A Phase III, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Patients With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

The purpose of this study is to evaluate the efficacy and safety of divarasib and pembrolizumab compared with pembrolizumab and pemetrexed and carboplatin or cisplatin, for the first-line treatment of adult participants with KRAS G12C-mutated, advanced or metastatic non squamous non-small cell lung cancer (NSCLC).

Start Date01 Dec 2025

Sponsor / Collaborator

Chugai Pharmaceutical Co., Ltd.

NCT06835465

/ CompletedPhase 1

A Phase 1, Open-Label, Single-Dose, Two-Period, Fixed Sequence, Crossover Study to Determine the Effect of Rifampin on the Pharmacokinetics of Divarasib in Healthy Subjects

This is a phase 1, open-label, two-period, fixed sequence drug-drug interaction study to evaluate the impact of multiple doses of rifampin on the pharmacokinetics (PK) and safety of divarasib in healthy participants.

Start Date21 Feb 2025

Sponsor / Collaborator

Genentech, Inc.

NCT06734208

/ RecruitingPhase 1

A Phase 1, Open-Label, Single-Dose, Parallel-Cohort Study to Evaluate the Pharmacokinetics of Divarasib in Subjects With Impaired Hepatic Function

This is a phase 1, open-label, single-dose, parallel-cohort study to determine the pharmacokinetics (PK) of divarasib in healthy participants and participants with varying degrees of hepatic impairment, as defined by Child-Pugh classification.

Start Date31 Jan 2025

Sponsor / Collaborator

Genentech, Inc.

100 Clinical Results associated with Divarasib

100 Translational Medicine associated with Divarasib

100 Patents (Medical) associated with Divarasib

Literatures (Medical) associated with Divarasib

01 Jul 2025·CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY

KRAS G12C inhibitors as monotherapy or in combination for metastatic colorectal cancer: A proportion and comparative meta-analysis of efficacy and toxicity from phase I-II-III trials

Review

Author: Öksüz, Nejat Emre ; Akkus, Erman ; Erul, Enes

BACKGROUND:

1-2 % of metastatic colorectal cancers (mCRC) harbor an activating KRAS-G12C mutation. This study aims to pool the results of available clinical trials of KRAS-G12C inhibitors, comparing monotherapy and combinations.

METHODS:

A systematic literature search was conducted in the MEDLINE database and ESMO/ASCO meeting abstracts. Phase I-II-III trials that investigated a KRAS-G12C inhibitor in patients with mCRC were included. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Pooled proportions and comparative subgroup analyses for monotherapy and combinations were presented with the random effects model.

RESULTS:

596 patients with previously treated mCRC in 14 study cohorts treated with one of sotorasib, adagrasib, divarasib, or olomorasib as monotherapy or in combination with cetuximab/panitumumab were included. Combination treatment revealed an ORR of 33.9 % (95 %CI: 20.7-48.4) (I²: 87.1), which is significantly higher than monotherapy [16.7 %, (95 %CI: 8.3-27.3) (I²: 73.2)] (p = 0.045). Median PFS was significantly longer with the combination [5.7 months (95 %CI: 4.4-7.1) (I²: 80.8) vs. 4.2 months (95 %CI: 3.6-4.7) (I²:0.0), p = 0.027]. Grade 3-4 treatment-related adverse events (TRAEs) were significantly more frequent with the combination [32.8 % (95 %CI: 26.4-39.6) (I²:42.5) vs.16.5 % (95 %CI: 4.9-33.1) (I²: 84.2), p = 0.047]. Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.

CONCLUSION:

This analysis suggests that KRAS-G12C inhibitors in combination with anti-EGFR agents may provide a doubled ORR and 1.5-month PFS benefit compared to monotherapy in previously treated mCRC patients, but with a doubled grade 3-4 TRAEs, including skin toxicities, paronychia, and hypomagnesemia. Treatment preferences should be individualized in these highly pretreated patients.

