Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial

被引：48

作者：

Desai, Jayesh ^{[1
,2
]}

Alonso, Guzman ^{[3
]}

Kim, Se Hyun ^{[4
]}

Cervantes, Andres ^{[5
]}

Karasic, Thomas ^{[6
]}

Medina, Laura ^{[7
]}

Shacham-Shmueli, Einat ^{[8
]}

Cosman, Rasha ^{[9
,10
]}

Falcon, Alejandro ^{[11
]}

Gort, Eelke ^{[12
]}

Guren, Tormod ^{[13
]}

Massarelli, Erminia ^{[14
]}

Miller Jr, Wilson H. ^{[15
,16
]}

Paz-Ares, Luis ^{[17
,18
]}

Prenen, Hans ^{[19
]}

Amatu, Alessio ^{[20
]}

Cremolini, Chiara ^{[21
]}

Kim, Tae Won ^{[22
]}

Moreno, Victor ^{[23
]}

Ou, Sai-Hong I. ^{[24
]}

Passardi, Alessandro ^{[25
]}

Sacher, Adrian ^{[26
,27
,28
]}

Santoro, Armando ^{[29
,30
]}

Stec, Rafal ^{[31
,32
]}

Ulahannan, Susanna ^{[33
,34
]}

Arbour, Kathryn ^{[35
]}

Lorusso, Patricia ^{[36
]}

Luo, Jia ^{[37
]}

Patel, Manish R. ^{[38
]}

Choi, Yoonha ^{[39
]}

Shi, Zhen ^{[39
]}

Mandlekar, Sandhya ^{[39
]}

Lin, Mark T. ^{[39
]}

Royer-Joo, Stephanie ^{[39
]}

Chang, Julie ^{[39
]}

Jun, Tomi ^{[39
]}

Dharia, Neekesh V. ^{[39
]}

Schutzman, Jennifer L. ^{[39
]}

Han, Sae-Won ^{[40
,41
]}

机构：

[1] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[2] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia

[3] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, Barcelona, Spain

[4] Seoul Natl Univ, Bundang Hosp, Seongnam, South Korea

[5] Hosp Clin Univ Valencia, Valencia, Spain

[6] Univ Penn, Abramson Canc Ctr, Philadelphia, PA USA

[7] Reg & Virgen de la Victoria Univ Hosp, Med Oncol Interctr Unit, IBIMA, Malaga, Spain

[8] Tel Aviv Univ, Sheba Med Ctr, Sackler Sch Med, Tel Aviv, Israel

[9] Univ New South Wales, St Vincents Hosp, Kinghorn Canc Ctr, Sydney, Australia

[10] Univ New South Wales, Sch Med, Sydney, Australia

[11] Hosp Univ Virgen del Rocio, Seville, Spain

[12] Univ Med Ctr Utrecht, Utrecht, Netherlands

[13] Oslo Univ Hosp, Radiumhosp, Oslo, Norway

[14] City Hope Comprehens Canc Ctr, Duarte, CA USA

[15] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ, Canada

[16] McGill Univ, Jewish Gen Hosp, Segal Canc Ctr, Montreal, PQ, Canada

[17] Univ Complutense, Hosp Univ 12 Octubre, H120 CNIO Lung Canc Unit, Madrid, Spain

[18] Ciberonc, Madrid, Spain

[19] Univ Hosp Antwerp, Edegem, Belgium

[20] Grande Osped Metropolitano Niguarda, Haematol & Oncol Div, Milan, Italy

[21] Univ Pisa, Pisa, Italy

[22] Univ Ulsan, Asan Med Ctr, Dept Oncol, Seoul, South Korea

[23] Hosp Univ Fdn Jimenez Diaz, START MADRID FJD, Madrid, Spain

[24] Univ Calif Irvine, Sch Med, Chao Family Comprehens Canc Ctr, Orange, CA USA

[25] IRCCS Ist Romagnolo Studio Tumori IRST Dino Amado, Dept Med Oncol, Meldola, Italy

[26] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[27] Univ Toronto, Dept Med, Toronto, ON, Canada

[28] Univ Toronto, Dept Immunol, Toronto, ON, Canada

[29] Humanitas Univ, Milan, Italy

[30] IRCCS Humanitas Res Hosp, Humanitas Canc Ctr, Milan, Italy

[31] Przychodnia Jozefow, Biokinet, Jozefow, Poland

[32] Warsaw Med Univ, Warsaw, Poland

[33] Stephenson Canc Ctr, Oklahoma City, OK USA

[34] Sarah Cannon Res Inst, Nashville, TN USA

[35] Mem Sloan Kettering Canc Ctr, New York, NY USA

[36] Yale Univ, Yale Canc Ctr, New Haven, CT USA

[37] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA

[38] Sarah Cannon Res Inst, Florida Canc Specialists, Sarasota, FL USA

[39] Genentech Inc, South San Francisco, CA USA

[40] Seoul Natl Univ Hosp, Seoul, South Korea

[41] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea

来源：

NATURE MEDICINE | 2023年 / 30卷 / 1期

关键词：

KRAS G12C; MUTATIONS;

D O I：

10.1038/s41591-023-02696-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

KRAS G12C mutation is prevalent in similar to 4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.

