輔助免疫腫瘤學(xué)：290億美元的市場(chǎng)將成為下一個(gè)關(guān)鍵戰(zhàn)場(chǎng)

1、The Credit Suisse Connections Series leverages our exceptional breadth of macro and micro research to deliver incisive cross-sector and cross-border thematic insights for our clients.Research Analysts European Pharma Team44 207 888 0304 HYPERLINK mailto:creditsuisse.pharmateam creditsuisse.pharmatea

2、mVamil Divan, MD212 538 5394 HYPERLINK mailto:vamil.divan vamil.divanTrung Huynh44 20 7888 2102 HYPERLINK mailto:trung.huynh trung.huynhDominic Lunn44 20 7883 0471 HYPERLINK mailto:dominic.lunn dominic.lunnJo Walton44 20 7888 0304 HYPERLINK mailto:jo.walton jo.waltonMatthew Weston PhD44 20 7888 3690

3、 HYPERLINK mailto:matthew.weston matthew.westonSpecialist Sales - Philip Gestrin44 20 7888 1000 HYPERLINK mailto:philip.gestrin philip.gestrin28 January 2019Global Equity Research Pharmaceuticals & BiotechnologyAdjuvant Immuno-oncologyCONNECTIONS SERIES$29bn market the next key battlegroundImmuno-on

4、cology harnesses a patients own immune system to fight cancer and has rapidly emerged as a $20bn+ revenue opportunity. Virtually all I-O approvals to date have been in the metastatic setting, when cancer has spread. Arguably a bigger I-O revenue opportunity is in the adjuvant setting where a patient

5、s tumour is caught early, surgically removed and drugs are used to prevent relapse. Adjuvant benefits from a large patient pool and longer duration of therapy vs metastatic.$29bn adjuvant I-O market. In this note we model the adjuvant opportunity across 8 key tumour types. We conclude the market rep

6、resents a $29bn peak sales opportunity (see Figure 1). Lung, triple-negative breast, head & neck and bladder are the biggest opportunities.Data readouts start in 2019E and build in 2020E. The opportunity is closer than many investors realise. Data in neo/adjuvant breast cancer is expected in 2019E w

7、ith lung, bladder and esophageal data in 2020E.Bristol Myers has the highest exposure, Roche in second place. Figure 2 sets out the potential company exposure to adjuvant I-O based on estimated trial readouts and the market opportunity by cancer type. BMY is uniquely positioned in Liver, Gastric and

8、 Esophageal and fast follower in Bladder, Head & Neck and Kidney. Roches position is based on its lead in triple-negative Breast and Bladder.MRK has lots to gain but most to lose from adjuvant I-O. One downside of adjuvant I-O is it may cannibalise metastatic use. As the metastatic market leader MRK

9、 has the most to lose, especially in lung. But this is well- balanced by an estimated $6bn adjuvant sales potential at MRK.Figure 1: Adjuvant I-O timeline by cancer typeFigure 2: Adjuvant peak potential, $bnAdjuvant lung (NSCLC)AZN2020Merck2021BMY20246,500Neo Adjuvant lung (NSCLC)Roche2020BMY2020AZN

10、2020Breast - TNBCRoche2019Merck20195,000Head & Neck (SCCHN)Pfizer2021BMY2022Roche20234,800Bladder - muscle invasiveRoche2020BMY2020AZN20253,600Bladder - non-muscle invasiveMerck2018*AZN2021Merck20223,500Liver (HCC)BMY20221,600GastricBMY20211,600Kidney (RCC)Roche2022BMY2022Merck20221,300 IndicationNo

11、. 1Year No. 2Year No. 3Year Market Size ($m)10.09.0Peak sales potential, $bn8.07.06.05.04.03.02.01.0 EsophagealBMY20201,200 TOTAL MARKET OPPORTUNITY29,1000.0BMYRoche MerckAZNPfizerSource: Company data, Credit Suisse estimates, . * Merck P2 NMI bladder data may be fileableSource: Credit Suisse estima

