Xegafri (rociletinib) / Clovis - LARVOL DELTA

Survival benefit of targeted therapy in EGFR-mutant NSCLC patients with leptomeningeal metastases (SNO 2025) - "The interventions included Afatinib, Erlotinib, Furmonertinib, Gefitinib, Osimertinib, and Rociletinib. This meta-analysis provides the first pooled survival estimate in EGFR-mutant NSCLC patients with LMD receiving targeted therapies. The findings suggest that modern EGFR TKIs may offer clinically meaningful survival benefits in this otherwise high-risk group. Prospective studies are needed to validate these results and to define optimal treatment strategies."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor

Survival benefit of targeted therapy in EGFR-mutant NSCLC patients with leptomeningeal metastases (WFNOS 2025) - "The interventions included Afatinib, Erlotinib, Furmonertinib, Gefitinib, Osimertinib, and Rociletinib. This meta-analysis provides the first pooled survival estimate in EGFR-mutant NSCLC patients with LMD receiving targeted therapies. The findings suggest that modern EGFR TKIs may offer clinically meaningful survival benefits in this otherwise high-risk group. Prospective studies are needed to validate these results and to define optimal treatment strategies."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor

Integrative Computational Approaches for TRPV1 Ion Channel Inhibitor Discovery: An Integrated Machine Learning, Drug Repurposing and Molecular Simulation Approach. (PubMed, J Chem Inf Model) - "Among these, CYM-5442 (CA6), Rociletinib (CA7), and SC-51089 (CA9) demonstrated strong binding affinities and thermodynamic stability, outperforming known modulators such as Capsazepine and Capsaicin. These findings highlight the effectiveness of combining ML and molecular simulations in drug discovery, offering valuable insights into the identification of novel TRPV1 modulators as a starting point for further experimental validation and optimization in the development of next-generation analgesics targeting the TRPV1 channel."

Journal • Inflammation • Pain • CA6 • CA9

Covalent inhibition of ACSL4 alleviates ferroptosis-induced acute liver injury. (PubMed, Cell Chem Biol) - "Here, we identify Rociletinib (ROC) as a potent inhibitor of ferroptosis through virtual screening and mechanistic studies...ROC effectively mitigates ferroptosis-mediated acute liver injury in mouse models. These findings establish ROC as the targeted covalent inhibitor directly targeting ACSL4, offering a promising therapeutic strategy for ferroptosis-related diseases."

Journal • Cardiovascular • Hepatology • Liver Failure • Reperfusion Injury • ACSL4

Identification of a covalent NEK7 inhibitor to alleviate NLRP3 inflammasome-driven metainflammation. (PubMed, Cell Commun Signal) - "Here we identify rociletinib (ROC), an anticancer drug in phase III clinical trial with high safety profile, as a highly potent and specific small-molecule antagonists of NEK7...Furthermore, ROC alleviates the pathological features of metainflammation on the mouse model of type 2 diabetes (T2D). In summary, our results identify ROC as a covalent inhibitor of NEK7 and demonstrates that targeting NEK7 provides a potential and promising strategy for the treatment of NLRP3 inflammasome-driven T2D."

Journal • Diabetes • Inflammation • Metabolic Disorders • Oncology • Type 2 Diabetes Mellitus • NLRP3

Design, preparation and biological evaluation of new Rociletinib-inspired analogs as irreversible EGFR inhibitors to treat non-small-cell-lung cancer. (PubMed, Bioorg Med Chem) - "We have identified 20, 21 and 23 as potent mutant EGFR inhibitors (≤20 nM), with comparable or better selectivity over WT EGFR, and lower activity at JAK3, than Osimertinib or Rociletinib. Compounds 21 displayed the best combination of EGFR mutant activity, JAK3 selectivity, cellular activity and physicochemical properties. Finally, kinetic studies on 21 were performed, confirming a covalent mechanism of action at EGFR."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • JAK3

Identification and validation of m6A-associated ferroptosis genes in renal clear cell carcinoma. (PubMed, Cell Biol Int) - "NIACIN, TAE-684, ROCILETINIB, and others treat ccRCC. We found ccRCC prognostic genes that work. This discovery may lead to new ccRCC treatments."

IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CHAC1 • EGFR • NNMT • TRIB3

Computational investigation of Moringa oleifera phytochemicals targeting EGFR: molecular docking, molecular dynamics simulation and density functional theory studies. (PubMed, J Biomol Struct Dyn) - "In comparison, the highest binding affinity from control drugs was displayed by Rociletinib (-9.0 kcal/mol)...ADMET analysis depicted acceptable outcomes for all top phytochemicals without displaying any toxicity. In conclusion, this report has identified promising EGFR-TK inhibitors to treat several cancers that can be further investigated through laboratory and clinical tests."