27 Mar 2025·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers

Article

Author: Liu, Yang ; Jiang, Jingjing ; Ling, Yun ; Wang, Zhengping ; Marquez, Abby ; Knox, John E. ; Flagella, Michael ; Zhao, Ruiping ; Pota, Kristof ; Yang, Yu Chi ; Schulze, Christopher J. ; Cregg, James ; Wang, Zhican ; Smith, Jacqueline A. M. ; Singh, Mallika ; Nichols, Robert ; Tomlinson, Aidan C. A. ; Yano, Jason ; Koltun, Elena S. ; Seamon, Kyle J. ; Huang, Yue ; Gill, Adrian L. ; Holderfield, Matthew ; Wildes, David ; Zhuang, Yongxian ; Wei, Xing

The discovery of elironrasib (RMC-6291) represents a significant breakthrough in targeting the previously deemed undruggable GTP-bound, active KRAS^G12C. To target the active state of RAS (RAS(ON)) directly, we have employed an innovative tri-complex inhibitor (TCI) modality involving formation of a complex with an inhibitor, the intracellular chaperone protein CypA, and the target protein KRAS^G12C in its GTP-bound form. The resulting tri-complex inhibits oncogenic signaling, inducing tumor regressions across various preclinical models of KRAS^G12C mutant human cancers. Here we report structure-guided medicinal chemistry efforts that led to the discovery of elironrasib, a potent, orally bioavailable, RAS(ON) G12C-selective, covalent, tri-complex inhibitor. The investigational agent elironrasib is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), with preliminary data indicating clinical activity in patients who had progressed on first-generation inactive state-selective KRAS^G12C inhibitors.

01 Feb 2025·DRUG METABOLISM AND DISPOSITION

In vitro metabolism of targeted covalent inhibitors and their thiol conjugates by gut microbiome from rats, mice, and humans

Article

Author: Torres, Elizabeth ; Zhang, Donglu ; Auster, Alexis ; Cai, Jingwei ; Wang, Shuai ; Khojasteh, S Cyrus ; Gu, Ting-Jia

Targeted covalent inhibitor (TCI) represents a noncanonical class of small molecules that function via "inactivating" the target protein through the formation of drug-protein adducts. The electrophilic groups (warheads) embedded in the TCIs are essential for their activity while also being recognized as sites susceptible to metabolism by various enzymes and endogenous nucleophiles. Given the growing knowledge of gut microbiome-mediated drug metabolism and its impact on drug absorption, distribution, metabolism, and excretion, the fate of the reactive warhead-containing TCIs in the gut warrants further understanding. In this study, we selected unsubstituted terminal acrylamides (ibrutinib, sotorasib, and divarasib), β-substituted acrylamides (afatinib, neratinib, and dacomitinib), an α-substituted acrylamide (adagrasib), an alkynamide (acalabrutinib), and a salicylaldehyde (voxelotor) to investigate. An anaerobic in vitro approach was utilized using both fecal slurry and feces-outgrown bacteria from rats, mice, and humans. The results showed that double bond reduction was the major metabolism captured for terminal acrylamides, but the activity decreases significantly when α or β substitutions are present; acalabrutinib was stable; and voxelotor was efficiently reduced to a benzyl alcohol metabolite. Synthesized TCI-GSH adducts can be efficiently hydrolyzed sequentially to cysteine adducts, which are rather stable from further microbiome modifications. There were no apparent species differences between rats, mice, and humans qualitatively, while the reductase activity observed was generally higher in the human gut microbiome. This study provides insights into both enzymatic and nonenzymatic reactions of TCIs and their thiol conjugates in the gut environment, which can be translated to the understanding of their absorption, distribution, metabolism, and excretion behavior during drug development. SIGNIFICANCE STATEMENT: Understanding the gut microbiome metabolism of targeted covalent inhibitors and their thiol conjugates will help interpret absorption, distribution, metabolism, and excretion studies for new targeted covalent inhibitors in delineating that from human metabolism, predicting clearance pathways, and assessing the impact on absorption/reabsorption. The species difference information can inform proper preclinical species for better human translation in overall drug behavior. The experimental conditions developed from this work can also be adapted to study gut microbiome metabolism in general across different species.

