N E W S & A N A LY S I S FROM THE ANALYST’S COUCH

The breast cancer market Basharut A. Syed Breast cancer (BC) is the most common cancer in women worldwide; it affects ~12% of females in the United States. Traditionally, BC has been classified into three distinct subtypes: hormone receptor (HR)-positive BC, in which tumours overexpress oestrogen receptors (ERs) and/or progesterone receptors (PRs); human epidermal growth factor receptor 2 (HER2)-positive BC, which is driven by the oncogene HER2 (also known as ERBB2 or NEU); and triple-negative BCs (TNBCs), which do not overexpress ER, PR or HER2. Around 83% of BC patients have HR-positive BC, and this proportion overlaps with the ~15% of patients who have HER2-positive BC — only ~5% have BC that is HER2-positive and ER-negative. About 12% have TNBC. Current treatments The HER2-positive disease subtype currently occupies the largest share of the BC drug market. The HER2-specific monoclonal antibody (mAb) trastuzumab (Herceptin; Roche) was launched in the United States in 1998 and, in combination with taxane chemotherapy, this drug has greatly improved prognosis for HER2-positive patients. In 2012, a second mAb, pertuzumab (Perjeta; Roche), was released; this drug works synergistically with trastuzumab when the two are co‑administered. In 2013, ado‑trastuzumab emtansine (Kadcyla; Roche), an antibody–drug conjugate (ADC) that uses the trastuzumab mAb to deliver a potent chemotoxin directly to tumour tissues, entered the market. With these newer drugs, the HER2 franchise is bolstered against competition — the European patents for trastuzumab expire in 2014–2015, and several companies are lining up biosimilars: most prominently, Celltrion and Hospira, who have gained approval for their version in Korea, and Mylan, which has a biosimilar approved in India. The challenge for Roche is to show that its new, premium-priced drugs can substantially improve on trastuzumab’s clinical effectiveness in as many lines of therapy as possible. Pertuzumab has already largely succeeded in this: in combination with trastuzumab and docetaxel, it showed a 15.7‑month improvement in overall survival compared with placebo plus trastuzumab and docetaxel as first-line therapy for metastatic disease. It is already approved in

Pink sofa by Iurii Andrieiev/ Hemera Collection

the United States as a neoadjuvant treatment for reducing tumour bulk prior to surgery. Another trial (called APHINITY) is ongoing to assess whether pertuzumab can improve progression-free survival as a post-surgery adjuvant, an indication for which a 1‑year course of trastuzumab is the current standard of care. For ado-trastuzumab emtansine, the clinical trial picture is, so far, less clear. It is approved as a second- and later-line of therapy for metastatic disease, but the MARIANNE trial failed to show any clinical benefit for the drug versus pertuzumab in first-line treatment.

In ER-positive BC, a range of effective drugs exist, and the prognosis is much better than for the other BC subtypes. The oldest of the hormonal therapies is tamoxifen, a prodrug that blocks oestrogen uptake by the ER. In the late 1990s, a third generation of aromatase inhibitors (AIs) entered the market; AIs block the aromatase enzyme that is responsible for the bulk of oestrogen production in post-menopausal women. For these patients, drugs such as the non-steroidal AIs letrozole (Femara; Novartis), anastrozole (Arimidex; AstraZeneca) and exemestane (Aromasin; ▶

Table 1 | Selected products in late-stage development for breast cancer Drug (alternative names)

Developer

Mode of action

Highest stage of development

Irreversible binder of HER1, HER2 and HER4

Phase III

HER2-positive and HR-positive Neratinib (HKI-272)

Pfizer/Puma Biotechnology

Nelipepimut-S (E75; NeuVax)

Galena Biopharma Therapeutic vaccine

Phase III

Palbociclib (Ibrance)

Pfizer

Oral small-molecule inhibitor of CDK4 and CDK6

Approved by FDA (February 2015)

Ribociclib (LEE011)

Novartis/Otsuka

Oral small-molecule inhibitor of CDK4 and CDK6

Phase III

Abemaciclib (LY2835219)

Eli Lilly

Oral small-molecule inhibitor of CDK4 and CDK6

Phase III

Buparlisib (BKM120)

