Nature Review Drug Discovery 对肿瘤综合疗法的总结分析（附原文）

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" T$ K  v1 D* f% a新年伊始，本期 Nature Review Drug Discovery 值得珍藏。
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* }/ n. s# V! h8 S先附上 Webster, Rachel M., Combination therapies in oncology: http://www.nature.com/nrd/journal/v15/n2/full/nrd.2016.3.html （Table, Figure 见附件）
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8 [) P+ h5 ~& ?0 a7 I) {+ G9 j2 OCombination therapies in oncology2 d% c! u: D5 H& X
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Rachel M. Webster
, L- E9 G# B8 v0 e( Z5 d3 QNature Reviews Drug Discovery 15, 81–82 (2016) doi:10.1038/nrd.2016.30 B- B6 U9 u/ o9 v
Published online 03 February 2016
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Subject terms: Cancer Combination drug therapy Drug discovery" G) h8 R2 @5 O6 H
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Oncology is one of the fastest-growing therapeutic areas in the pharmaceutical industry. A rising demand for more tolerable therapies drives the development of novel combination strategies. Several regimens that include two or more molecularly targeted agents have recently been approved, and a number of combinations are in late-phase clinical development.
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  x; G, ]% A2 N2 w/ QApproved combination therapies
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9 ?! C9 G% k/ J. ~A combination of the two HER2 (also known as ERBB2)-targeted drugs pertuzumab (Perjeta; Roche) and trastuzumab (Herceptin; Roche), together with the chemotherapeutic agent docetaxel, was approved by the FDA in June 2012. As the first combination regimen in oncology that contains more than one targeted agent, it achieved a 15.7-month improvement in overall survival (OS) over a combination of trastuzumab and docetaxel in HER2-positive metastatic breast cancer.
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5 d( r$ `: Z7 [( ~! w( N0 Z' R$ U- R( _The first combination of a BRAF inhibitor (dabrafenib; Tafinlar) and a MAPK/ERK kinase (MEK) inhibitor (trametinib; Mekinist) was granted accelerated FDA approval in January 2014 for the treatment of unresectable or metastatic BRAFV600E/K melanoma. Both agents were developed by GlaxoSmithKline (GSK) and acquired by Novartis in March 2015. The combination exhibits a lower incidence of cutaneous squamous cell carcinomas (SCCs) and keratocanthomas compared with single-agent BRAF inhibitors such as dabrafenib or vemurafenib (Zelboraf; Roche), and has had an impact on the market share of vemurafenib. In November 2015, a combination of the MEK inhibitor cobimetinib (Cotellic; Exelixis) and vemurafenib received FDA approval for the same indication. This may protect vemurafenib's share of the BRAFV600E/K melanoma market and give cobimetinib a foothold in the marketplace., f+ c5 z+ |5 p" ^, r; E

0 K( Q2 h$ s: c1 w6 ?! zIn October 2015, the FDA granted accelerated approval to the first immune checkpoint inhibitor combination, the programmed cell death protein 1 (PD1) inhibitor nivolumab (Opdivo; Bristol-Myers Squibb (BMS)) and the cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitor ipilimumab (Yervoy; BMS), for BRAFV600 wild-type unresectable or metastatic melanoma. Approval was based on the Phase II CheckMate-069 trial, in which the combination demonstrated a remarkable response rate (61% overall response rate (ORR), including a 22% complete response rate) versus ipilimumab alone (11% ORR and no complete responses). Phase III OS data for the combination have yet to be announced, but it achieved an impressive progression-free survival (PFS) over ipilimumab alone (11.5 months versus 2.9 months) in the Phase III CheckMate-067 trial. A lack of Phase III data on both OS and durability of response is expected to constrain uptake of the combination in the near term; a high incidence of grade 3 or 4 adverse events (55%) compared with ipilimumab (27%) and nivolumab (19%) may also impede its uptake.( T( }) u& e8 N* C) k& e

