Lumakras (sotorasib) / Amgen, Roche - LARVOL DELTA

CodeBreaK 201: A Study of Sotorasib (AMG 510) in Participants With Stage IV NSCLC Whose Tumors Harbor a KRAS p.G12C Mutation in Need of First-line Treatment (clinicaltrials.gov) - P2 | N=42 | Active, not recruiting | Sponsor: Amgen | Trial completion date: Jan 2026 ➔ May 2025 | Trial primary completion date: Jan 2026 ➔ May 2025

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1 • STK11

Ficerafusp alfa reverses acquired resistance to the KRAS-G12C inhibitor sotorasib in KRAS-G12C-mutated lung tumors (AACR 2025) - "Recent approvals of KRAS-G12C inhibitors (G12Ci) such as sotorasib (AMG510) and adagrasib have improved treatment responses and overall survival rates2...The combination of sotorasib with ficerafusp alfa resulted in a significant reduction in sotorasib-resistant NCI-H1373 tumors over sotorasib in combination with cetuximab.This study reinforces the hypothesis that TGF-β plays an important role in acquired resistance to G12Ci. Our findings suggest that combining G12Ci with ficerafusp alfa could overcome G12Ci drug-resistance in KRAS-G12C-mutated lung cancer."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • TGFB1

IBI3019, a first-in-class EGFR/CDH17/CD16A tri-specific antibody, demonstrated potent efficacy against CRC and an excellent safety profile in preclinical studies (AACR 2025) - "Inhibition of EGFR signaling is clinically effective in colorectal cancer (CRC) as evidenced by the approval for Cetuximab in combination with chemotherapy or Encorafenib, a BRAF inhibitor, and the promising clinical results when combined with KRAS inhibitors, such as Adagrasib or Sotorasib...Additionally, IBI3019 incorporates a high affinity CD16A single domain antibody that mediates stronger antibody-dependent cell cytotoxicity (ADCC) than IgG1 used in Cetuximab or the low fucosylated Fc of Amivantamab, a bispecific antibody targeting c-MET and EGFR, both in vitro and in vivo...It exhibited strong synergy with Fulzerasib, a KRAS G12C inhibitor and MRTX1133, a KRAS-G12D inhibitor...IBI3019 is a highly optimized FIC molecule with enhanced EGFR blocking capability and ADCC, maximizing tumor inhibition while minimizing toxicity. Its superior efficacy and safety profile support further clinical evaluation."

Preclinical • Trispecific • Colorectal Cancer • Oncology • Solid Tumor • CDH17 • FCGR3A • KRAS • MET

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. (PubMed, Crit Rev Oncol Hematol) - "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."

Journal • Monotherapy • P1/2 data • Retrospective data • Review • Colorectal Cancer • Oncology • Solid Tumor • KRAS

BBO-8520, a first-in-class direct dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C, exhibits robust efficacy in non-small cell lung cancer preclinical models (AACR 2025) - P1 | "Sotorasib and adagrasib, allele-specific KRASG12C covalent inhibitors that only target KRASG12C in the inactive GDP-bound (OFF) state, have been approved for patients with KRASG12C locally advanced or metastatic non-small cell lung cancer (NSCLC)...BBO-8520 also exhibits strong combination benefit in vivo in the KRASG12 CDX model NCI-H2122 when combined with either BBO-10203, a selective RAS:PI3Kα breaker that blocks RAS-mediated activation of AKT in clinical development (NCT06625775), or the anti-EGFR antibody cetuximab. In summary, BBO-8520 is a first in class, potent and selective KRASG12C dual GTP-bound (ON) and GDP-bound (OFF) inhibitor that exhibits robust efficacy and may improve upon approved, KRASG12C GDP-bound (OFF)-only inhibitors in NSCLC. BBO-8520 has entered phase 1 clinical trials in patients with KRASG12C NSCLC that are either naïve or have experienced first-generation KRASG12C (OFF) inhibitors (NCT06343402)."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PIK3CA

D3S-001, a next generation GDP-bound KRAS G12C inhibitor, as monotherapy in KRAS G12C inhibitor resistant non-small cell lung cancer (AACR 2025) - P1/2 | "In pre-clinical studies, D3S-001 resulted in tumor regression in xenograft models that are resistant to sotorasib (soto) and adagrasib (ada). These findings highlight the potential of D3S-001 to overcome the limitations of earlier KRAS G12Ci and address unmet needs in G12Ci resistant NSCLC, offering a promising therapeutic option for pts with KRAS G12C-mutant cancers."

Monotherapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • CDKN2A • EGFR • KRAS • MYC • NTRK1 • NTRK2 • NTRK3 • PIK3CG • TP53

Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer. (PubMed, Cell Death Dis) - "While KRAS-G12C inhibitors, including sotorasib and adagrasib, have shown promise in clinical trials, their efficacy is limited by primary and acquired resistance mechanisms. Mechanistically, the combination therapy inhibited c-Myc/ORC2 signaling, leading to cell cycle arrest and apoptosis. These findings suggest that the combination of anlotinib and KRAS-G12C inhibitors represents a promising novel therapeutic approach for KRAS-G12C-mutant NSCLC."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • MYC

Characteristics of RWE used in Regulatory Decision-Making for Marketing Authorization Applications (MAAs) (ISPOR 2025) - "Descriptive analyses were performed to identify trends in the characteristics of drugs and of the RWE. Seven medicines were analyzed: idecabtagene vicleucel (ide-cel), omburtamab, sotorasib, alpelisib, palovarotene, tacrolimus, and omaveloxolone. MAAs containing RWE submitted to the FDA were predominantly for rare diseases medicines and for first-in-class indications. Acceptability of RWE varied based on entire body of evidence. Further investigation into factors influencing RWE acceptability and its integration into MAAs across other regulators such as EMA is warranted."

Hematological Disorders • Rare Diseases

STAT3 Inhibition Prevents Adaptive Resistance and Augments Nature Killer (NK) Cell Cytotoxicity to KRASG12C Inhibitors in Non-Small Cell Lung Cancer (NSCLC) (ATS 2025) - "Through high-throughput screening of a customized pharmacological library containing 423 compounds, we identified napabucasin, a signal transducer and activator of transcription 3 (STAT3) inhibitor, synergistically potentiated KRASG12C inhibitor sotorasib-induced growth inhibition both in sensitive and resistant KRASG12C NSCLC cell lines. Our study dissected an unknown mechanism of adaptive resistance of KRASG12C inhibitors, with the STAT3 activation not only sustaining the regrowth of tumor cells under KRAS inhibition but also up-regulating HLA-B transcription to dampen the cytotoxicity of infiltrated NK cells. Together, these studies identified a promising combinational therapeutic strategy for KRASG12C-mutant NSCLC and demonstrated STAT3 activation as a pivotal mediator of adaptive resistance for KRASG12C inhibitors, implying the altered STAT3 phosphorylation levels under treatment as the predictive biomarker of sensitivity."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HLA-B • KRAS

For Colon Cancer That No Longer Responds to Treatment, A New Drug Combination Offers Hope (Businesswire) - P3 | N=160 | CodeBreak300 (NCT05198934) | Sponsor: Amgen | "The trial, called CodeBreaK 300, is the first to compare the sotorasib/panitumumab combination head-to-head against the standard of care in this patient population....More than 30% of patients in the high dose sotorasib group achieved an objective response, which researchers defined as shrinking tumor volume by more than half. Only 1.9% of patients in the standard –of care group achieved the same result....Notably, even though the trial was not designed to measure overall survival due to its small size, results suggested a benefit. Researchers noted that overall survival in the high dose sotorasib group was prolonged by 30% compared to standard of care."