News (Medical) associated with Divarasib

06 Mar 2025

·www.prnewswire.com

TEPMETKO Continues to Strengthens its Position as a Leading METex14 Skipping NSCLC Therapy | DelveInsight

With increasing biomarker-driven cancer treatments, TEPMETKO benefits from growing adoption in precision oncology. Competition from other MET inhibitors like TABRECTA (capmatinib) exists, but TEPMETKO's once-daily dosing and efficacy profile offer differentiation. LAS VEGAS, March 6, 2025 /PRNewswire/ -- DelveInsight's " TEPMETKO Market Size, Forecast, and Market Insight Report" highlights the details around TEPMETKO, a kinase inhibitor indicated for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. The report provides product descriptions, patent details, and competitor products (marketed and emerging therapies) of TEPMETKO. The report also highlights the historical and forecasted sales from 2020 to 2034 segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. EMD Serono's TEPMETKO (tepotinib) Overview TEPMETKO is a kinase inhibitor prescribed for adult patients with metastatic non-small cell lung cancer (NSCLC) carrying MET exon 14 skipping alterations. The active component is Tepotinib (as hydrochloride monohydrate), administered orally. Patients should be cautioned about the heightened risk of severe or fatal interstitial lung disease/pneumonitis, liver toxicity, and potential embryo-fetal toxicity, necessitating effective contraception during and shortly after treatment. Tepotinib specifically targets MET, including variants with exon 14 skipping mutations. It blocks HGF-dependent and independent MET phosphorylation, disrupting MET-driven signaling pathways. Additionally, at clinically relevant concentrations, Tepotinib inhibits melatonin 2 and imidazoline 1 receptors. In vitro studies show that it suppresses tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent cancer cells. In mouse models with MET-driven tumors, including those with MET exon 14 skipping alterations, Tepotinib reduced tumor growth, sustained MET phosphorylation inhibition, and, in one case, decreased metastasis formation. The recommended dose of TEPMETKO is 450 mg taken orally once daily until disease progression or intolerable toxicity occurs. Patients should take it at the same time each day, swallowing tablets whole without chewing, crushing, or splitting them. If a dose is missed and less than eight hours remain until the next scheduled dose, patients should skip it. In cases of vomiting after taking TEPMETKO, the next dose should be taken at the usual time. Learn more about TEPMETKO projected market size for NSCLC @ TEPMETKO Market Potential Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 81% of all diagnosed cases. Early detection greatly improves outcomes, but diagnosing NSCLC and other lung cancers is challenging because their symptoms are often mistaken for common illnesses or the long-term effects of smoking. Consequently, 80% of NSCLC cases are already at advanced stages by the time they are identified, making treatment more difficult. Around 80% of EGFR mutations in NSCLC involve either exon 19 deletions or the exon 21 L858R substitution, both of which are classified as sensitizing mutations. Until the last decade, chemotherapy was the primary treatment for advanced and metastatic lung cancer. However, this changed in 2015 with the approval of the first immune checkpoint inhibitor (ICI), KEYTRUDA (pembrolizumab), as a second-line therapy for advanced cases. This was followed by TECENTRIQ (atezolizumab) in 2016. Both therapies were later approved for first-line treatment, broadening their use to a larger patient population. In 2020, the combination of OPDIVO (nivolumab) and ipilimumab also received approval as a first-line treatment for metastatic NSCLC. According to DelveInsight, the NSCLC market size across the 7MM is projected to grow from USD 30 billion in 2024, with a substantial CAGR through 2034. This growth is largely driven by the introduction of emerging therapies during the forecast period (2025–2034). Discover more about the NSCLC market in detail @ Non-small Cell Lung Cancer Market Report Emerging Competitors of TEPMETKO The NSCLC pipeline is very robust with the promising therapies such as Telisotuzumab vedotin (AbbVie), Patritumab deruxtecan (Daiichi Sankyo/AstraZeneca), Datopotamab deruxtecan (Daiichi Sankyo/AstraZeneca), Eftilagimod alpha (Immutep), BNT311/GEN1046 (acasunlimab) (Genmab), V940 (mRNA-4157) + Pembrolizumab (Moderna Therapeutics/Merck), Plinabulin + Docetaxel (BeyondSpring), Olomorasib (LY3537982) (Eli Lilly and Company), Zipalertinib (Cullinan Oncology/Taiho Pharma), Ceralasertib (AZD6738) (AstraZeneca), TEDOPI (EP-2101; IDM 2101; OSE-2101) (OSE Immuno-therapeutics), Sigvotatug vedotin (PF08046047) (Pfizer), ANKTIVA (N-803) (ImmunityBio), Aumolertinib/Almonertinib/HS-10206 (Jiangsu Hansoh Pharmaceutical), Niraparib (GSK), Savolitinib (AstraZeneca/Hutchison MediPharma), TRODELVY (Gilead Sciences), Pyrotinib (Jiangsu HengRui Medicine), Ociperlimab (BGB-A1217) (BieGene), Volrustomig (AstraZeneca), Gotistobart (BNT316/ONC-392) (OncoC4/BioNTech), Ivonescimab (AK112/SMT112) (Akeso Biopharma/Summit Therapeutics), ZYNYZ (retifanlimab/INCMGA00012) (Incyte/Macrogenics), Divarasib (GDC-6036) (Roche/Genentech), Tiragolumab (RG6058) (Roche), Sacituzumab Tirumotecan (Merck and Kelun-Biotech), JEMPERLI (dostarlimab/TSR-042) (GSK and AnaptysBio), Zongertinib (BI-1810631) (Boehringer Ingelheim), BAY 2927088 (Bayer), Serplulimab (HLX10) (Shanghai Henlius Biotech), Rilvegostomig (AZD2936) (AstraZeneca), MK-1084 (Merck, Taiho Pharmaceutical, and Astex), Domvanalimab (Arcus Biosciences and Gilead Sciences), OPDUALAG (nivolumab and relatlimab) (Bristol-Myers Squibb), Belrestotug + JEMPERLI (iTeos Therapeutics and GSK), Firmonertinib (ArriVent BioPharma), Sunvozertinib (DZD9008) (Dizal Pharmaceutical), Cobolimab (GSK), Livmoniplimab (AbbVie), Fianlimab (REGN3767) (Regeneron Pharmaceuticals), BNT327/PM8002 (Biotheus/BioNTech), HS-20117 (Hansoh BioMedical), IO102-IO103 + Pembrolizumab (IO Biotech), Naptumomab estafenatox (NeoTX Therapeutics/Active Biotech), FF-10832 (FUJIFILM Corporation), BNT116 (BioNTechSE/Regeneron Pharmaceuticals), CAN-2409 (Candel Therapeutics), Mecbotamab Vedotin (BA3011/CAB-AXL-ADC) (BioAtla), Bemcentinib (BGB 324/BGB-3234/R-428) (BerGenBio/Rigel Pharmaceuticals), DOVBLERON (taletrectinib/AB-106/IBI-344) (Nuvation Bio/Innovent Biologics/Daiichi Sankyo/Nippon Kayaku), Lifileucel (Iovance Biotherapeutics), IBI363 (Innovent Biologics), Sotevtamab (AB-16B5) (Alethia Biotherapeutics), Avutometinib (VS6766) (Verastem Oncology), Vebreltinib (APL-101) (Apollomics), LP-300 (Lantern Pharma), JNJ-90301900 (Johnson & Johnson Innovative Medicine), AMG 193 (Amgen), Luveltamab tazevibulin (Sutro Biopharma), PRT3789 (Prelude Therapeutics), Disitamab vedotin (Seagen), PADCEV (enfortumab vedotin) (Astellas Pharma), RP1 (Replimune), TIVDAK (tisotumab vedotin) (Seagen), Zanidatamab (Jazz Pharmaceuticals), Utidelone injectable (UTD1) (Beijing Biostar Pharmaceuticals), REGN5093-M114 (Regeneron Pharmaceuticals), SLC-391 (SignalChem Lifesciences), fulzerasib (GenFleet), Davutamig (REGN5093) (Regeneron Pharmaceuticals), TAS3351 (Taiho Oncology), H002 (RedCloud Bio), JIN-A02 (J INTS BIO), FWD1509 (Forward Pharma), Sabestomig (AZD7789) (AstraZeneca), Sasanlimab (Pfizer), Selvigaltin (GB1211) (Galecto Biotech), Vepafestinib Helsinn (Healthcare/Taiho Pharmaceutical), EP0031 (A400/ KL590586) (Ellipses Pharma/Kelun-Biotech), Pamvatamig (MCLA-129) (Merus), Zidesamtinib (NVL-520) (Nuvalent), NVL-655 (Nuvalent), RMC-4630 (Revolution Medicines), REQORSA (quaratusugene ozeplasmid) (Genprex), PDC*lung01 (PDC*line Pharma), Evalstotug (BA3071) (BioAtla and BeiGene), PT-112 (Promontory Therapeutics), MRT-2359 (Monte Rosa Therapeutics), GAIA-102 (GAIA BioMedicine), Rigosertib (Traws Pharma), HMBD-001 (Hummingbird Bioscience), PLB1004 (Avistone Biotechnology), ANS03 (Avistone Biotechnology), MYTX-011 (Mythic Therapeutics), A166 (Sichuan Kelun-Biotech Bio-pharmaceutical), Atamparib (BN-2397) (Ribon Therapeutics), DELTACEL (KB-GDT-01) (Kiromic BioPharma), Carotuximab (ENV-105) (Kairos Pharma), YL202 (MediLink Therapeutics), and others. To know more about the number of competing drugs in development, visit @ TEPMETKO Market Positioning Compared to Other Drugs Key Milestones of TEPMETKO In February 2024, the FDA granted traditional approval to TEPMETKO for adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. In February 2022, the EC approved TEPMETKO as monotherapy for the treatment of adult patients with advanced NSCLC harboring alterations leading to METex14 skipping who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy. In February 2021, Merck announced that the US FDA has approved TEPMETKO following priority review for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations. This indication was approved under accelerated approval based on ORR and DOR. In October 2020, TEPMETKO received ODD for treating