Novartis

Oral small-molecule inhibitor of PI3K

Phase III

Entinostat (SNDX-275; MS-275)

Bayer/Syndax Pharmaceuticals

Histone deacetylase inhibitor; normalizes ERα expression and inhibits growth factor signalling pathways

Phase III

Oral PARP inhibitor

Pre-registration

Talazoparib (BMN 673) BioMarin

Oral PARP inhibitor

Phase III

Niraparib (MK-4827)

Merck & Co./ Tesaro

Oral PARP inhibitor

Phase III

Veliparib (ABT-888)

AbbVie

Oral PARP inhibitor

Phase III

Etirinotecan pegol (NKTR-102)

Nektar

PEGylated form of DNA TII irinotecan

Phase III

Glembatumumab vedotin (CDX-011)

Celldex Therapeutics

ADC targeting GPNMB

Phase II

HR-positive

HER2-negative and HR-negative (TNBC) Olaparib (AZD-2281; Lynparza)

AstraZeneca

ADC, antibody-drug conjugate; CDK, cyclin-dependent kinase; ERα, oestrogen receptor‑α; FDA, US Food and Drug Administration; GPNMB, glycoprotein non‑metastatic melanoma protein B; HER, human epidermal growth factor receptor; HR, hormone receptor (oestrogen and/or progesterone receptors); PARP, poly(ADP-ribose) polymerase; PEG, polyethylene glycol; PI3K, phosphatidylinositol 3-kinase; TII, topoisomerase I inhibitor; TNBC, triple-negative breast cancer.

NATURE REVIEWS | DRUG DISCOVERY

VOLUME 14 | APRIL 2015 | 233 © 2015 Macmillan Publishers Limited. All rights reserved

N E W S & A N A LY S I S FROM THE ANALYST’S COUCH ▶ Pfizer) are preferred over tamoxifen.

Fulvestrant (Faslodex; AstraZeneca), a selective ER downregulator, provides another option for patients with metastatic ER-positive BC that has become refractory to earlier lines of hormonal therapy. These patients may alternatively receive everolimus (Afinitor; Novartis), a mammalian target of rapamycin (mTOR) inhibitor that counteracts resistance to the hormonal therapies if co-administered with them. Chemotherapy drugs, principally taxanes, can also be used in combination with the hormonal therapies. For TNBC, far fewer options exist, and the prognosis is bleak. No targeted agents supplement the standard BC chemotherapy options; bevacizumab (Avastin; Roche) is approved for the disease in Europe, but the US Food and Drug Administration (FDA) revoked the BC label for this drug in 2010. Emerging therapies In the HER2-positive setting, one promising immunotherapy is the peptide vaccine nelipepimut-S (also known as E75; NeuVax; Galena Biopharma) (TABLE 1). Phase II results from a 60‑month study reported that only 5.6% of patients who were given NeuVax showed cancer recurrence, compared with 25.9% in the control arm. Overall, a reduction of 78.4% in cancer recurrence was reported. If the ongoing Phase III PRESENT study confirms these results, NeuVax will become the preferred treatment option.

18 16

Sales (US$ millions)

14 12

Others Bevacizumab Fulvestrant Pertuzumab Everolimus Trastuzumab

Total 16.11

Total 11.27

6.98

4.30

0.70 0.84

10 8 6 4 2 0

0.43 0.63 0.70 0.71

2.46 1.59

4.50

3.54

2014

2019

Figure 1 | Market potential for products for breast cancer, in 2014 and| forecast for Nature Reviews Drug Discovery 2019.  Sales figures in US$. Source: IMS Health, IMS MIDAS Analytics Link