P3 data • Colorectal Cancer

Development of a novel selective CDK4 inhibitor for HR+/HER2- breast cancer (AACR 2025) - "In MCF7-xenograft mouse model, TY-2072 showed significant suppression of tumor growth in a dose-dependent manner at 20 and 40 mg/kg BID, TY-2072 exhibited synergetic effects with Fulvestrant on anti-tumor growth inhibition with good tolerance, evidenced by the maintenance of body weight of the animals throughout the study. TY-2072 demonstrates high selectivity against CDK4, and more than 17-fold selectivity against CDK6 compared to palbociclib, proving that TY-2072 is a CDK4 inhibitor rather than a CDK4/6 dual inhibitor. Western blot assays showed a dose-dependent reduction in phosphorylated RB (Ser780) in breast cancer cell lines after 48 hours TY-2072 treatment. The anti-proliferation effects of CDK4 inhibitors were assessed with MCF7 (breast cancer, CDK4 sensitive), JEKO-1 (mantle cell lymphoma), and MOLM13 (acute myeloid leukemia, CDK6 sensitive) through a CTG cell viability assay after 5-day incubation."

Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Leukemia • Lung Cancer • Lymphoma • Mantle Cell Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2 • KRAS

AMG 410: An H/NRAS-sparing pan-KRAS inhibitor with dual GTP(on)/GDP(off)-state activity for the treatment of diverse KRAS-mutant tumors (AACR 2025) - "Approved inhibitors (sotorasib & adagrasib) are only effective for tumors harboring the KRAS G12C mutation, however, and major unmet need remains for the larger population of patients (~140k patients/year, USA) that bear other oncogenic KRAS mutations (e.g., KRAS G12D, G12V, etc.).Leveraging insights from KRAS G12Ci, we here report the structure- and property-based design of a non-covalent "pan-KRAS" inhibitor, AMG 410, which binds to the most clinically relevant KRAS mutants (e.g., G12D, G12V, G13D; IC50 values = 1-4 nM) via the same allosteric pocket employed by approved KRAS G12C inhibitors. AMG 410 demonstrates strong pre-clinical efficacy, robustly lowing phosphorylated ERK levels throughout dosing cycles and achieving tumor stasis or regression across a broad set of colorectal, pancreatic, and lung cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models harboring a diverse set of KRAS mutant alleles including G12D, G12V,..."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • KRAS • NRAS

Prediction of sotorasib response duration and identification of clinically actionable resistance mechanisms using an RNA- and machine learning–based patient classifier. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Machine learning

Impact of standard vs reduced dosing of sotorasib on efficacy and toxicity in KRAS G12C–mutated advanced non-small cell lung cancer: A systematic review and meta-analysis. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Metastases • Retrospective data • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

S1900E: A phase II study examining impact of co-mutations on sotorasib for previously treated stage IV/recurrent KRAS G12C mutated (MUT) non-squamous (Non-sq) non-small cell lung cancer (NSCLC) (ECOG-ACRIN led Lung-MAP Sub-study). (ASCO 2025) - P2 | "Clinical Trial Registration Number: NCT04625647 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Metastases • P2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Biomarkers of emergent resistance to sotorasib plus panitumumab in KRAS G12C-mutated metastatic colorectal cancer (mCRC) from the randomized, phase 3 CodeBreaK 300 study. (ASCO 2025) - P3 | "Clinical Trial Registration Number: NCT05198934 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Biomarker • Clinical • Metastases • P3 data • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Long-term safety and efficacy of sotorasib plus panitumumab and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreaK 101 (phase 1b). (ASCO 2025) - P3 | "Clinical Trial Registration Number: NCT05198934 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Metastases • P1 data • Colorectal Cancer • Oncology • Solid Tumor • KRAS

AMGEN REPORTS FIRST QUARTER 2025 FINANCIAL RESULTS (PRNewswire) - "Product Sales Performance:...(i) LUMAKRAS/LUMYKRAS (sotorasib) sales increased 4% year-over-year to $85 million in the first quarter, driven by volume growth, partially offset by lower net selling price...; (ii) IMDELLTRA (tarlatamab-dlle)/IMDYLLTRA (tarlatamab) generated $81 million of sales in the first quarter. Sales increased 21% quarter-over-quarter driven by volume growth."