NSCLC with MET genomic tumor aberrations In March 2020, EMD Serono (the biopharmaceutical business of Merck KGaA), announced that the MHLW approved TEPMETKO for the treatment of patients with unresectable, advanced, or recurrent NSCLC with METex14 skipping alterations. In September 2019, the US FDA granted BTD for tepotinib in patients with metastatic NSCLC harboring METex14 skipping alterations who progressed following platinum-based cancer therapy Discover how TEPMETKO is shaping the NSCLC treatment landscape @ TEPMETKO NSCLC TEPMETKO Market Dynamics TEPMETKO competes in a growing but highly specialized market where MET-targeted therapies are gaining traction due to their efficacy in addressing MET-altered tumors. The market for MET inhibitors is expanding as precision oncology advances and molecular diagnostics become more widely available, enabling better identification of patients who would benefit from targeted treatments like TEPMETKO. A key factor shaping TEPMETKO's market dynamics is competition. It directly competes with Novartis' TABRECTA (capmatinib), another MET inhibitor approved for the same indication. While TEPMETKO offers the advantage of once-daily dosing compared to TABRECTA's twice-daily regimen, both drugs have similar efficacy profiles, making physician and patient preference an important differentiator. Additionally, broader competition from next-generation MET inhibitors and combination therapies in clinical trials could impact TEPMETKO's long-term market position. Regulatory approvals and market access play a crucial role in TEPMETKO's adoption. The drug has been approved in multiple regions, including the U.S., Europe, and Japan, but reimbursement and pricing strategies vary by market. Payer policies, along with the cost-benefit analysis of MET inhibitors compared to other targeted therapies, influence prescription trends. Furthermore, real-world evidence and post-marketing studies will be critical in demonstrating TEPMETKO's sustained effectiveness and safety, which could support expanded indications and increased market penetration. Looking ahead, the MET inhibitor market is expected to grow with advances in biomarker-driven therapy, further refining patient selection. TEPMETKO's success will depend on continued clinical development, potential label expansions, and strategic partnerships to strengthen its competitive edge. As new entrants emerge, Merck KGaA's ability to differentiate TEPMETKO through combination strategies or enhanced formulations may determine its long-term sustainability in this evolving landscape. Dive deeper to get more insight into TEPMETKO's strengths & weaknesses relative to competitors @ TEPMETKO Market Drug Report Table of Contents Related Reports Non-small Cell Lung Cancer Market Non-small Cell Lung Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key NSCLC companies including Daiichi Sankyo, AstraZeneca, Gilead Sciences, BieGene, AbbVie, Roche, Merck, Novartis, Pfizer, Takeda Pharmaceuticals, Eli Lilly, BerGenBio, GlaxoSmithKline, Duality biologics, among others. Non-small Cell Lung Cancer Pipeline Non-small Cell Lung Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key non-small cell lung cancer companies, including BridgeBio Pharma, Daiichi Sankyo, EMD Serono, Merck, BridgeBio Pharma, Abbvie, Pfizer, Eli Lilly and Company BioNTech SE, Shenzhen TargetRx, Taiho Pharmaceutical, Chong Kun Dang, Bristol Myers Squibb, Innovent Biologics, Xuanzhu Biopharmaceutical, Bayer, GeneScience Pharmaceuticals, InventisBio, Apollomics, Imugene, Ono Pharmaceutical, Pierre Fabre, Jiangsu Hengrui Medicine Co., Bristol-Myers Squibb, Surface Oncology, Inhibrx, Sinocelltech, Mirati Therapeutics, REVOLUTION Medicines, Yong Shun Technology Development, Iovance Biotherapeutics, Galecto Biotech, among others. C-MET Metastatic Non-small Cell Lung Cancer Market C-MET Metastatic Non-small Cell Lung Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key C-MET mNSCLC companies, including Novartis, Merck, EMD Serono, AbbVie, Regeneron Pharmaceuticals, Mythic Therapeutics, Apollomics, Johnson & Johnson Innovation, Haihe Biopharma, among others. C-MET Non-small Cell Lung Cancer Pipeline C-MET Non-small Cell Lung Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key C-MET non-small cell lung cancer companies, including AbbVie, Janssen Research & Development, Beijing Pearl Biotechnology Limited Liability Company, Novartis, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Drug ApprovalImmunotherapyPriority Review

