nazartinib (EGF816)

P1, N=18, Completed, University of Cologne | Recruiting --> Completed | Trial completion date: Apr 2023 --> Nov 2023

P1, N=255, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Apr 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

P1, N=255, Recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Feb 2024 --> Aug 2024

P2, N=11, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Oct 2025 --> Jun 2024 | Trial primary completion date: Oct 2022 --> Dec 2023

Data from drug combination screens with EGF816 and ceritinib indicate that dasatinib and agents disrupting microtubules act synergistically across many cell lines. Finally, we show that a higher-order-combination screen with 26 selected drugs in two resistant EGFR-mutant lung cancer cell lines identified active triplet combinations.

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2023 --> Mar 2024 | Trial primary completion date: Sep 2023 --> Mar 2024

First-line nazartinib demonstrated promising efficacy, including clinically meaningful antitumor activity in the brain, and manageable safety in patients with EGFR-mutant NSCLC.

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2022 --> Sep 2023 | Trial primary completion date: Nov 2022 --> Sep 2023

P1, N=255, Recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2023 --> Feb 2024 | Trial primary completion date: Aug 2023 --> Feb 2024

P1/2, N=225, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2022 --> Oct 2023

P2, N=64, Terminated, Novartis Pharmaceuticals | Completed --> Terminated; Sponsor decision due to low patient recruitment caused by the change in the treatment landscape of NSCLC.

P2, N=11, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting

P1/2, N=177, Active, not recruiting, Novartis Pharmaceuticals | Completed --> Active, not recruiting | Trial completion date: Nov 2020 --> Jul 2025 | Trial primary completion date: Nov 2020 --> Jul 2025

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.

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=157 --> 105

P2, N=64, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Dec 2021 --> Feb 2021

The study will investigate the clinical safety and efficacy of nazartinib in patients suffering from EGFR-mutated NSCLC. The anticipated results of the study are expected to provide clinical basis for nazartinib to treat patients suffering from EGFR-mutated NSCLC.

P1, N=157, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Nov 2022 | Trial primary completion date: Mar 2024 --> Nov 2022

P1, N=289, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P1, N=255, Recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2022 --> Aug 2023 | Trial primary completion date: Aug 2022 --> Aug 2023

P1, N=157, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2022 --> Mar 2024 | Trial primary completion date: May 2022 --> Mar 2024

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).

P2, N=11, Recruiting, Massachusetts General Hospital | N=36 --> 11 | Trial completion date: Mar 2025 --> Oct 2025 | Trial primary completion date: Mar 2021 --> Oct 2022

P1, N=290, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2020 --> Mar 2021 | Trial primary completion date: Nov 2020 --> Mar 2021

Exon 20 insertion mutation is associated with lack of sensitivity to first-generation EGFR TKIs (erlotinib/gefitinib) and a partial response to second-generation (afatinib) and third-generation (osimertinib/rociletinib); promising results for nazartinib and poziotinib are on line. Conclusion Studies showed that different exon 20 insertions lead to different response to EGFR TKIs depending on the location in the kinase domain that they affect. Therefore, it is important to report the mutation and make the follow up.

Exon 20 insertion mutation is associated with lack of sensitivity to first-generation EGFR TKIs (erlotinib/gefitinib) and a partial response to second-generation (afatinib) and third-generation (osimertinib/rociletinib); promising results for nazartinib and poziotinib are on line. Conclusion Studies showed that different exon 20 insertions lead to different response to EGFR TKIs depending on the location in the kinase domain that they affect. Therefore, it is important to report the mutation and make the follow up.

Exon 20 insertion mutation is associated with lack of sensitivity to first-generation EGFR TKIs (erlotinib/gefitinib) and a partial response to second-generation (afatinib) and third-generation (osimertinib/rociletinib); promising results for nazartinib and poziotinib are on line. Conclusion Studies showed that different exon 20 insertions lead to different response to EGFR TKIs depending on the location in the kinase domain that they affect. Therefore, it is important to report the mutation and make the follow up.

Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.

P1/2, N=177, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P2, N=64, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | Trial completion date: Apr 2022 --> Dec 2021 | Trial primary completion date: Apr 2022 --> Dec 2021

Treatment with nazartinib 100 mg QD and trametinib 1 mg QD resulted in a DLT in two of six individuals. Thus, three additional patients will be enrolled in a third cohort at the same dose level. Efficacy data are premature and needs further evaluation.

Treatment with nazartinib 100 mg QD and trametinib 1 mg QD resulted in a DLT in two of six individuals. Thus, three additional patients will be enrolled in a third cohort at the same dose level. Efficacy data are premature and needs further evaluation.

Treatment with nazartinib 100 mg QD and trametinib 1 mg QD resulted in a DLT in two of six individuals. Thus, three additional patients will be enrolled in a third cohort at the same dose level. Efficacy data are premature and needs further evaluation.

No abstract available

Best objective response according to RECIST 1.1 was stable disease in one patient (afatinib-resistant, T790M-negative), lasting for more than 4 months and progressive disease in the other patient (osimertinib-resistant, T790M-negative). Treatment with nazartinib 100 mg QD and trametinib 1 mg QD resulted in a DLT in one of three patients. Thus, three additional patients will be enrolled at the same dose level. Efficacy data is premature.

Experimental procedures: The combination efficacy and synergy of TNO155 with EGF816 (a 3rd generation EGFR inhibitor), dabrafenib+trametinib or a tool KRAS G12C inhibitor (G12Ci) were respectively assessed in a number of EGFR mutant lung cancer models, BRAFV600E colorectal cancer models and KRASG12C lung and colorectal cancer models. Our findings suggest that SHP2 inhibition is an effective strategy to block the feedback activation of wild type and G12C KRAS, as well as NRAS and HRAS, by a variety of RTKs, in response to ERK inhibition. Given the mutant selective properties of those inhibitors we studied, the tolerability of their combinations with TNO155 is highly expected. Our data provide pre-clinical rationale to explore those TNO155 combinations in the corresponding cancer indications in clinic.

P1, N=255, Recruiting, Novartis Pharmaceuticals | N=135 --> 255

After additional follow-up, median OS was still not reached and the safety profile was manageable. Nazartinib is a promising 3rd generation EGFR TKI for tx-naïve pts with adv EGFR-mut NSCLC, including pts with baseline BM. Research Funding: Novartis Pharmaceuticals

P1/2, N=177, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Sep 2019 --> Jul 2020

This was further verified by theoretical examination of the NAZ docking on the HSA surface that revealed an HSA-NAZ complex where NAZ is bound to HSA Sudlow site I driven by hydrogen bonding in addition to electrostatic forces in the form of pi-H bond. The HSA binding pocket for NAZ was shown to encompass ARG 257, ARG 222, LYS 199 and GLU 292 with a total binding energy of -25.59 kJ mol.