NEWS & ANALYSIS
From the analyst’s Couch The breast cancer drug market
Paul Wilcock and Rachel M. Webster Anthony Nilber Moraes Credit: Stock Photo Paz/Alamy Barros
Breast cancer is the most common cancer in treatment. The first-line standard of care 40% of patients) advanced or metastatic women and accounts for the most cancer- for metastatic disease is a cyclin-dependent disease, in combination with nanoparti- related deaths among women globally. It is a kinase 4 and 6 (CDK4/6) inhibitor — cle paclitaxel (Abraxane, Celgene). The heterogeneous malignancy that is classified palbociclib (Ibrance, Pfizer), ribociclib approval of atezolizumab was based on into different subtypes based on the status (Kisqali, Novartis) or abemaciclib (Verzenio/ progression-free survival data from a the oestrogen receptor (ER) and progesterone Verzenios/Virginio, Eli Lilly) — in combina- phase III trial (IMpassion130); however, in receptor (PR) — collectively known as tion with endocrine therapy. These therapies August 2020, atezolizumab (plus paclitaxel) hormone receptors (HRs) — and the human gained regulatory approval in 2015–2017 and failed to meet progression-free survival epidermal growth factor receptor 2 (HER2, have received successive label expansions; as a co-primary end point in another trial also known as ERBB2). HR and HER2 status they are also being assessed in late-phase (IMpassion131), which treated the same determine drug treatment options. trials as adjuvant treatments for early- population as in IMpassion130. Other stage disease. The pivotal monarchE trial, phase III trials of atezolizumab are in Current treatments assessing adjuvant abemaciclib, has met its early-stage triple-negative and HER2-positive HER2-positive breast cancer. Approximately primary end point of invasive disease-free disease. 20% of breast cancers are HER2-positive. survival. The PD1 inhibitor pembrolizumab Trastuzumab (Herceptin, Roche) was the In 2019, the FDA approved the PI3K (Keytruda, Merck & Co.) in combination first HER2-targeting agent to be approved inhibitor alpelisib (Piqray, Novartis) for with chemotherapy was approved by the (in 1998). Since then, a plethora of HER2- PIK3CA-mutated (approximately 40% of FDA in November 2020 for the treatment of targeting agents have been approved, includ- patients) advanced or metastatic disease patients with locally recurrent unresectable ing pertuzumab (Perjeta, Roche), trastu- following progression with an endocrine or metastatic triple-negative breast cancer zumab emtansine (T-DM1; Kadcyla, Roche), therapy. Everolimus (Afinitor, Novartis) with who express PDL1. Approval was based on lapatinib (Tykerb/Tyverb, Novartis), neratinib exemestane is also a treatment option for the KEYNOTE-355 trial. A supplemental (Nerlynx, Puma), trastuzumab deruxtecan HR-positive/HER2-negative recurrent disease. Biologics License Application is under FDA (Enhertu, Daiichi Sankyo/AstraZeneca), review for neoadjuvant pembrolizumab in tucatinib (Tukysa, Seagen/Pfizer) and Triple-negative breast cancer. In 2019, the combination with chemotherapy followed margetuximab (Margenza, MacroGenics). PDL1 inhibitor atezolizumab (Tecentriq, by adjuvant pembrolizumab for early- Trastuzumab plus chemotherapy with Roche) was granted FDA accelerated stage disease. The prescription drug user or without pertuzumab is the adjuvant or approval for PDL1-positive (approximately fee act (PDUFA) date is 29 March 2021. neoadjuvant standard of care for early- stage disease. Trastuzumab emtansine and neratinib are adjuvant treatment Table 1 | Select therapies in the late-phase pipeline for breast cancer options. Pertuzumab plus trastuzumab Product Companies Target Development and chemotherapy is the first-line and or MOA status trastuzumab emtansine is the second-line Oral paclitaxel + encequidar Athenex Taxane Preregistration