12、tesDISCLOSURE APPENDIX AT THE BACK OF THIS REPORT CONTAINS IMPORTANT DISCLOSURES, ANALYST CERTIFICATIONS, LEGAL ENTITY DISCLOSURE AND THE STATUS OF NON-US ANALYSTS. US Disclosure: CreditSuisse does and seeks to do business with companies covered in its research reports. As a result, investors should

13、 be aware that the Firm may have a conflict of interest that could affect the objectivity of this report. Investors should consider this report as only a single factor in making their investment decision.Table of contents HYPERLINK l _bookmark0 Adjuvant immuno-oncology3 HYPERLINK l _bookmark1 What i

14、s the adjuvant setting?3 HYPERLINK l _bookmark2 Immuno-oncology in the adjuvant setting4 HYPERLINK l _bookmark3 Key market conclusions $29bn sales potential5 HYPERLINK l _bookmark4 Key company conclusions - who are the winners?6 HYPERLINK l _bookmark5 Outstanding questions on I-O in adjuvant7 HYPERL

15、INK l _bookmark6 NSCLC lung cancer11 HYPERLINK l _bookmark7 Adjuvant trial timelines11 HYPERLINK l _bookmark8 Peak sales potential $6.5bn13 HYPERLINK l _bookmark9 Triple-negative Breast Cancer (TNBC)15 HYPERLINK l _bookmark10 Adjuvant/neoadjuvant trial timelines15 HYPERLINK l _bookmark11 Peak sales

16、potential $5bn17 HYPERLINK l _bookmark12 Head and Neck cancer (SCCHN)18 HYPERLINK l _bookmark13 Adjuvant trial timelines18 HYPERLINK l _bookmark14 Peak sales potential $4.8bn19 HYPERLINK l _bookmark15 Bladder Cancer20 HYPERLINK l _bookmark16 Adjuvant trial timelines20 HYPERLINK l _bookmark17 Peak sa

17、les potential: $3.5bn each for NMIBC & MIBC22 HYPERLINK l _bookmark18 Liver cancer (HCC)23 HYPERLINK l _bookmark19 Adjuvant trial timelines23 HYPERLINK l _bookmark20 Peak sales potential $1.6bn23 HYPERLINK l _bookmark21 Gastric cancer25 HYPERLINK l _bookmark22 Adjuvant trial timeline25 HYPERLINK l _

18、bookmark23 Peak sales potential $1.6bn26 HYPERLINK l _bookmark24 Renal Cell Carcinoma27 HYPERLINK l _bookmark25 Adjuvant trial timelines27 HYPERLINK l _bookmark26 Peak sales potential $1.3bn28 HYPERLINK l _bookmark27 Esophageal cancer29 HYPERLINK l _bookmark28 Adjuvant trial timeline29 HYPERLINK l _

19、bookmark29 Peak sales potential $1.2bn30Therapy used after surgery to preventrelapseAdjuvant immuno-oncologyWhat is the adjuvant setting?Adjuvant cancer therapy is given to lower the risk of relapse in patients already treated for cancer. In most cases, adjuvant therapy is used in patients where the

20、ir tumour has been diagnosed early, hasnt spread and is eligible for surgical removal. While these patients are theoretically cured by surgery, it has been widely documented that they have a significantly higher risk of relapse over time. Adjuvant therapy is used when it has been demonstrated to low

21、er this risk of relapse. It can be in the form of chemotherapy, radiation therapy, hormone therapy or targeted drugs.Adjuvant oncology benefits from a large patient pool. Figure 3 and Figure 4 set out the stage of cancer at diagnosis for Breast and Lung cancer. The data is based on UK NHS reported d

22、iagnosis rates but the levels are broadly similar across the developed world. For breast cancer, 76% of patients are diagnosed with localised disease (Stage 0,1,2) and 9% with regional disease. The vast majority of these would be considered eligible for surgery and potential candidates for adjuvant