One possible addition to the market in the near future is neratinib (Puma Biotechnology/Pfizer), a tyrosine kinase inhibitor that blocks the receptors HER1, HER2 and HER4. Little was expected of this drug given the poor clinical and market performance of lapatinib (Tykerb; GlaxoSmithKline), another tyrosine kinase inhibitor used in BC. Nevertheless, neratinib was successful in the ExteNET trial in July 2014, indicating that it might successfully challenge trastuzumab in the adjuvant setting. However, Puma has since delayed its new drug application for neratinib until 2016, and full presentation of its data is still awaited. For ER-positive BC, there are few new hormonal agents in development. Instead, attention has focused on metastatic disease that has become refractory to the existing drugs. Several companies are trialling new agents that, like everolimus, may reduce the development of drug resistance if given in combination with hormonal therapies. Classes under investigation in Phase III trials include phosphoinositide 3-kinase (PI3K) inhibitors, such as buparlisib (Novartis), and histone deacetylase inhibitors, such as entinostat (Bayer/Syndax). However, most attention has focused on the cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors, which are led by palbociclib (Ibrance, Pfizer). In Feburary 2015, palbociclib won approval under the expedited pathway allowed by the FDA’s breakthrough therapy designation. The pivotal PALOMA‑1 trial showed that palbociclib plus letrozole extended progression-free survival by 10 months compared with letrozole alone, and improved the overall response rate by 16%. The drug is expected to have a better toxicity profile than everolimus and is likely to become the next blockbuster in the BC market. Other promising CDK4 and CDK6 inhibitors in late-stage development include ribociclib (Novartis) and abemaciclib (Eli Lilly). For drug developers, TNBC represents a major unmet need. Several drugs are in the late-stage pipeline, including olaparib (AstraZeneca), a poly(ADP‑ribose) polymerase (PARP) inhibitor that has recently been approved for ovarian cancer, and three other PARP inhibitors: talazoparib (BMN‑673; BioMarin), niraparib (Merck & Co./Tesaro) and veliparib (AbbVie). These may be very effective for the small subset of TNBC patients who carry germline mutations in the breast cancer susceptibility genes BRCA1 or BRCA2.

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Another drug class of interest is the topoisomerase I inhibitors (TIIs). Etirinotecan pegol (NKTR-102; Nektar), a long-acting TII, is currently undergoing Phase III studies for refractory HER2-negative metastatic BC. The earlier (Phase II) pipeline for TNBC contains the ADC glembatumumab vedotin (Celldex) — an antibody directed against glycoprotein non-metastatic melanoma protein B (GPNMB) that is linked to the potent cytotoxic agent monomethyl auristatin E. Further back in the pipeline, other options, such as androgen-receptor blockers (which are already important in prostate cancer), may offer potential for TNBC. Market indicators The current BC market is worth ~US$11.27 billion (FIG. 1) (IMS Health, IMS MIDAS). It has grown substantially from a 2012 value of $9.55 billion, with a compound annual growth rate (CAGR) of 8.5% (12 months to Q3, 2012–2014). Three manufacturers — Roche, Novartis and AstraZeneca — accounted for almost 75% of the BC market. The top five products collectively accounted for ~62% of the sales revenue, with Roche’s Herceptin dominating the market (with $4.5 billion, or a 40.0% share, of the total sales in the 12 months to Q3, 2014). However, this drug will probably be challenged by biosimilars and novel therapies. The United States remains the leading national market, with 45.0% of the total sales for 12 months to Q3, 2014. The market is projected to reach $16.11 billion by 2019 (CAGR 7.4%, 2014–2019 (see FIG. 1)), driven largely by HER2-positive subtype therapies such as Perjeta and Kadcyla. However, a substantial unmet need remains for novel targeted agents for patients with HER2-negative BC or TNBC. Several PARP inhibitors are being evaluated for the treatment of TNBC and could offer hope for these patients. Basharut A. Syed, Ph.D. is at IMS Health Ltd, 210 Pentonville Road, London N1 9JY, UK. e-mail: [email protected] doi:10.1038/nrd4571 The author declares no competing interests.

FURTHER INFORMATION US breast cancer statistics: http://www.breastcancer.org/ symptoms/understand_bc/statistics US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status: http://jnci.oxfordjournals. org/content/early/2014/04/27/jnci.dju055.abstract Roche media release (Dec 2014): http://www.roche.com/ media/media_releases/ med-cor-2014-12-19.htm ALL LINKS ARE ACTIVE IN THE ONLINE PDF

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The breast cancer market.

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