standard of care for metastatic disease. (Oraxol) However, trastuzumab deruxtecan (approved in 2019), tucatinib plus trastuzumab and Trastuzumab duocarmazine Byondis HER2 Phase III capecitabine, neratinib plus capecitabine, Nivolumab (Opdivo) Bristol Myers Squibb/Ono PD1 Phase III and margetuximab plus chemotherapy (all approved in 2020) are beginning to erode Ipatasertib Roche/Genentech/Chugai AKT Phase III trastuzumab emtansine and trastuzumab Capivasertib AstraZeneca AKT Phase III prescriptions for recurrent disease. Balixafortide Polyphor CXCR4 Phase III Trastuzumab deruxetecan is also being tested as a post-neoadjuvant treatment, and Veliparib AbbVie PARP Phase III tucatinib in combination with trastuzumab Elacestrant Radius Health SERD Phase III emtansine is being tested for patients who are trastuzumab-treated and taxane-treated Tesetaxel Odonate Therapeutics Taxane Phase III with advanced or metastatic disease. Adagloxad simolenin OBI Pharma Vaccine Phase III
HR-positive/HER2- negative breast cancer. GDC-0077 Roche/Genentech PI3K Phase II/III Early-stage disease is treated with hormonal Lasofoxifene Sermonix Pharmaceuticals SERM Phase II therapy, typically for 5–10 years. Patients AKT, protein kinase B; CXCR4, CXC chemokine receptor 4; HER2, human epidermal growth factor receptor 2, with intermediate and high-risk disease may also known as ERBB2; MOA, mechanism of action; PARP, poly-ADP ribose polymerase; SERD, selective also receive chemotherapy prior to hormonal oestrogen receptor degrader; SERM, selective oestrogen receptor modulator.
Nature Reviews | Drug DiSCOvEry volume 20 | May 2021 | 339 NEWS & ANALYSIS
Pembrolizumab is also being assessed in Trastuzumab duocarmazine (Byondis) PARP inhibitors, veliparib is being evaluated early-stage ER-positive/HER2- negative is a HER2-targeting ADC that is being with chemotherapy. Two hormonal therapies disease. assessed in pretreated advanced or metastatic are in pivotal trials for pretreated ER-positive/ Two poly-ADP ribose polymerase HER2-positive breast cancer (TULIP trial), HER2-negative metastatic breast cancer: (PARP) inhibitors are approved for the same population that multiple other elacestrant (Radius Health) and lasofoxifene chemotherapy-pretreated, germline HER2-targeting agents are approved for. The (Sermonix Pharmaceuticals). Other drugs BRCA1/2-mutated, HER2-negative advanced PD1 inhibitor nivolumab (Opdivo, Bristol in the late-phase pipeline include two oral or metastatic breast cancer. The prevalence of Myers Squibb/Ono) is in development taxanes, a PI3K inhibitor and a vaccine BRCA1/2 mutations in triple-negative (15%) for early-stage, previously untreated, targeted to Globo H (Table 1). and HR-positive/HER2-negative (3–4%) high-risk ER-positive/HER- negative disease breast cancer is low. Olaparib (Lynparza, (CheckMate 7FL trial), mirroring an Market indicators AstraZeneca) was first to market, followed ongoing phase III trial (KEYNOTE-756) In 2019, the breast cancer market totalled by talazoparib (Talzenna, Pfizer) (both FDA for pembrolizumab. US$20.2 billion and was dominated by sales approved in 2018); olaparib is also being Two AKT inhibitors are in development of therapies targeting HER2 or CDK4/6 assessed as an adjuvant treatment for high-risk for advanced and metastatic breast cancer. (68% of sales). Despite competition from BRCA1/2-mutated HER2-negative disease. One of these, ipatasertib (Roche) plus generic and biosimilar agents during our Sacituzumab govitecan (Trodelvy, chemotherapy is being evaluated with 2019–2029 forecast period, including Immunomedics) is a trophoblast cell surface (IPATunity170) or without (IPATunity130) competitors for the key agents trastuzumab antigen 2 (TROP2)-targeted antibody– atezolizumab as a first-line treatment for and palbociclib, the breast cancer drug conjugate (ADC). It