3 r9 }5 O0 Y* P& x1 @For multiple myeloma, combinations of the proteasome inhibitor bortezomib (Velcade; Takeda/Millennium) or the immunomodulatory agent lenalidomide (Revlimid; Celgene) with a steroid or alkylating agent have been entrenched for a decade. However, several combinations of these agents with other targeted agents have recently been approved. The histone deacetylase (HDAC) inhibitor panobinostat (Farydak; Novartis) gained accelerated FDA approval in combination with bortezomib in February 2015, and the proteasome inhibitor carfilzomib (Kyprolis; Amgen) in combination with lenalidomide secured approval from the FDA and European Medicines Agency (EMA) in July 2015 and November 2015, respectively. Moreover, the next-generation oral proteasome inhibitor ixazomib (Ninlaro; Takeda/Millennium) and the first-in-class signalling lymphocyte activation molecule family 7 (SLAMF7)-directed immunostimulatory antibody elotuzumab (Empliciti; BMS) both received FDA approval in November 2015 in combination with lenalidomide.+ S( A/ H* m4 v; c' K7 F3 l) |" Y3 p
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Late-phase pipeline
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; Q. {7 G# D: ~# h3 m) bMany combinations in clinical development involve immune checkpoint inhibitors such as ipilimumab, nivolumab and pembrolizumab (Keytruda; Merck & Co.). A combination of nivolumab and ipilimumab is in Phase III trials for non-small-cell lung cancer (NSCLC), small-cell lung cancer, squamous cell carcinoma of the head and neck (SCCHN), and renal cell carcinoma (RCC) (Table 1).
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" |. L$ Y% S9 S& VA Phase III (IMmotion151) trial of the anti-PDL1 antibody atezolizumab (Roche) in combination with the anti-angiogenic agent bevacizumab (Avastin; Roche) is being compared with monotherapy comprising the multi-kinase inhibitor sunitinib (Sutent; Pfizer) for metastatic RCC. Approval of this combination could affect sunitinib's strong position as first-line treatment and reinvigorate bevacizumab's market share.
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The first oncolytic viral therapy, talimogene laherparepvec (Imlygic; Amgen), was approved by the FDA in October 2015 for the treatment of unresectable lesions in patients with melanoma who undergo recurrence after initial surgery. It showed a durable response rate (DRR) compared with granulocyte–macrophage colony-stimulating factor (GM-CSF) (16.3% versus 2.1%, respectively) in the Phase III (OPTiM) trial, but has not shown a statistically significant improvement in OS or an effect on visceral metastases, thus limiting its use. This novel therapy may show greater promise as part of a combination regimen and a collaboration with several developers of immune checkpoint inhibitors has been initiated. A Phase III trial evaluating talimogene laherparepvec with pembrolizumab is due to be completed in 2018.
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Several other targeted combination therapies are in late-phase trials (Table 1). Notably, BRAF–MEK-inhibitor combinations continue to be evaluated in melanoma, while novel targeted hormone combinations are under investigation in prostate cancer. The angiogenesis inhibitor cediranib (AstraZeneca) has had mixed results in clinical development as monotherapy and is now being investigated in combination with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza; AstraZeneca) in patients with ovarian cancer. Therapeutic vaccines are also in late-phase combination trials.
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Market opportunity6 e/ p& L0 @  H& [
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Key oncology markets are expected to more than double by 2024 (Fig. 1). Growth in oncology sales will be driven by the increased incidence of most cancers and a full development pipeline. Notably, the forecast market sizes for non-Hodgkin lymphoma (NHL), multiple myeloma (MM) and breast cancer are similar, despite a respective fourfold and tenfold difference between NHL and MM incidence compared with that of breast cancer. The size of the NHL and MM markets is largely a reflection of the success of lenalidomide, bortezomib and the B cell-targeted rituximab (Rituxan/MabThera; Roche) and a trend towards their use in combination with novel emerging agents.; p, \, p: j. h  v% x" U. b
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Targeted monotherapy has raised the efficacy bar for developers, but combined drug therapy with synergistic activity promises to substantially improve efficacy and maximize the chances of clinical and commercial success. Drug combinations are a powerful tool for demonstrating clinical differentiation versus competitors and for securing a foothold in crowded oncology markets; they also allow companies to salvage pipeline assets that otherwise would not have progressed in monotherapy programmes. In the quest to bring new innovative drug combinations to the global market, developers are diversifying their franchises by making strategic partnerships and deals. However, as development of high-priced combination therapies grows, payer pressure and reimbursement challenges intensify, making pricing strategy and other factors such as the identification and validation of a predictive biomarker critically important considerations.& T8 r, A2 u8 j: o1 j& m- q* y3 x
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Table 1: Selected combination therapies in the late-phase oncology pipeline ［见附件］
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6 x. `8 T$ B9 S3 h1 t5 u5 oFigure 1: Incidence and major market oncology sales predicted for 2024. ［见附件］
/ r3 x9 i( g. g8 r" ?) zKey oncology markets are expected to grow to over US$110 billion by 2024 across the seven major pharmaceutical markets (United States, France, Germany, Italy, Spain, United Kingdom and Japan). NHL, non-Hodgkin lymphoma; NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; SCLC, small-cell lung cancer. Source: company reports. *NHL includes chronic lymphocytic leukaemia and small lymphocytic lymphoma.
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# Y9 Z) [  n7 }" x3 X4 w2 I! p; `Author information
* c1 q- L- V. }- XAffiliations
$ s" h( T' z# s6 t5 BDecision Resources, 9 Appold Street, London EC2A 2AP, UK.9 l) m4 |: a# t- O- U
Rachel M. Webster3 E! F: b* c# \+ z3 s- k: X
Competing interests statement
5 h9 l  b# d& X4 aThe author declares no competing interests.
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Corresponding author. l9 x! B; O9 k: s" C: z- ~
Correspondence to: Rachel M. Webster
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