23、therapy. For lung cancer the level of early diagnosis is significantly lower with only 23% of patients diagnosed with Localised disease and 21% with Regional disease. The vast majority of localised patients and approximately 30% of regional patients would be eligible for surgery and subsequent adjuv

24、ant therapy.Figure 3: Tumour stage at diagnosis breastFigure 4: Tumour stage at diagnosis lungBreast cancerLung cancerDistant, 5%Regional, 9%Unknown, 10%Localised, 76%Unknown, 10%Distant, 46%Localised, 23%Regional, 21%Source: UK NHS diagnosis data, Credit Suisse analysisSource: UK NHS diagnosis data

25、, Credit Suisse analysisLonger duration of therapy and strong patient compliance. Patients diagnosed earlier tend to be younger, significantly more healthy and are essentially cured post surgery. As such they are much more able to tolerate therapy and survive for the duration of the treatment regime

26、n. Given the well-established link between prior cancer diagnosis and relapse, adjuvant patients are also highly motivated to seek and maintain therapy. Figure 5 and Figure 6 set out the revenue impact on Herceptin and Arimidex following their approval in their respective adjuvant breast cancer sett

27、ings. In both cases, adjuvant approval drove a four-fold increase in revenue over time.Figure 5: Herceptin - impact of adjuvant approvalFigure 6: Arimidex impact of adjuvant approvalGastric2009Adjuvant breast20055000120040001000Sales, US$m30002000800Sales, US$m600400Adjuvant 2002100020001998 2000 20

28、02 2004 2006 2008 2010 2012 2014 2016 2018Herceptin USHerceptin ex-US, ex-Japan01998200020022004200620082010Arimidex USArimidex ex-USSource: IQVIA prescription data, Credit Suisse estimatesSource: IQVIA prescription data, Credit Suisse estimatesWhat is in this report?Adjuvant melanoma approvals supp

29、ort potential of I-O post-surgeryImmuno-oncology in the adjuvant settingImmuno-oncology harnesses a patients own immune system to fight cancer and has rapidly emerged as a $20bn+ revenue opportunity. Virtually all I-O approvals to date have been in the metastatic setting, when cancer has spread from

30、 the primary tumour site. I-O has the potential to also become a new therapy option in the adjuvant setting if studies demonstrate a reduction in the risk of relapse.A host of studies evaluating I-O (both anti-PD-1s and anti-PDL1s) are ongoing and due to start reading out from 2020E. Many of the stu

31、dies will likely have interim analyses included in the statistical plan, raising the possibility of potential earlier headlines in 2019.8 key tumour types. In this report we evaluate head & neck cancer, non-small cell lung cancer, triple negative breast cancer, bladder cancer, liver cancer, esophage

32、al and gastric cancer and renal cell carcinoma. We set out:Peak sales potential in adjuvant setting by cancer type.Timing of adjuvant trial readouts.Relative competitive situation in adjuvant by cancer typeWe note that I-O (BMYs Opdivo and MRKs Keytruda) are already approved in adjuvant melanoma bas

33、ed on the results of the Checkmate 238 and KN-054 studies respectively. Opdivo was first approved in this setting in December 2017 so we do not consider it in this analysis. However, the benefits of I-O in adjuvant melanoma do provide support for the potential of I-O in the post-surgical setting.Key

34、 market conclusions $29bn sales potentialAdjuvant immuno-oncology has the potential to be a $29.1bn peak sales market.The largest adjuvant revenue markets are non-small cell lung cancer (NSCLC,$6.5bn), Triple Negative Breast Cancer ($4.6bn) and head & neck cancer (SCCHN,$4.1bn). Bladder cancers - mu

35、scle invasive and non-muscle invasive - are also a very substantial market, we estimate c$3.5bn each. Liver, esophageal, gastric and renal cell carcinoma sit around $1.0 to 2.0bn each.Lung is due to be the most competitive setting (8 studies in adjuvant/neoadjuvant ongoing) followed by head & neck a

