Roche/Genetech discover resistance mechanism to Tecentriq

IMvigor201 trial 의 responder 와 non-responder 의 biomarker study 를 ESMO 에 발표하였다.

Resistance 의 원인은 TGF-beta.

TGF-beta 가 microenvironment 에서 stromal barrier 를 만들어, T cell penetration 을 저해한다는 내용.



ASCO 2017 – Perjeta + Herceptin (APHINITY)

2017년 3월, Roche 는 APHINITY study (Perjeta + Herceptin + Chemo 과 Herceptin + Chemo 의 비교) 에서 유의미한 positive data 를 얻었다고 발표했다.

지난 포스트

로슈 발표 내용

이미 Perjeta 를 포함한 combination therapy 는 임상 2상 결과를 바탕으로 FDA accelerated approval 을 받았고, (링크)

이번 ASCO 2017 에서 발표한 임상 3상 (APHINITY) 에 대한 전체 결과는 다음과 같다.

결론부터 말하자면, 지난 3월의 발표가 설레발이었던 것. Positive data 이지만 너무나 실망스럽고, safety 까지 감안하자면 글쎄,,, 게다가 경제적인 면까지도 생각하지 않을 수 없다.

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스크린샷 2017 06 10 오후 11 40 14


위 내용은 NEJM 에도 ASCO 발표가 있었던 그 날 바로 발표되었다. 자세한 내용은 논문을 참고.

NEJM result paper 링크

NEJM editorial 링크

왠지 bladder cancer 에서 atezolizumab 임상 3상 결과도 그렇고, Roche 결과들이 참으로 안타깝네.

Atezolizumab failed a PhIII study in advanced bladder cancer

이미 first line therapy 까지 승인을 받았건만! 링크

오늘 press 발표에 따르면, 임상3상 (IMvigor211) 에서 기존 chemo 대비 OS 에 도달하지 못했다고 한다.

이미 작년에 승인받은 것이야, 임상2상 (IMvigor210) 결과를 바탕으로 accelerated approval 받은 것이고, confirmation study 에서 결과를 얻지 못했으니…

일단 FDA 가 어떤 결정을 내릴지, 이대로 퇴출될건지, 새로운 전략은 있는지, 뉴스를 기다려 봅시다.

BMS 도 그렇고 Roche 도 그렇고, I/O 분야가 참 쉬운게 아닌가보다.



FDA grants atezolizumab accelerated approval as frontline therapy in advanced bladder cancer

Atezolizumab 이 작년 bladder cancer 에서 런칭한 이후 1년만에 first line therapy 로 업그레이드 되면서, 이 암종에서 standard of care 가 될 것으로 보인다.

1. Patients with advanced bladder cancer who are not eligible for standard cisplatin chemo

2. Based on data from the single-arm phase II IMvigor210 trial

3. ORR 23.5%, CR 6.7%

Atezolizumab vs docetaxel in patients with previously treated NSCLC (OAK): a phase 3, open-label, multicentre randomised controlled trial

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.

Achim Rittmeyer, Fabrice Barlesi, Daniel Waterkamp, Keunchil Park, Fortunato Ciardiello, Joachim von Pawel, Shirish M Gadgeel, Toyoaki Hida, Dariusz M Kowalski, Manuel Cobo Dols, Diego L Cortinovis, Joseph Leach, Jonathan Polikoff, Carlos Barrios, Fairooz Kabbinavar, Osvaldo Arén Frontera, Filippo De Marinis, Hande Turna, Jong-Seok Lee, Marcus Ballinger, Marcin Kowanetz, Pei He, Daniel S Chen, Alan Sandler, David R Gandara, and OAK Study Group.

BACKGROUND:Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer.

METHODS:We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m(2) every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with, number NCT02008227.

FINDINGS:Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.

INTERPRETATION:To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.

FUNDING:F. Hoffmann-La Roche Ltd, Genentech, Inc.

Lancet, 2017 vol. 389 (10066) pp. 255-265.

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스크린샷 2017-03-23 오전 12.46.33TC1/2/3 or IC1/2/3: PD-L1 >= 1%
TC2/3 or IC2/3: 5%
TC3: 50% Tumor PD-L1
IC3: 10% Immune cell PD-L1
TC0 and IC0: PD-L1 < 1%

All images are from 여기.

Perjeta + Herceptin (APHINITY P3)

Roche 는 정말 약도 잘 만들지만, 그 보다도 약 파는 능력은 가히 둘째가라면 서러워하는 (second to none) 회사 인 듯.

Perjeta (Pertuzumab) 은 Herceptin (Trastuzumab) 과 동일하게 her2 에 결합해 signaling 을 저해 하는데, 일단은 결합 부위가 다르다.
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APHINITY clinical trial 에 대해서는, ASCOpost 를 참고.

(Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer) 

APHINITY (NCT01358877/BO25126/BIG 4-11) is an international, phase III, randomized, double-blind, placebo-controlled, two-arm study evaluating the efficacy and safety of pertuzumab plus trastuzumab and chemotherapy compared to trastuzumab and chemotherapy as an adjuvant therapy in 4,805 people with operable HER2-positive early breast cancer.

People enrolled in the study underwent surgery and were randomized to one of two arms (1:1) to receive either:

  • Six to eight cycles of chemotherapy (anthracycline-containing or non–anthracycline-containing regimen) with pertuzumab and trastuzumab, followed by pertuzumab and trastuzumab every 3 weeks for a total of 1 year of treatment.
  • Six to eight cycles of chemotherapy (anthracycline-containing or non–anthracycline-containing regimen) with placebo and trastuzumab, followed by placebo and trastuzumab every 3 weeks for a total of 1 year of treatment. 

Radiotherapy and/or endocrine therapy could be initiated at the end of adjuvant chemotherapy. The APHINITY study allowed for a range of standard chemotherapy regimens to be used and both lymph node–positive and lymph node–negative participants were eligible for enrollment. The primary efficacy endpoint of the APHINITY study is invasive disease–free survival. Secondary endpoints include cardiac and overall safety, overall survival, disease-free survival, and health-related quality of life.