KRYSTAL-12 Trial

[Slide 1] IS umori, ron Squibb Institute Milan, company, of Italy; Oncology, San "Airway Diego, Research CA, USA; Center 20Gustave North, Roussy German & Paris Center Saclay for Lung University, Villejuif, France ASCO UAL MEETING ASCO ASCO AS ASCO --- [Slide 2] 2024 ASCO ANNUAL MEETING KRYSTAL-12: phase 3 study of adagrasib versus docetaxel in patients with previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation Tony S. K. Mok, 1 Wenxiu Yao, 2 Michaël Duruisseaux, 3-5 Ludovic Doucet, 6 Aitor Azkárate Martínez,⁷ Vanesa Gregorc, 8 Oscar Juan-Vidal, 9 Shun Lu, 10 Charlotte De Bondt, 11 Filippo de Marinis, 12 Helena Linardou, 13 Young-Chul Kim, 14 Robert Jotte, 15 Enriqueta Felip, 16 Giuseppe Lo Russo, 17 Martin Reck, 18 Mary F. Michenzie, 19 Wenjing Yang, 19 Julie N. Meade, 19a Fabrice Barlesi²⁰ 'Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Sichuan Cancer Hospital & Institute, Chengdu, China; Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Lyon, France; "Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France; Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France; ⁶Institut de Cancérologie de l'Ouest, Nantes, France; Hospital Universitario Son Espases, Mallorca, Spain; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; Hospital Universitari i Politècnic La Fe, Valencia, Spain; 10Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; "Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; 12Istituto Europeo di Oncologia, IRCCS, Milan, Italy; ¹Fourth Oncology Department & Comprehensive Clinical Trials Center, Metropolitan Hospital, Athens, Greece; 14Chonnam National University Medical School and CNU Hwasun Hospital, Hwasun-Gun, Republic of Korea; 15Rocky Mountain Cancer Center, US Oncology Research, Denver, CO, USA; 16Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain; ¹⁷Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 18Airway Research Center North, German Center for Lung Research, LungenClinic, Grosshansdorf, Germany; 19Mirati Therapeutics, a Bristol Myers Squibb company, San Diego, CA, USA; 20Gustave Roussy & Paris Saclay University, Villejuif, France Affiliation at the time of study Abstract number LBA8509 --- [Slide 3] KRYSTAL-12: ADA in previously treated KRASG12C NSCLC Key takeaways In the phase 3 KRYSTAL-12 trial, adagrasib (ADA) demonstrated a statistically significant and clinically meaningful improvement in PFS over docetaxel (DOCE) in patients with previously treated KRASG12C-mutated NSCLC - PFS benefit was observed across key subgroups ORR was also significantly higher with ADA vs DOCE; overall, the responses were deep and appear to be durable ADA showed intracranial efficacy among patients with brain metastases at baseline, with a response rate that was more than double that observed with DOCE The safety profiles of ADA and DOCE were consistent with previous reports, with no new safety signals --- [Slide 4] KRYSTAL-12: ADA in previously treated KRASG12C NSCLC KRYSTAL-12ᵃ study design Key eligibility criteria Locally advanced or metastatic NSCLC N = 453 ADA 600 mg BID POd with KRASG¹²ᶜ mutationᵇ R Prior treatment with platinum-based 2:1 chemotherapy and anti-PD-(L)1 therapy ECOG PS 0-1 DOCE 75 mg/m² Q3W IV Stable brain metastases allowed Stratified by: Crossover from DOCE to ADA was allowed in cases where disease Region (non-Asia-Pacific vs Asia-Pacific) progression per RECIST v1.1 was confirmed by real-time BICR Prior treatment (sequential vs concurrent chemotherapy and immunotherapy) Primary endpoint Secondary endpoints PFS by BICR (RECIST v1.1) ORR by BICR (RECIST v1.1) Safety DOR Patient-reported OS outcomes Database lock: March 19, 2024. Data cut-off: December 31, 2023. NCT04685135. Detected in tumor tissue using sponsor-approved local or central testing. No washout period was required between prior therapy and study treatment. Tablet formulation, except for four patients who initially received the capsule formulation. "Other crossover criteria: ECOG PS 0-2, recovery from DOCE-related AEs to grade 1 or baseline (except peripheral neuropathy and alopecia for which grade 2 is acceptable).