36、nd kidney cancer (RCC) which also have four studies ongoing each.BMY and Roche are expected to be first in three key markets. Based on timelines and company public comments, US Merck is expected to be first with data in two tumour types, while AZN and Pfizer are due to be the leader in one each. BMY

37、 has the largest number of studies in early stage cancers (9, including adjuvant melanoma not evaluated), followed by Roche (5), AZN (6), Merck (5, including adjuvant melanoma) and Pfizer/Merck KGaA (2, including Merkel Cell Carcinoma not evaluated).Figure 7: CS expected first/ second/ third to mark

38、et with I-O in adjuvant/neoadjuvant settingsNo. of IndicationCompetitorsNo. 1Year No. 2Year No. 3Year Market Size ($m)Adjuvant lung (NSCLC)4AZN2020Merck2021BMY20246,500Neo Adjuvant lung (NSCLC)4Roche2020BMY2020AZN2020Breast - TNBC3Roche2019Merck20195,000Head & Neck (SCCHN)4Pfizer2021BMY2022Roche2023

39、4,800Bladder - muscle invasive3Roche2020BMY2020AZN20253,600Bladder - non-muscle invasive2Merck2018*AZN2021Merck20223,500Liver (HCC)1BMY20221,600Gastric1BMY20211,600Kidney (RCC)4Roche2022BMY2022Merck20221,300Esophageal1BMY20201,200TOTAL MARKET OPPORTUNITY29,100Source: Company data, Credit Suisse esti

40、mates, * Phase 2 trial. Unclear whether registrationalKey company conclusions - who are the winners?Standard methodology based on speed to market in each indication. The success of each agent in adjuvant I-O will clearly be determined by the relative clinical efficacy in each setting. However, to da

41、te, evidence from metastatic cancer suggests relatively little difference in the relative efficacy of the key PD-1/L1 agents. Based on this observation, we use the expected speed to market to determine the likely adjuvant market shares in each tumour setting. We assumes that: 1) in a three player ma

42、rket the first mover (typically less than one year ahead of the second player) is able to capture 50% of the market, the second player 40% and the third 10% ; 2) in a two player market the first mover gains 60% and the second 40%; and 3) where a company is the sole player they gain 100% of the marke

43、t.We estimate that BMY has the largest potential opportunity in adjuvant cancer ($9.6bn potential peak sales). BMY benefits from its unique adjuvant positions in esophageal, gastric and liver cancer. It is also a fast-follower in neoadjuvant lung, muscle-invasive bladder, kidney (RCC) and head & nec

44、k cancers.Roche is second with a total potential of $7.0bn based on its lead in triple-negative breast, muscle-invasive bladder and neoadjuvant lung. Merck is a close third with$6.0bn sales potential.AZN has $4.1bn potential largely based on its apparent lead in adjuvant lung cancer where the compan

45、y has indicated first data readout will be in 2020E. We do, however, note that AZs lung study is in collaboration with an academic cooperative group and is still indicated as recruiting on . Astra already has significant experience in a setting closely aligned to adjuvant treatment - the Stage 3 non

46、-resectable lung PACIFIC setting.Pfizer/Merck KGaA has $2.4bn adjuvant sales potential based on avelumabs leading position in head & neck cancer (SCCHN).Figure 8: Adjuvant market share potential by company and time to market3rd to market2nd to market 1st to market10.09.0Peak sales potential, $bn8.07

47、.06.05.04.03.02.01.00.0BMYRocheMerckAZNPfizerSource:Credit Suisse estimates,Outstanding questions on I-O in adjuvantRole of PD-L1 status in adjuvant settingAll tumour types being studied in the adjuvant setting have proof of concept in metastatic disease. One possible exception is gastric cancer whe