Sales • Colorectal Cancer • Non Small Cell Lung Cancer • Small Cell Lung Cancer

VIC-1911 Monotherapy in Combination With Sotorasib for the Treatment of KRAS G12C-Mutant Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=3 | Terminated | Sponsor: Vitrac Therapeutics, LLC | Phase classification: P1a/1b ➔ P1

Monotherapy • Phase classification • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

Preclinical characterization of SGR-4174, a potent and selective SOS1 inhibitor for the treatment of pan KRAS mutant cancers in combination with KRAS pathway inhibitors (AACR 2025) - "Compared to other published SOS1 inhibitors (BI-3406, MRTX0902), SGR-4174 is more potent, and demonstrated similar anti-tumor activity and target engagement at a lower dose both in monotherapy and combination therapy studies in xenograft tumor models. SGR-4174 was well tolerated as monotherapy and in combination with sotorasib or trametinib.SGR-4174 demonstrated favorable PK properties across preclinical species and toxicity profile was well characterized. Our comprehensive preclinical efficacy and safety data support progressing SGR-4174 to clinical development to treat KRAS mutant cancers."

Combination therapy • Preclinical • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • EGFR • KRAS

Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: a systematic review. (PubMed, Front Immunol) - "Due to the unique activation mechanism of KRAS G12C has led to the development of specific inhibitors, such as AMG 510 and MRTX849, which show promising therapeutic potential. However, results from the CodeBreaK 200 Phase III trial indicated that AMG 510 did not significantly improve overall survival compared to docetaxel...Ongoing research is crucial to refine treatment regimens and identify suitable patient populations. This review focuses on the development of KRAS G12C inhibitors in monotherapy and combination therapies for NSCLC, discussing major clinical trials and future research directions."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Potency and Safety of KRAS G12C Inhibitors in Solid Tumors: A Systematic Review. (PubMed, Clin Med Insights Oncol) - "In this study, we comprehensively evaluate the effectiveness and toxicity of relevant KRAS G12C inhibitors (Sotorasib, Adagrasib, Garsorasib, and Divarasib) in patients with colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), and pancreatic ductal adenocarcinomas (PDAC). However, Adagrasib and Sotorasib are moderately efficient in CRC clinical trials. This study confirms that patients treated with these KRAS G12C inhibitors, exclusively or combined with conventional therapies, achieve better treatment responses and modulate the progressions of these solid tumors."

Journal • Review • Colorectal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Cost-Effectiveness And Value of Information Analyses of Sotorasib Versus Docetaxel in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer With KRAS G12C Mutation (ISPOR 2025) - "Sotorasib may require a higher WTP threshold or a reduction in acquisition cost to be considered cost-effective. The estimated EVPI exceeds the cost of conducting another trial, future research to acquire additional evidence is considered worthwhile to inform clinical and policy decisions."

Clinical • Cost effectiveness • HEOR • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Two first-generation KRAS inhibitor safety profiles: a disproportionality analysis of individual reports from the FDA adverse event reporting system. (PubMed, Expert Opin Drug Saf) - "The median time to onset was 50 days for sotorasib and 21 days for adagrasib. Our research revealed potential new AE signals and provided a comprehensive safety profile of KRAS inhibitors, emphasizing the importance of careful monitoring and supportive care."

Adverse events • Journal • Cardiovascular • CNS Disorders • Colorectal Cancer • Epilepsy • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatitis • Pneumonia • Solid Tumor • KRAS

mRNA-Mediated Rescue Loss of p53 Tumor Suppressor Function as a Potent New Strategy for Cancer Therapy across Pan-p53 Alterations. (ASGCT 2025) - "ADGN-531/sotorasib synergy was evaluated in vitro on NCI-H358 (p53 null/KRAS G12C ) and Mia-PACA (p53 R48W /KRAS G12C ) cells and in vivo on NCI-H358 mouse xenograft. Our study provides a proof-of-concept that restoration of tumor suppressor function by ADGN-531 could be used as a single agent therapy in P53 altered tumors independent of other driver mutations e.g., KRAS, or with other therapies for potent combinatorial cancer treatment. Disease Focus of Abstract:Cancer Solid Tumors"

Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BAX • CDKN1A • KRAS • TP53