17 Jan 2025

·endpts.com

After three-month delay, Amgen’s Lumakras clinches FDA green light in colorectal cancer

Amgen’s Lumakras has secured an FDA approval in combination with the drugmaker’s Vectibix for a subset of patients with metastatic colorectal cancer, marking a positive change for the selective KRAS G12C inhibitor after a spate of regulatory setbacks and delays in recent years. The FDA was meant to make a decision on Lumakras plus Vectibix in October, but it pushed the deadline by three months to review supplemental data that Amgen had provided. On Thursday, the agency also approved the so-called therascreen KRAS RGQ PCR Kit, a companion diagnostic that can help identify colorectal cancer patients eligible for treatment with the doublet. In 2021, Lumakras won accelerated approval for KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer but two years later, the FDA declined to convert that to a full approval, instead requesting another confirmatory study to keep the product on the market. At the time of the first regulatory win, analysts projected that Lumakras could reach more than $1 billion in peak sales but sales have been slow to ramp up in line with expectations, although recent figures are improving. In the third quarter of 2024, Lumakras sales reached $98 million . The Thursday green light was based on data from the Phase 3 CodeBreaK 300 trial of 160 patients with KRAS G12C-mutated metastatic colorectal cancer who had previously received chemotherapy, according to a Thursday release . Subjects given 960 mg Lumakras plus Vectibix achieved 5.6 months median progression-free survival compared with two months for standard of care, good for a two-sided p-value of 0.005. The doublet also achieved a 30.2% response rate but didn’t improve overall survival, although Amgen said the trial wasn’t powered for significance in that measure. In the broader KRAS space, the FDA greenlit Bristol Myers Squibb’s Krazati plus Eli Lilly’s Erbitux in June last year for previously treated locally advanced or metastatic colorectal cancer patients. Meanwhile, Roche is advancing its own contender called divarasib, which is currently going head to head with Krazati and Lumakras in a Phase 3 trial in second-line lung cancer.

