecast to become the best-selling class of drugs for this indication. Tecentriq in combination with Abraxane was the first immunotherapy approved for TNBC patients in the first-line setting, but the failure of the confirmatory Phase III IMpassion131 study of the combination of Tecentriq and paclitaxel as a first-line treatment for TNBC patients with PD-L1-positive tumors has allowed recently approved competitor Keytruda to gain market share in the first-line setting. Following this, Genentech announced its decision to voluntarily withdraw the US accelerated approval for Tecentriq. Although Tecentriq is still approved in the five major European markets and Japan, this is still a significant blow for the drug’s commercial outlook and will allow competitor Keytruda to gain significant ground. However, Roche and Chugai have ongoing trials investigating Tecentriq in both the neoadjuvant and adjuvant settings which may allow Tecentriq to maintain some market share. Moreover, data from the ongoing IMpassion132 trial may allow Tecentriq to re-enter the first-line US TNBC market, but these data will likely not be released until the trial’s primary completion date in 2023, allowing Keytruda to gain dominance in this indication. Furthermore, after the release of event-free survival data from the Phase III KEYNOTE-522 trial, Keytruda has gained approval in the neoadjuvant/adjuvant setting first in the US, which will likely limit Tecentriq’s uptake.
• Although approved PARP inhibitors Lynparza and Talzenna are restricted to the relatively small germline BRCA1/2-mutated (gBRCAm) population, they are forecast to dominate within this patient segment. An expected label expansion into the adjuvant treatment setting for gBRCAm patients will add to Lynparza’s sales, making it one of the best-selling TNBC therapies over the next 10 years.
• Halaven became a standard of care for third-line and later treatment of TNBC following approval, but its market share has declined due to competition with recently approved and current pipeline drugs utilizing Halaven as a comparator therapy in clinical trials. Halaven had been in development with the CXCR4 inhibitor balixafortide, but despite showing efficacy in a Phase Ib study, recent results from the Phase III FORTRESS study were resoundingly negative and the trial was suspended. With no further trials planned, it seems the development of balixafortide in this indication has come to an end.
• In early 2020, Trodelvy received accelerated approval in the US for the treatment of TNBC patients who have failed at least two prior therapies, based on positive efficacy results in a Phase I/II study. Given the high unmet need and poor prognosis in this line of treatment, Trodelvy has experienced remarkably quick uptake after its launch despite the inclusion of two black box warnings on its label. The confirmatory Phase III ASCENT study was halted early due to evidence of strong efficacy, and the FDA granted full approval to Trodelvy in April 2021. Gilead has also announced it is initiating a Phase III trial investigating Trodelvy in combination with Keytruda for first-line metastatic TNBC patients. This represents a lucrative label expansion for Trodelvy and Keytruda, as the first-line metastatic setting is dominated by genericized chemotherapies, with Keytruda and Tecentriq being recommended only in patients with high PD-1 expression. If this dual combination shows strong efficacy with an acceptable safety profile, it could become the new first-line standard of care.
• Capivasertib and Piqray are both in development in the front-line setting for the 25–30% of patients who present with PTEN/PIK3CA/AKT-altered tumors. While these novel therapies will dominate within this subgroup, their overall commercial potential is limited by the biomarker restriction. Capivasertib will likely be the first Akt inhibitor to market after late-phase competitor ipatasertib failed in the Phase III IPATunity130 trial and Roche’s subsequent decision to discontinue the Phase III IPATunity170 trial.
• Key recent events include the release of updated results from the Phase III KEYNOTE-522 trial of Keytruda, as well as the FDA’s meeting re-examining Tecentriq’s accelerated approval in the first-line setting.
• Key upcoming catalysts for late 2021 and early 2022 include topline readouts from the Phase II VIOLETTE study of Lynparza and olaparib, and from the Phase III CAPitello-291 study of capivasertib.
• The overall likelihood of approval of a Phase I breast cancer asset is 7.8%, and the average probability a drug advances from Phase III is 55.2%. Breast cancer drugs, on average, take 9.9 years from Phase I to approval, compared to 9.7 years in the overall oncology space.