ASCO 2017 – Epacadostat

AACR 에 이어 ASCO 에서도 Incyte 의 epacadostat 이 주목을 받았다.

ASCO abstract 에서 epacadostat 으로 105개의 연구결과가 검색 되었고, 이 중 주목할만한 내용 몇 개를 보자면,

1. Epacadostat + Pembrolizumab in NSCLC
ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. 대부분의 환자가 1차 chemo 환자라는 점에서, 그리고 pembrolizumab 이 1st-line therapy 가 가능하다는 점에서, epacadostat combination 이 1st-line 으로 가게되면 더욱 response rate 가 올라갈 것으로 기대. 임상 3상 진행 예정.
http://abstracts.asco.org/199/AbstView_199_181148.html 

2. Epa + Pemb in advanced RCC
ORR (CR+PR) and DCR (CR+PR+SD) for pts with 0–1 prior tx was 47% (9/19; 1 CR, 8 PR) and 58% (11/19; 1 CR, 8 PR, 2 SD), respectively; for pts with ≥2 prior tx, ORR and DCR were 0% and 36% (4/11; all SD). 역시 임상 3상 예정.
http://abstracts.asco.org/199/AbstView_199_184165.html
 

3. E + P in advanced urothelial carcinoma
for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). 임상 3상 예정.
http://abstracts.asco.org/199/AbstView_199_183204.html
 

4. E + P in Triple-negative BC & Ovarian cancer
For TNBC pts, ORR (CR+PR) was 10% (n = 4; all PR) and DCR (CR+PR+SD) was 36% (n = 14; 10 SD); ORR and DCR for pts with ≤2 prior tx were 12% (n = 2) and 29% (n = 5), respectively, and for ≥3 prior tx were 9% (n = 2) and 41% (n = 9).

For OVC pts, ORR was 8% (n = 3; all PR) and DCR was 35% (n = 13; 10 SD); ORR and DCR for pts with ≤2 prior tx were 13% (n = 1) and 25% (n = 2), and for ≥3 prior tx were 7% (n = 2) and 38% (n = 11)

TNBC, OVC 에서의 반응률은 좀 낮은 편.
http://abstracts.asco.org/199/AbstView_199_183215.html 

5. E + P in SCCHN
Of 36 efficacy-evaluable pts, 81% (n = 29) received 1–2 prior lines of tx and 19% (n = 7) received ≥3 prior lines of tx. ORR (CR+PR) and DCR (CR+PR+SD) for pts with 1–2 prior tx were 34% (2 CR, 8 PR) and 62% (8 SD), respectively; for pts with ≥3 prior tx, ORR and DCR were 14% (1 PR) and 43% (2 SD). Response was observed regardless of HPV status.
역시 임상 3상 예정.
http://abstracts.asco.org/199/AbstView_199_184180.html 

6. Epacadostat + Nivolumab in advanced solid tumors
 1) Of 30 MEL pts, 8 were treated with E 100 mg and 22 were more recently enrolled and treated with E 300 mg. ORR (CR+PR) and DCR in MEL pts treated with E 100 mg were 75% (n = 6; all PR) and 100% (n = 8; 2 SD), respectively. Preliminary DCR in MEL pts treated with E 300 mg was 64% (n = 14).
 2) Of 29 OVC pts, 18 were treated with E 100 mg and 11 with E 300 mg.ORR and DCR for OVC pts treated with E 100 mg were 11% (n = 2; 2 PR) and 28% (n = 5; 3 SD); for 11 OVC pts treated with E 300 mg, ORR and DCR were 18% (n = 2; 2 PR) and 36% (n = 4; 2 SD).
 3) For 25 CRC pts (all E 100 mg), ORR and DCR were 4% (n = 1; PR) and 24% (n = 6; 5 SD)
http://abstracts.asco.org/199/AbstView_199_184081.html

일단 safety 측면에서 CTLA-4 antibody를 능가한다고 하니, 내년쯤 PD-(L)1 의 combi partner 로 승인 받지 않을까

AACR 2017 – IDO inhibitors

PD-(L)1 다음의 면역치료제는 IDO inhibitor 가 될 것이다. 라는 것이 이번 AACR 의 주제인 것 같다.

위 포스트에서 NewLink data 와 Incyte 를 봤는데, 실제 IDO inhibitor 는 정말 여기저기서 개발하고 있더라.

BMS 와 Roche 도 자체적으로 IDO inhibitor 를 개발하고 있으면서, Incyte 나 NewLink 와도 공동으로 병용투여 스터디를 진행중.

NewImage

출처는 여기

 

특히 선두주자인 Incyte 의 epacadostat 은 이미 PD-(L)1 약물이 안착한 다양한 암종에서 RR 을 올리기 위한 임상 스터디를 진행 중이다. 이미 Merck, BMS, Roche, AZ 와 partnership 을 체결한 Incyte 가 첫번째 IDO inhibitor 를 런칭하게 되지 않을까. 또한 IDO inhibitor 를 시작으로 PD-(L)1 에 이은 2세대 면역치료제가 시장에 나오게 될 것. (그러면 Yervoy 가 병용에서 사라지면서, BMS 는 더더욱 어두워지려나,,, 한번 추락하고 계속 밀리는 우리 BMS ㅠㅠ 최근 Parker institute 와 체결한 공동연구가 힘이 되기를…)

NewImage

출처는 여기

 

Inhibitor 들은 작용기전에 있어 약간 다른 경향을 보이는데, Indoximod 의 경우 면역세포에서 tryptophan degradation 에 의한 signaling inhibitor 로 작용하고, epacadostat 과 RG6078 (GDC-0919) 는 direct IDO enzyme inhibitor 로 작용한다.

Arginase inhibitor CB-1158

Originator: Calithera Biosciences

Buyer: Incyte

Upfront payment: $45m

Estimated value: ~$500m

Target molecule: Arginase

Target cell: MDSC

Clinical setting: Combination with anti-PD-1 ab

Current stage: P1

Another Arginase inhibitors:

Target evaluation: fast-follow 가능?

http://www.calithera.com/wp-content/uploads/2016/01/Keystone-immunotherapy-2016-poster.final_.pdf

https://globenewswire.com/news-release/2017/01/30/911912/0/en/Incyte-and-Calithera-Biosciences-Announce-Global-Collaboration-to-Develop-and-Commercialize-CB-1158-a-First-in-class-Small-Molecule-Arginase-Inhibitor.html