calderasib (MK-1084) / Merck (MSD), Otsuka - LARVOL DELTA

The KRAS G12C inhibitor MK-1084 for KRAS G12C–mutated advanced colorectal cancer (CRC): Results from KANDLELIT-001. (ASCO 2025) - P1 | "Preliminary data suggest that MK-1084 monotherapy, MK-1084 + cetuximab, and MK-1084 + cetuximab + mFOLFOX6 have manageable safety profiles and show evidence of antitumor activity in pts with advanced, KRAS G12C-mutated CRC. Pts continue to be followed, and enrollment continues."

Metastases • Colorectal Cancer • Dermatitis • Dermatology • Febrile Neutropenia • Immunology • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

MK-1084 monotherapy in participants (Pts) with KRAS G12C–mutated advanced solid tumors: Activity and safety in the phase I KANDLELIT-001 study (ESMO 2025) - P1 | "Enrollment is ongoing. Table: 926MO CRC NSCLC PDAC HBC Various Total Sample size 53 21 15 8 15 112 ORR 38% (95% CI; 24.8–52.1) 38% (95% CI; 18.1–61.6) 27% (95% CI; 7.8–55.1) 75% (95% CI; 34.9–96.8) 20% (95% CI; 4.3–48.1) 37% (95% CI; 27.7–46.2) DCR 83% (95% CI; 70.2–91.9) 76% (95% CI; 52.8–91.8) 47% (95% CI; 21.3–73.4) 88% (95% CI; 47.3–99.7) 80% (95% CI; 51.9–95.7) 77% (95% CI; 67.9–84.2) CRC, colorectal cancer; HBC, hepatobiliary cancer; NSCLC, non–small cell lung cancer; PDAC, Pancreatic ductal adenocarcinoma."

Clinical • Metastases • Monotherapy • P1 data • Biliary Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Direct Amidation of Tertiary N-Benzylamines. (PubMed, Org Lett) - "The chemistry reported herein achieves this goal by enabling the direct amidation of tertiary N-benzylamines under mild conditions, yielding medicinally important acrylamides as well as a variety of other amides with high yields and broad functional group tolerance. The method is easily implemented and we showcase its utility in the endgame synthesis of sensitive acrylamide Active Pharmaceutical Ingredients (APIs), including the KRASG12C inhibitor MK-1084."

Journal • KRAS

A Clinical Study of MK-1084 With Rosuvastatin and Metformin in Healthy People (MK-1084-016) (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion

Asymmetric Synthesis of KRAS G12C Inhibitor MK-1084 via a Crystallization-Induced Diastereomer Transformation (CIDT). (PubMed, Org Lett) - "Herein, we report an efficient synthetic approach to manufacture MK-1084 to enable clinical trials. By leveraging the in-depth understanding of the inherent properties of axial chirality, we discovered and developed a one-pot crystallization-induced diastereomer transformation (CIDT)/carbonylation process to establish the unique and challenging macrocyclic core with double axial chiral centers from a racemic advanced precursor and readily available raw materials."

Journal • KRAS

KANDLELIT-012: Phase 3 study of MK-1084 (a KRAS G12C inhibitor) plus cetuximab and mFOLFOX6 with or without bevacizumab for KRAS G12C-mutant colorectal cancer. (ASCO-GI 2026) - P3 | "In Part 1, 15 participants will receive MK-1084 PO plus cetuximab 500 mg IV Q2W and mFOLFOX6 Q2W (oxaliplatin: 85 mg/m2 IV; leucovorin: 400 mg/m2 IV; 5-fluorouracil: 400 mg/m2 bolus on day 1, then 1200 mg/m2/day for 2 days IV). Secondary end points include objective response rate and duration of response per RECIST v1.1 by BICR, overall survival, and safety. This study is currently enrolling."

P3 data • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS • MSI

KEYMAKER-U01 Substudy 01J: A Study of Pembrolizumab Plus MK-1084 in Participants With Non-Small Cell Lung Cancer (NSCLC) With Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) G12C Mutations (MK-3475-01J/KEYMAKER-U01J) (clinicaltrials.gov) - P2 | N=130 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

Merck Initiates Phase 3 KANDLELIT-007 Trial Evaluating Calderasib (MK-1084), an Investigational Oral KRAS G12C Inhibitor, in Combination With KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph) in Certain Patients With Advanced NSCLC (Merck (MSD) Press Release) - "This randomized, unblinded open-label, multicenter clinical trial (NCT07190248) will evaluate calderasib given orally once daily in combination with KEYTRUDA QLEX administered subcutaneously, compared with subcutaneous KEYTRUDA QLEX in combination with intravenous pemetrexed and chemotherapy (carboplatin or cisplatin), in newly diagnosed patients with KRAS G12C-mutant advanced or metastatic nonsquamous NSCLC....The trial will enroll approximately 675 patients globally."