Phase 3Clinical ResultDrug ApprovalAccelerated Approval

17 Oct 2024

·endpts.com

FDA delays colorectal cancer decision for Amgen's Lumakras, a setback in race with Bristol Myers

The FDA has pushed back its decision deadline to move Amgen’s KRAS inhibitor Lumakras into metastatic colorectal cancer to January, the company told Endpoints News . The regulator was supposed to decide Thursday whether to approve the drug in combination with Amgen’s EGFR drug Vectibix for chemorefractory metastatic colorectal cancer patients who have a KRAS G12C mutation. After Endpoints sent Amgen questions about the status of the review, the company said the new deadline for action is three months from now, on Jan. 17, 2025. Amgen said the delay was to “allow additional time for review of supplemental data recently submitted to the agency.” Lumakras is currently approved under the accelerated pathway for non-small cell lung cancer. Another KRAS inhibitor, Bristol Myers Squibb’s Krazati, is also approved under the accelerated pathway in both lung cancer and colorectal cancer. The colorectal market is a large one, though KRAS G12C mutations make up just 3% to 4% of metastatic cases. Cancers of the colon and rectum are projected to make up 8% of all new cancer diagnoses in 2024, according to the National Cancer Institute . That places those cancers just behind breast, prostate and lung cancers. The FDA cleared Bristol Myers’ Krazati for use with Eli Lilly’s Erbitux in June for previously treated locally advanced or metastatic colorectal cancer patients. Amgen applied for approval in metastatic colorectal cancer with results from the CodeBreaK 300 study, which showed that a 960 mg dose of the drug resulted in a 30.2% response rate. However, it didn’t improve overall survival, according to data presented in June , though Amgen said the study wasn’t powered to show a statistically significant improvement in survival. Lumakras was the first KRAS inhibitor to win regulatory approval in 2021. It marked a major medical breakthrough. Researchers have long known that KRAS mutations drive cancer, but hadn’t been able to treat them in a targeted fashion. The efficacy of the drugs, though, has been modest. In lung cancer, the FDA declined to convert Lumakras’ accelerated approval to a full one in December, citing concerns around the reliability of the pivotal trial data and noting that the median progression-free survival benefit could be less than what Amgen claimed — and potentially as little as five days. Commercially, sales of Lumakras have been tepid, generating $167 million for the first half of the year. Roche is developing its own KRAS inhibitor divarasib, which it is studying in a Phase 3 trial head-to-head against Krazati and Lumakras in second-line lung cancer and Phase 1/1b for colorectal cancer. Other companies, including Revolution Medicines, are developing RAS inhibitors that they hope can be more effective and go beyond the single mutation G12C, which could help treat more patients.

Drug ApprovalPhase 3Accelerated ApprovalClinical Result

100 Deals associated with Divarasib

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
KRAS G12C mutant non-squamous non-small cell lung cancer	Phase 3	-	-	01 Dec 2025
Advanced Lung Non-Small Cell Carcinoma	Phase 3	China	Roche China Holding Ltd.	07 Nov 2022
Advanced Lung Non-Small Cell Carcinoma	Phase 3	China	F. Hoffmann-La Roche Ltd.	07 Nov 2022
Advanced Lung Non-Small Cell Carcinoma	Phase 3	Australia	F. Hoffmann-La Roche Ltd.	07 Nov 2022
Advanced Lung Non-Small Cell Carcinoma	Phase 3	Australia	Roche China Holding Ltd.	07 Nov 2022
KRAS G12C mutant Non-small Cell Lung Cancer	Phase 3	China	F. Hoffmann-La Roche Ltd.	07 Nov 2022
KRAS G12C mutant Non-small Cell Lung Cancer	Phase 3	China	Roche China Holding Ltd.	07 Nov 2022
KRAS G12C mutant Non-small Cell Lung Cancer	Phase 3	Australia	Roche China Holding Ltd.	07 Nov 2022
KRAS G12C mutant Non-small Cell Lung Cancer	Phase 3	Australia	F. Hoffmann-La Roche Ltd.	07 Nov 2022
metastatic non-small cell lung cancer	Phase 3	China	F. Hoffmann-La Roche Ltd.	07 Nov 2022