引用

页码：271 / 278

页数：18

共 30 条

[1] American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy
Allegra, Carmen J.
Jessup, J. Milburn
Somerfield, Mark R.
Hamilton, Stanley R.
Hammond, Elizabeth H.
Hayes, Daniel F.
McAllister, Pamela K.
Morton, Roscoe F.
Schilsky, Richard L.
[J]. JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (12) : 2091 - 2096
[2] EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer
Amodio, Vito
Yaeger, Rona
Arcella, Pamela
Cancelliere, Carlotta
Lamba, Simona
Lorenzato, Annalisa
Arena, Sabrina
Montone, Monica
Mussolin, Benedetta
Bian, Yu
Whaley, Adele
Pinnelli, Marika
Murciano-Goroff, Yonina R.
Vakiani, Efsevia
Valeri, Nicola
Liao, Wei-Li
Bhalkikar, Anuja
Thyparambil, Sheeno
Zhao, Hui-Yong
de Stanchina, Elisa
Marsoni, Silvia
Siena, Salvatore
Bertotti, Andrea
Trusolino, Livio
Li, Bob T.
Rosen, Neal
Di Nicolantonio, Federica
Bardelli, Alberto
Misale, Sandra
[J]. CANCER DISCOVERY, 2020, 10 (08) : 1129 - 1139
[3] [Anonymous], 2004, ERBITUX (cetuximab) [package insert]
[4] Acquired Resistance to KRASG12C Inhibition in Cancer
Awad, M. M.
Liu, S.
Rybkin, I. I.
Arbour, K. C.
Dilly, J.
Zhu, V. W.
Johnson, M. L.
Heist, R. S.
Patil, T.
Riely, G. J.
Jacobson, J. O.
Yang, X.
Persky, N. S.
Root, D. E.
Lowder, K. E.
Feng, H.
Zhang, S. S.
Haigis, K. M.
Hung, Y. P.
Sholl, L. M.
Wolpin, B. M.
Wiese, J.
Christiansen, J.
Lee, J.
Schrock, A. B.
Lim, L. P.
Garg, K.
Li, M.
Engstrom, L. D.
Waters, L.
Lawson, J. D.
Olson, P.
Lito, P.
Ou, S. -H. I.
Christensen, J. G.
Janne, P. A.
Aguirre, A. J.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2021, 384 (25) : 2382 - 2393
[5] Bob TL, 2022, J CLIN ONCOL, V40
[6] Sotorasib versus docetaxel for previously treated non-small- cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial
de Langen, Adrianus Johannes
Johnson, Melissa L.
Mazieres, Julien
Dingemans, Anne -Marie C.
Mountzios, Giannis
Pless, Miklos
Wolf, Jurgen
Schuler, Martin
Lena, Herve
Skoulidis, Ferdinandos
Yoneshima, Yasuto
Kim, Sang-We
Linardou, Helena
Novello, Silvia
van der Wekken, Anthonie J.
Chen, Yuanbin
Peters, Solange
Felip, Enriqueta
Solomon, Benjamin J.
Ramalingam, Suresh S.
Dooms, Christophe
Lindsay, Colin R.
Ferreira, Carlos Gil
Blais, Normand
Obiozor, Cynthia C.
Wang, Yang
Mehta, Bhakti
Varrieur, Tracy
Ngarmchamnanrith, Gataree
Stollenwerk, Bjorn
Waterhouse, David
Paz-Ares, Luis
[J]. LANCET, 2023, 401 (10378) : 733 - 746
[7] Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C
Fakih, Marwan G.
Salvatore, Lisa
Esaki, Taito
Modest, Dominik P.
Lopez-Bravo, David P.
Taieb, Julien
Karamouzis, Michalis V.
Ruiz-Garcia, Erika
Kim, Tae-Won
Kuboki, Yasutoshi
Meriggi, Fausto
Cunningham, David
Yeh, Kun-Huei
Chan, Emily
Chao, Joseph
Saportas, Yaneth
Tran, Qui
Cremolini, Chiara
Pietrantonio, Filippo
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2023, 389 (23) : 2125 - 2139
[8] Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial
Fakih, Marwan G.
Kopetz, Scott
Kuboki, Yasutoshi
Kim, Tae Won
Munster, Pamela N.
Krauss, John C.
Falchook, Gerald S.
Han, Sae-Won
Heinemann, Volker
Muro, Kei
Strickler, John H.
Hong, David S.
Denlinger, Crystal S.
Girotto, Gustavo
Lee, Myung-Ah
Henary, Haby
Tran, Qui
Park, Joseph K.
Ngarmchamnanrith, Gataree
Prenen, Hans
Price, Timothy J.
[J]. LANCET ONCOLOGY, 2022, 23 (01) : 115 - 124
[9] Comprehensive Clinical and Molecular Characterization of KRASG12C-Mutant Colorectal Cancer
Henry, Jason T.
Coker, Oluwadara
Chowdhury, Saikat
Shen, John Paul
Morris, Van K.
Dasari, Arvind
Raghav, Kanwal
Nusrat, Maliha
Kee, Bryan
Parseghian, Christine
Pant, Shubham
Jeyakumar, Nikeshan
Zhu, Limin
Nishioka, Yujiro
Fogelman, David
Wolff, Robert A.
Hong, David
Overman, Michael J.
Vauthey, JeanNicolas
Kopetz, Scott
Johnson, Benny
[J]. JCO PRECISION ONCOLOGY, 2021, 5 : 613 - 621
[10] Biomarkers of acquired resistance to sotorasib (soto) plus panitumumab (pani) in chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC)
Hong, David S.
Kuboki, Yasutoshi
Yaeger, Rona
Strickler, John H.
Masuishi, Toshiki
Langer, Corey
Shergill, Ardaman
Kim, Edward
Hindoyan, Antreas
Tran, Qui
Mukundan, Lata
Chan, Emily
Anderson, Abraham
Fakih, Marwan G.
[J]. CANCER RESEARCH, 2023, 83 (07)

← 1 2 3 →