Trial status • Lung Non-Squamous Non-Small Cell Cancer

A Clinical Study of MK-1084 With Other Treatments for Non-small Cell Lung Cancer (MK-3475-01F) (clinicaltrials.gov) - P1/2 | N=190 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Oct 2031 ➔ Jul 2036

Trial completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Clinical Study of MK-1084 With Targeted Therapy and Chemotherapy in People With Colorectal Cancer (MK-1084-012/KANDLELIT-012) (clinicaltrials.gov) - P3 | N=477 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial primary completion date: Aug 2029 ➔ Mar 2029

Trial primary completion date • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • KRAS

A Clinical Study of MK-1084 With Other Treatments for Non-small Cell Lung Cancer (MK-3475-01F) (clinicaltrials.gov) - P1/2 | N=190 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1/2 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

KANDLELIT-014: A Clinical Study of MK-1084 in People With Advanced Solid Tumors (MK-1084-014) (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • Pan tumor • Oncology • Solid Tumor • KRAS

A Study of MK-1084 in Participants With Hepatic Impairment and Healthy Volunteers (MK-1084-017) (clinicaltrials.gov) - P1 | N=58 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

KEYMAKER-U01 Substudy 01J: A Study of Pembrolizumab Plus MK-1084 in Participants With Non-Small Cell Lung Cancer (NSCLC) With Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) G12C Mutations (MK-3475-01J/KEYMAKER-U01J) (clinicaltrials.gov) - P2 | N=130 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P2 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor

MK-1084 for KRAS G12C-mutated advanced colorectal cancer (CRC): Updated findings from KANDLELIT-001 (ESMO Asia 2025) - P1 | "In arm 6, pts with advanced CRC and 0-1 prior systemic therapies received MK-1084 (total daily dose 25-100 mg) plus cetuximab 500 mg/m2 Q2W and mFOLFOX6... Updated data continue to show manageable safety profiles and evidence of antitumor activity for MK-1084–based regimens in pts with advanced, KRAS G12C-mutated CRC. The phase 3 KANDLELIT-012 study is evaluating MK-1084 + cetuximab + mFOLFOX as first-line therapy for KRAS G12C-mut advanced CRC."

Metastases • Colorectal Cancer • Oncology • Solid Tumor • KRAS

A Clinical Study of MK-1084 With Rosuvastatin and Metformin in Healthy People (MK-1084-016) (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed

A Clinical Study of MK-1084 With Rosuvastatin and Metformin in Healthy People (MK-1084-016) (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open

A Clinical Study of MK-1084 and Other Treatments for Participants With Non-Small Cell Lung Cancer (MK-1084-007/KANDLELIT-007) (clinicaltrials.gov) - P3 | N=675 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

A Clinical Study of MK-1084 With Rosuvastatin and Metformin in Healthy People (MK-1084-016) (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

A Study of MK-1084 in Participants With Hepatic Impairment and Healthy Volunteers (MK-1084-017) (clinicaltrials.gov) - P1 | N=58 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial • Hepatology

A Study to Evaluate the Effect of Formulation and Food on MK-1084 in Healthy Adult Participants (MK-1084-011) (clinicaltrials.gov) - P1 | N=52 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion

KANDLELIT-014: A Clinical Study of MK-1084 in People With Advanced Solid Tumors (MK-1084-014) (clinicaltrials.gov) - P2 | N=150 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

Monotherapy • New P2 trial • Pan tumor • Oncology • Solid Tumor • KRAS

A Clinical Study of MK-1084 and Other Treatments for Participants With Non-Small Cell Lung Cancer (MK-1084-007/KANDLELIT-007) (clinicaltrials.gov) - P3 | N=675 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P3 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

A Clinical Study of MK-1084 With Targeted Therapy and Chemotherapy in People With Colorectal Cancer (MK-1084-012/KANDLELIT-012) (clinicaltrials.gov) - P3 | N=477 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • KRAS

A Clinical Study of MK-1084 With Targeted Therapy and Chemotherapy in People With Colorectal Cancer (MK-1084-012/KANDLELIT-012) (clinicaltrials.gov) - P3 | N=477 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jun 2031 ➔ Oct 2030

Trial completion date • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • KRAS