gained FDA triple-negative disease. However, primary market is forecast to grow 9% annually accelerated approval in 2020 for third-line results from the IPATunity130 trial failed to to $47.7 billion (Fig. 1). The continued and later-line metastatic triple-negative demonstrate a clinical benefit for ipatasertib uptake and expanded use of CDK4/6 disease based on a single-arm phase II trial. in combination with paclitaxel. Ipatasertib inhibitors and entry of 14 premium-priced A confirmatory phase III (ASCENT) is also being assessed in combination with agents, including therapies approved in trial is ongoing. It is also in phase III trials palbociclib for HR-positive/HER2- negative 2019 or 2020 (trastuzumab deruxtecan, for pretreated advanced or metastatic disease (IPATunity150). The other AKT tucatinib, margetuximab, atezolizumab, HR-positive/HER2-negative disease inhibitor, capivasertib (AstraZeneca) is being pembrolizumab, alpelisib and sacituzumab (TROPICS-02 trial), and for early-stage assessed for triple-negative (CAPItello290) govitecan) will fuel this sales growth. HER2-negative disease regardless of HR and HR-positive/HER2- negative By 2029, the CDK4/6 and HER2-targeted status (SASCIA trial). (CAPItello291) disease. agents are expected to maintain their share Balixafortide (Polyphor) is a CXCR4 (73%) of breast cancer sales, attributing for Emerging therapies inhibitor. It is being combined with eribulin approximately $20 billion and $15 billion, The breast cancer late-phase pipeline is (Halaven, Eisai) for pretreated HER2-negative respectively. Trastuzumab deruxtecan diverse, spanning approved drug classes recurrent or metastatic breast cancer. is expected to become the top-selling and novel mechanisms of action (including Veliparib (AbbVie) is also being developed HER2-targeted drug owing to its anticipated inhibitors of AKT and CXCR4) in a variety for patients who are HER2-negative, but for broad use for HER2-positive, HR-positive/ of treatment settings (Table 1). BRCA1/2-mutated tumours; unlike approved HER2-negative and triple-negative cancers and its long treatment duration. The 50 anticipated label expansion of two CDK4/6 47.7 inhibitors (abemaciclib and ribociclib) for 45 42.4 early-stage HR-positive/HER2- negative breast cancer will also drive sales, adding $14 billion 40 in 2029 (69% of drug class sales) in our 35 forecast, with abemaciclib contributing $13 billion (94%) of adjuvant sales. 30 New drug classes are expected to enter the breast cancer market, diversifying treatment 25 Angiogenesis inhibitors options for patients who are triple-negative 20.2 CXCR4 inhibitors 20 and HR-positive/HER2- negative. However, PARP inhibitors sales of some therapies will be constrained TROP2-targeting agents 15 PI3K/AKT/mTOR pathway inhibitors by their biomarker-defined populations and
Major-market sales (US$ billions) Major-market Cytotoxic agents approvals in smaller late-line populations, 10 PD1/PDL1 inhibitors as well as strong competition from established Hormonal agents and emerging therapies. 5 CDK4/6 inhibitors HER2-targeted agents Paul Wilcock and Rachel M. Webster ✉ 0 2019 2024 2029 Decision Resources Group (part of Clarivate), London, UK. Fig. 1 | Estimated major-market sales of key therapies for breast cancer, by drug class. ✉e-mail: [email protected] The figure shows the 2019–2029 forecast for the seven major markets: the USA, France, Germany, https://doi.org/10.1038/d41573-021-00018-6 Italy, Spain, United Kingdom and Japan. AKT, protein kinase B; CXCR4, CXC chemokine receptor 4; CDK4/6, cyclin-dependent kinase 4/6; HER2, human epidermal growth factor receptor 2, also Competing interests known as ERBB2; PARP, poly-ADP ribose polymerase; TROP2, trophoblast cell surface antigen 2. The authors declare no competing interests.
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