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04449874 (AACR2025)	Phase 1	Metastatic Solid Tumor \| Advanced Malignant Solid Neoplasm \| Non-Small Cell Lung Cancer ... KRAS G12C View more	74	Divarasib 200 mg	tswncdigow(rsfvyqepbh) = 11 (14.9%) patients kzjhqbhzjh (wlojtpbwsa )	Positive	28 Apr 2025
NCT04449874 (AACR2025)	Phase 1		74	Divarasib 400 mg		Positive	28 Apr 2025
NCT04449874 (WCLC2024) Manual	Phase 1	KRAS G12C mutation positive tumors KRAS G12C	104	Divarasib 50-400 mg	qlswrytnps(vithvwnppf) = kfaspunhzq cmqgofafao (urbibdkosb ) View more	Positive	09 Sep 2024
NCT04449874 (WCLC2024) Manual	Phase 1	KRAS G12C mutation positive tumors KRAS G12C	104	Divarasib+atezolizumab	qlswrytnps(vithvwnppf) = oirjyxnrgg cmqgofafao (urbibdkosb ) View more	Positive	09 Sep 2024
WCLC2024	Phase 3	metastatic non-small cell lung cancer KRAS G12C+	-	Divarasib	acfdfmosws(kqeubvwxpm) = nclzejvszx gpqdkjqpjf (towmornnid, 39.6 - 72.2) View more	-	09 Sep 2024
NCT04449874 (Literature) Manual	Phase 1	KRAS G12C mutation Solid Tumors KRAS G12C Mutation	137	GDC-6036	-	Positive	24 Aug 2023
NCT04449874 (Literature) Manual	Phase 1	KRAS G12C mutation Solid Tumors KRAS G12C Mutation	137	GDC-6036 (NSCLC)	ogezhhuudu(xiajjufgzm) = ejogkzaxxs qzkdcdwgon (awqztuhpqd, 39.9 - 66.7) View more	Positive	24 Aug 2023
NCT04449874 (GO42144, NEWS) Manual	Phase 1	Non-Small Cell Lung Cancer \| Colorectal Cancer \| KRAS G12C mutation positive tumors KRAS G12C Positive	137	Divarasib	wozcforuvg(trngnxwrmv) = yexydqnout zhdqpvgnss (atnleqnarh ) View more	Positive	24 Aug 2023
NCT04449874 (GO42144, NEWS) Manual	Phase 1		137	Divarasib (non-small-cell lung cancer)	sawxvhpdwd(jkxlyeqrtg) = sqajjaaugy anshysgdra (scnrznwpbd ) View more	Positive	24 Aug 2023
NCT04449874 (Pubmed)	Phase 1	Metastatic Solid Tumor \| Advanced Malignant Solid Neoplasm \| Non-Small Cell Lung Cancer ... View more	137	Divarasib	pbavziweyt(dpjpskafmt) = qtatoyvcbc chugopxdoe (ywtkatkbqn, 39.9 - 66.7)	-	24 Aug 2023
NCT04449874 (AACR2023) Manual	Phase 1	Colorectal Cancer KRAS G12C Mutation	29	GDC-6036+cetuximab	wtxablpciu(eaoqrraceh) = jygzjfjdva zopyqgyahl (xprddrcsxw ) View more	Positive	14 Apr 2023
NCT04449874 (ESMO2022)	Phase 1	KRAS G12C mutation Solid Tumors	14	GDC-6036	mokftpoybr(hjrwedjlbj) = eokqzefkgk gsjuprdpth (uqcgzxcncu ) View more	-	12 Sep 2022
NCT04449874 (ESMO2022) Manual	Phase 1	KRAS G12C mutant Colorectal Cancer KRAS G12C mutation	43	GDC-6036	lcjgpxpida(vefkdipasp) = The most frequent GDC-6036-related AEs (≥ 10% pts) were nausea, diarrhea, vomiting, dyspepsia, fatigue, and decreased appetite zxsscctffp (phshqsulad ) View more	Positive	10 Sep 2022

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