[Slide 1] KRYSTAL-12: ADA in previously treated KRASGIZC NSCLC KRYSTAL-12ᵃ study design Key eligibility criteria Locally advanced or metastatic NSCLC N = 453 ADA 600 mg BID POd with KRASG12C mutationᵇ R Prior treatment with platinum-based 2:1 chemotherapy and anti-PD-(L)1 therapy< ECOG PS 0-1 DOCE 75 mg/m² Q3W IV Stable brain metastases allowed Stratified by: Crossover from DOCE to ADA was allowed in cases where disease Region (non-Asia-Pacific vs Asia-Pacific) progression per RECIST v1.1 was confirmed by real-time BICR* Prior treatment (sequential vs concurrent chemotherapy and immunotherapy) Primary endpoint Secondary endpoints PFS by BICR (RECIST v1.1) ORR by BICR (RECIST v1.1) Safety DOR Patient-reported os outcomes Database lock: March 19, 2024. Data cut-off: December 31, 2023. NCT04685135. Detected in tumor tissue using sponsor-approved local or central testing. No washout period was required between prior therapy and study treatment. Tablet formulation, except for four patients who initially received the capsule formulation. "Other crossover criteria: ECOG PS 0-2, recovery from DOCE-related AEs to grade 1 or baseline (except peripheral neuropathy and alopecia for which grade 2 is acceptable). --- [Slide 2] KRYSTAL-12: ADA in previously treated KRASC12C NSCLC Primary endpoint: PFSa per BICR ADA DOCE 100 (n = 301) (n = 152) Events, n (%) 164 (55) 93 (61) 80 Median PFS, mo 5.5 3.8 (95% CI) (4.5-6.7) (2.7-4.7) 60 HR (95% CI) 0.58 (0.45-0.76) PFS (%) 45% Pvalue < 0.0001 40 30% 20 DOCE ADA 0 0 3 6 9 12 15 18 21 24 27 30 Months from randomization No. at risk ADA 301 160 77 41 19 8 5 1 0 0 0 DOCE 152 51 24 9 2 0 0 0 0 0 0 Median follow-up: 7.2 months. "Time from randomization to the date of disease progression per BICR or death due to any cause, whichever occurs first. For patients who started a subsequent anticancer therapy prior to disease progression or death, PFS was censored at the date of the last tumor assessment prior to the start of the new therapy. --- [Slide 3] KRYSTAL-12: ADA in previously treated KRASG12C NSCLC PFS subgroup analysis per BICR Median PFS, mo ADA DOCE Unstratified HR (95% CI) Unstratified HR (n = 301) (n = 152) Overall (N = 453) 5.5 3.8 0.58 < 65 years (n a 234) 5.4 2.9 0.56 > 65 years (n a 219) 5.9 4.2 0.60 Male (n = 303) 5.4 2.9 0.55 Female (n = 150) 5.6 5.6 0.64 Non-Asia-Pacific (n = 335) 5.7 3.4 0.55 Asia-Pacific (n = 118) 5.4 3.9 0.66 ECOG PS 0 (n = 143) 11.1 5.8 0.44 ECOG PS 1 (n = 309) 4.6 2.8 0.61 Current smoker (n = 86) 4.2 4.4 0.89 Former smoker (n = 340) 5.8 3.6 0.51 Never smoker (n = 26) 5.5 6.2 0.70 Brain metastases at baseline (n = 80)ᵃ 4.1 4.2 0.71 No brain metastases at baseline (n = 373)* 5.8 3.6 0.55 Liver metastases at baseline (n # 64)ᵃ 4.5 1.4 0.43 No liver metastases at baseline (n = 389)ᵃ 5.6 4.2 0.59 Bone metastases at baseline (n = 107)a 4.4 2.8 0.56 No bone metastases at baseline (n = 346)a 5.8 4.2 0.58 PD-L1 < 1% (n = 95) 5.8 2.8 0.44 PD-L1 1-49% (n = 195) 5.9 3.6 0.56 PD-L1 ≥ 50% (n = 100) 5.0 3.9 0.62 Sequential chemo-immunotherapy (n = 121) 5.8 2.9 0.53 Concurrent chemo-immunotherapy (n = 332) 5.4 3.9 0.60 0.1 0.5 1 2 4 Favors ADA Favors DOCE Median follow-up: 7.2 months. Bold text indicates stratification factors. In accordance with RECIST v1.1 per BICR. --- [Slide 4] KRYSTAL-12: ADA in previously treated KRASG12C NSCLC Tumor response per BICR 50 Odds Ratio, 4.68 (95% CI, 2.56-8.56) 100 ADA (n = 256)ᵈ P< < 0.0001 80 40 60 32 20 ORRᵃ (%) 30 20 Change from baseline in sum of diameters (%) 40 0 -20 -40 -60 10 9 -80 Confirmed BOR -100 CR PR 0 100 SD DOCE (n = 120)ᵈ ADA DOCE PD 80 NE n/N: 96/301 14/152 60 ADA DOCE Tumor response (n = 301) (n = 152) DCR,ᵇ n (%) 236 (78) 89 (59) Median DOR,ᶜ mo 8.3 5.4 (2.9-8.5) Change from baseline in sum of diameters (%) 40 20 0 -20 -40 (95% CI) (6.1-10.4) -60 Remaining in response 64 39 -80 at 6 mo, % -100 ORR is defined as the percent of patients documented to have a confirmed CR/PR by BICR (per RECIST v1.1). Disease control rate (DCR) is defined as the percent of patients documented to have a confirmed CR/PR/SD by BICR (per RECIST v1.1). DOR is defined as the time from the date of first documentation of CR/PR to the first documentation of PD or death due to any cause in the absence of documented PD. DOR is only calculated for patients with confirmed CR/PR. Waterfall plots include patients with at least one target lesion at baseline and at least one post-baseline tumor assessment.