48、re Keytruda has accelerated approval in the third line metastatic setting but a large P3 study (Keynote-061) in second- line metastatic gastric recently failed to show benefit over chemo.For many tumour types in the metastatic setting, efficacy of PD-1/PD-L1 inhibitors has been correlated with the e

49、xpression of PD-L1 biomarkers on the tumour or surrounding cells (Figure 9). This raises the question of tumour PD-L1 status in the adjuvant setting. However, adjuvant therapy is given after the surgical removal of the primary tumour to prevent relapse. There is no data that we are aware of that lin

50、ks the PD-L1 status of the primary tumour to the PD-L1 status of any subsequent relapse.In virtually all cancer settings discussed in this note, the trial protocol allows for the recruitment of all comers, regardless of PD-L1 biomarker status. The one exception is Roches study of Tecentriq in muscle

51、-invasive bladder cancer (MIBC) where only PD-L1 positive patients are eligible.Figure 9: Role of PD-L1 biomarker in metastatic I-O monotherapyIndicationProof of concept of I-O in metastatic diseaseMetastatic mono approval/dataAdjuvant lung (NSCLC)PDL1 +Neo Adjuvant lung (NSCLC)PDL1 +Breast - TNBCPD

52、L1 + ()Head & Neck (SCCHN)PDL1 +Bladder - muscle invasivePDL1 +Bladder - non-muscle invasivePDL1 +Liver (HCC)All comersGastric/PDL1 +Kidney (RCC)All comersEsophagealPDL1 +Source: Company data, Credit Suisse estimates. () IMpassion130 data submitted to FDACannibalisation of metastatic settingIf futur

53、e clinical data supports the use of I-O in the adjuvant setting, how much will it cannibalise I-O use in metastatic indications? Cannabalisation could come in two forms:i) Efficacy in adjuvant leads to a reduction in relapse rate and thus a shrinking of the metastatic market over timeii) Patients wh

54、o fail adjuvant I-O therapy are no longer considered eligible for metastatic I-O.Given the large size of the global oncology market and the relatively early stages of I-O roll out (especially ex-US) we see little of impact of (i) in the forseable future. For driver (ii), our conversations with clini

55、cians have given a broadly-consistent answer to this question.If a patient were to relapse during adjuvant I-O therapy or within 6-12 months of completing adjuvant, clinicians would consider them an I-O failure and not support metastatic I-O treatment. If a patient were to relapse more than 12 month

56、s following completion of adjuvant I-O treatment then (if reimbursed!) clinicians would consider metastatic I-O as the preferred option. Clearly in time, clinical studies on sequencing therapies will be able to answer this question. Before then we see reimbursement as the key barrier to multiple lin

57、es of I-O treatment.Figure 10 sets out Credit Suisse Global Researchs worldwide end user sales for PD- 1/PD-L1 in 2019E. Unsurprisingly, the risk of cannibalisation is highest at Merck & Co and Bristol Myers. Lung cancer is the key cancer type at risk given that AstraZeneca appears in the lead for d

58、ata readout in the adjuvant NSCLC setting and Roche is in the lead in neoadjuvant.Figure 10: Credit Suisse PD-1/PD-L1 worldwide end-user sales, 2019E12,0002019E WW end user sales, $m10,0008,0006,0004,0002,000-MRKKeytrudaBMYOpdivoROGTecentriqAZNImfinziPFEBavencioSANLibtayoSource: Credit Suisse estima

59、tesSafety of longer-duration I-O useIn general, adjuvant treatment settings have a longer median duration of therapy versus metastatic treatment as patients are often younger (having been diagnosed earlier) and are in better general health. Metastatic trials of PD-1/PD-L1 checkpoint inhibitor therap

60、y have demonstrated significantly improved tolerability relative to cytotoxic chemotherapy. However, I-O treatments do bring a specific group of immune-related side effects (see Figure 11).Figure 12 and Figure 13 set out a schematic of the average duration of these immune- related adverse events (AE