Journal • Oncology • EGFR

An integrated transomics approach reveals significant differences between EGFR inhibitors with the potential to identify novel targets to overcome EGFR resistance (AACR 2023) - "Approved drugs included erlotinib, afatinib (first- and second-generation EGFRi, respectively), and osimertinib (third-generation drug that can overcome the T790M gatekeeper mutation that confers resistance to earlier drugs). The remaining drugs (maverlertinib, naquotinib, olmutinib, rociletinib) are unapproved third-generation inhibitors...Transomic analysis of EGFRi has the potential to identify important differences between successful drugs, drugs that failed in clinical development, and to identify non-EGFR targets that may overcome resistance to current drugs. This hypothesis is currently being investigated across various resistant and undruggable cancers to unlock novel therapeutic targets."

Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

CBL Mutations as Potential Mediators of EGFR TKI Resistance Effectively Treated with Sitravatinib (WCLC 2017) - P1; "...The patient is a 77 year-old female, lifelong non-smoker with metastatic lung adenocarcinoma characterized by EGFR exon19del initially treated with erlotinib with a partial response (PR) of 9 months. Upon disease progression (PD), a new EGFR T790M mutation led to treatment with rociletinib (an experimental inhibitor of EGFR T790M) with stable disease for 11 months. Upon PD she was treated with osimertinib without response. She then received carboplatin/pemetrexed with a PR...Loss of function mutations in CBL represent a unique class of mutations that may be responsible for acquired resistance to 3[rd] generation EGFR TKI. Sitravatinib has demonstrated clinical activity in a patient with NSCLC characterized by EGFR exon19del and CBL C384R mutations. The clinical trial with sitravatinib is currently enrolling patients with CBL loss of function mutations."

Next-generation sequencing • Non Small Cell Lung Cancer

The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC (WCLC 2017) - P2; "...In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M...One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis...Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting."

Non Small Cell Lung Cancer

Antitumor activity of MET antibody emibetuzumab (LY2875358) in combination with EGFR inhibitors in erlotinib resistant (ER) xenograft mouse models (AACR 2017) - P2; "...Combination of emibetuzumab with EGFR TKIs (erlotinib, AZD9291, CO1686) or EGFR Ab (necitumumab, cetuximab) was evaluated in 3 ER xenograft models...Model 2: ER cell line HCC827-A8 was derived from HCC827 parental xenograft tumor serially passed in vivo with long term treatment of gefitinib and erlotinib... The three erlotinib resistant models with MET amp and retaining sensitizing EGFRmt (ex19 del or L858R), and no acquired T790M were found resistant to other EGFR inhibitors (Abs and TKIs). Emibetuzumab in combination with either EGFR TKI or Ab showed anti-tumor activity in MET amp ER xenograft models including tumor regression in 2 out of 3 models. The combination of emibetuzumab with erlotinib is being evaluated in NSCLC patients with EGFR activating mutation (NCT01897480)."

Biosimilar • Lung Cancer • Non Small Cell Lung Cancer • Oncology

Trastuzumab and paclitaxel in patients (pts) with EGFR mutated non-small-cell lung cancer (NSCLC) that express HER2 after progression on EGFR TKI treatment. (ASCO 2017) - P2; "Last TKI was erlotinib (n = 6), gefitinib (n = 4), rociletinib (n = 3) or osimertinib (n = 8). The study met its primary end-point. Paclitaxel-trastuzumab induces durable objective tumor responses in EGFR TKI pretreated pts with an activating EGFR mutation and HER2 bypass track activation. The treatment was well tolerated."

Clinical • Biosimilar • Gene Therapies • Non Small Cell Lung Cancer • Pain

Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC) (WCLC 2017) - P1/2,P3; "Patients (N=900) were to be randomized (1:1:1) to rociletinib 500 or 625 mg BID or investigator’s choice of chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). Incomplete enrollment precluded hypothesis testing. However, the data show a trend toward longer PFS and higher ORR with rociletinib."

Clinical • P3 data • Non Small Cell Lung Cancer

Overview of the multifaceted resistances toward EGFR-TKIs and new chemotherapeutic strategies in non-small cell lung cancer. (PubMed, Biochem Pharmacol) - "However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanism of resistances towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever evolving and adaptive nature of NSCLC."