[Slide 1] ASCO "KRYSTAL-12 confirmed the efficacy of adagrasib as second-line therapy for patients with KRASG12C mutations, with evidence of higher tumor response rates and longer PFS over current standard care." Tony S.K. Mok, MD, FASCO The Chinese University of Hong Kong

[Slide 1] KRYSTAL-12: ADA in previously treated KRAS NSCLC KRYSTAL- - 12ª study design Key eligibility criteria Locally advanced or metastatic NSCLC N 453 ADA 600 mg BID with KRASG12C mutationb R Prior treatment with platinum-based 2: 1 chemotherapy and anti-PD-(L)1 therapy ECOG PS 0-1 DOCE 75 mg/m2 Q3W IV Stable brain metastases allowed Stratified by: Crossover from DOCE to ADA was allowed in cases where disease Region (non-Asia-Pacific vs Asia-Pacific) progression per RECIST v1.1 was confirmed by real-time BICR* Prior treatment (sequential vs concurrent chemotherapy and immunotherapy) Primary endpoint Secondary endpoints PFS by BICR (RECIST v1.1) ORR by BICR (RECIST v1.1) Safety DOR Patient-reported os outcomes Database lock: March 19. 2024. Data cut-off: December 31, 2023. *NCT04685135 Detected in tumor tissue using sponsor-approved local or central testing. No washout period was required between prior therapy and study treatment. Tablet formulation, except for four patients who initially received the capsule formulation. Other crossover criteria: ECOG PS 0-2, recovery from DOCE-related AEs to grade 1 or baseline (except peripheral neuropathy and alopecia for which grade 2 is acceptable). 2024 AS --- [Slide 2] KRYSTAL-12 ADA in previously treated KRASG120 NSCLC Summary In the phase 3 KRYSTAL-12 trial, ADA demonstrated a statistically significant and clinically meaningful improvement in PFS over DOCE in patients with previously treated KRAS612C-mutated NSCLC (median PFS, 5.5 vs 3.8 mo, respectively; HR, 0.58; P < 0.0001) - PFS benefit was observed across key subgroups ORR was also significantly higher with ADA vs DOCE (32% vs 9%; odds ratio, 4.68; P < 0.0001); overall, the responses were deep and appear to be durable ADA showed intracranial efficacy among patients with brain metastases at baseline, with a response rate that was more than double that observed with DOCE (intracranial ORR, 24% vs 11%) The safety profiles of ADA and DOCE were consistent with previous reports, with no new safety signals These results reinforce ADA as an efficacious treatment option for patients with KRASG12C-mutated NSCLC after disease progression on prior chemotherapy and immunotherapy A phase 3 trial comparing first-line ADA plus pembrolizumab vs pembrolizumab alone is currently enrolling patients with advanced KRASG12C-mutated NSCLC and PD-L1 TPS 50% (KRYSTAL-7; NCT04613596) Copies through Quick and may 2024 ASCO AAINIIAL AACCTINIC

[Slide 1] KRYSTAL-12: ADA in previously treated KRASG12C NSCLC KRYSTAL-12ᵃ study design Key eligibility criteria Locally advanced or metastatic NSCLC ADA 600 mg BID POd N = 453 with KRASG12C mutationᵇ R Prior treatment with platinum-based 2:1 chemotherapy and anti-PD-(L)1 therapy ECOG PS 0-1 DOCE 75 mg/m² Q3W IV Stable brain metastases allowed Stratified by: Crossover from DOCE to ADA was allowed in cases where disease Region (non-Asia-Pacific vs Asia-Pacific) progression per RECIST v1.1 was confirmed by real-time BICR Prior treatment (sequential vs concurrent chemotherapy and immunotherapy) Primary endpoint Secondary endpoints PFS by BICR (RECIST v1.1) ORR by BICR (RECIST v1.1) Safety DOR Patient-reported os outcomes Database lock: March 19, 2024. Data cut-off: December 31, 2023. NCT04685135. Detected in tumor tissue using sponsor-approved local or central testing. No washout period was required between prior therapy and study treatment. Tablet formulation, except for four patients who initially received the capsule formulation. "Other crossover criteria: ECOG PS 0-2, recovery from DOCE-related AEs to grade 1 or baseline (except peripheral neuropathy and alopecia for which grade 2 is acceptable). --- [Slide 2] KRYSTAL-12: ADA in previously treated KRASG12C NSCLC Summary In the phase 3 KRYSTAL-12 trial, ADA demonstrated a statistically significant and clinically meaningful improvement in PFS over DOCE in patients with previously treated KRASG¹²ᶜ-mutated NSCLC (median PFS, 5.5 vs 3.8 mo, respectively; HR, 0.58; P < 0.0001) — PFS benefit was observed across key subgroups ORR was also significantly higher with ADA VS DOCE (32% VS 9%; odds ratio, 4.68; P < 0.0001); overall, the responses were deep and appear to be durable ADA showed intracranial efficacy among patients with brain metastases at baseline, with a response rate that was more than double that observed with DOCE (intracranial ORR, 24% VS 11%) The safety profiles of ADA and DOCE were consistent with previous reports, with no new safety signals These results reinforce ADA as an efficacious treatment option for patients with KRASG¹²ᶜ-mutated NSCLC after disease progression on prior chemotherapy and immunotherapy Copies of this slide deck obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO or the author of this slide deck.

[Slide 1] KRYSTAL-12: ADA in previously treated KRASG NSCLC Lay summary Why is this study important? Who took part in the study and what treatments were used? A specific change (mutation) in the KRAS gene, KRASG¹²ᶜ, is one of the most common mutations that can lead to the 301 people in the The study included 152 people in the development of non-small cell lung cancer (NSCLC) ADA group 453 people from DOCE group (taken as tablets There are limited fully approved treatment options, other 22 countries (given into a vein 2 times a day) every 3 weeks) than chemotherapy, for people with metastatic NSCLC (cancer that has spread to other parts of the body or that comes back) and a KRAS mutation What did the researchers look at? Adagrasib (ADA) is a drug that specifically targets KRASG Primary assessment Additional assessments (the mutated KRAS protein) to suppress tumor growth Progression-free survival (PFS): Objective response rate (ORR): The main goal of this study was to find out if ADA worked how long did each person live how many people had tumors better than the standard chemotherapy drug docetaxel without the cancer getting worse (DOCE) when given to people with metastatic NSCLC and a partly or completely shrink? KRAS mutation after chemotherapy and immunotherapy after being assigned treatment? What side effects did people have? What were the main results of the study? PFS Tumor shrinkage (ORR) Overall tumor shrinkage in the brain What do these People who took ADA lived longer More than 3x as many people who For people whose cancer had spread to the results mean? without their cancer getting worse took ADA had tumors shrink than brain, these brain tumors shrank in more than than those who took DOCE those who took DOCE 2x as many people who took ADA Overall, these results Median PFS (number of months half of the people lived without the cancer support the use of getting worse or spreading) 32% 9% 24% 11% ADA over DOCE in ADA previously treated 5.5 months ADA DOCE ADA DOCE people with metastatic NSCLC and a KRASG12C DOCE Side effects for both treatments were similar to those seen previously mutation 3.8 months with these drugs, and no new side effects were reported