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

Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686. (PubMed, Eur J Med Chem) - "Furthermore, 1q could significantly induce the apoptosis of H1975 cells and arrest the cells in G/G phase. These findings demonstrated that compound 1q could be used as initial lead compound for the development of new EGFR degraders based therapy."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • EGFR

Beyond osimertinib: The development of 3-generation EGFR Tyrosine Kinase Inhibitors. (PubMed, J Thorac Oncol) - P3 | "In this review, we profiled many of the third-generation EGFR TKIs in late stage clinical development (e.g. almonertinib, lazertinib, alflutinib, rezivertinib, ASK120069, SH-1028, D-0316 and abivertinib) of their interim results of phase 1-3 trials and their chemical structures when publicly available. Additionally, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, maverlertinib) including phase 3 results of rociletinib and naquotinib. We further profiled the next-generation combination clinical trial design of third-generation EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704) and ACROSS2 (NCT04500717)."

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

Preclinical Models for Acquired Resistance to Third-Generation EGFR Inhibitors in NSCLC: Functional Studies and Drug Combinations Used to Overcome Resistance. (PubMed, Front Oncol) - "This review provides an overview of preclinical studies developed to investigate the mechanisms of acquired resistance to 3rd G EGFR-TKIs, including osimertinib and rociletinib, across all lines of therapy. In fact, some of the models described were first generated to be resistant to first- and second-generation EGFR-TKIs and often carried the T790M mutation, while others had never been exposed to TKIs. The review further describes the therapeutic opportunities to overcome resistance, based on preclinical studies."

Journal • Preclinical • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • NRAS

Analysis to determine the effect of mutations on binding to small chemical molecules. (PubMed, J Bioinform Comput Biol) - "In this paper, the authors present and describe, in detail, an original software-implemented numerical methodology used to determine the effect of mutations on binding to small chemical molecules, on the example of gefitinib, AMPPNP, CO-1686, ASP8273, erlotinib binding with EGFR protein, and imatinib binding with PPARgamma. Furthermore, the developed numerical approach makes it possible to determine the stability of a molecular complex, which consists of a protein and a small chemical molecule. The description of the software package that implements the presented algorithm is given in the website: https://binomlabs.com/."

Journal • EGFR • PPARG

Discovery of highly potent and selective EGFR TKIs against NSCLC based on molecular dynamic simulation. (PubMed, Eur J Med Chem) - "The third-generation EGFR tyrosine kinase inhibitors (TKIs) Rociletinib and Osimertinib (AZD9291) achieved remarkable clinical efficacy. In addition, the compound 7m showed considerable activity against NCI-H1975 and HCC827 cells, arrested NCI-H1975 cell cycle at the G2/M stage and significantly induced apoptosis in NCI-H1975 cell. These encouraged results indicated that 7m will be used as a candidate targeting EGFR for further pharmacodynamic and pharmacokinetic studies, and all these studies provide important clues for the discovery of potent EGFR inhibitors with high selectivity."

Journal • Dermatology • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

"Especially pertinent for those who remember the sorry tale of $CLVS & rociletinib." (@JacobPlieth)

Mechanisms and management of 3rd‑generation EGFR‑TKI resistance in advanced non‑small cell lung cancer (Review). (PubMed, Int J Oncol) - "Other 3rd‑generation EGFR‑TKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulin‑like growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelial‑mesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinib‑resistant patients, and multiple clinical studies on novel combined therapies are ongoing."

Journal • Review • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • EGFR • HER-2 • MET

Cellular Origins of EGFR-Driven Lung Cancer Cells Determine Sensitivity to Therapy. (PubMed, Adv Sci (Weinh)) - "Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, are developed. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Efficacy and Safety of Rociletinib Versus Chemotherapy in Patients With EGFR-Mutated NSCLC: The Results of TIGER-3, a Phase 3 Randomized Study. (PubMed, JTO Clin Res Rep) - P3 | "Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point."

Clinical • Journal • P3 data • Developmental Disorders • Diabetes • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

LC-MS/MS Estimation of Rociletinib Levels in Human Liver Microsomes: Application to Metabolic Stability Estimation. (PubMed, Drug Des Devel Ther) - "RLC and bosutinib (BOS) (internal standard; IS) were separated using an isocratic elution system with a C column (reversed stationary phase). RLC exhibited a moderate extraction ratio indicative of good bioavailability. The developed analytical method herein is the first LC-MS/MS assay for RLC metabolic stability."

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