Can't cure a tumor after drug resistance? Perhaps woritinib combined with osimertinib is a breakthrough in the conclusion of the pharmacokinetic safety of clinical data

On May 3, 2021, the e-journal Springer Link reported the results of the TATTON study part C, which was designed to evaluate the initial efficacy and pharmacokinetic (PK) results of the monotherapy of voulitinib in patients with advanced solid tumors and data from volitinib combined with osiminib for patients with advanced non-small cell lung cancer (NSCLC) with advanced EGFR mutations, whose disease had progressed in previous EGFR-TKI therapy.

Volitinib is a potent and selective MET tyrosine kinase inhibitor (TKI). In a previous Phase II study (NCT02897479), the drug showed clinical efficacy and manageable safety in Patients with METex14-altered non-small cell lung cancer in China.

Trade name: Voressa

Generic name: Savolitinib/volitinib (sivotinib/volitinib)

Codename: HMPL-504/AZD6094

Target: c-MET

First approval in the United States: Not approved

First approval in China: June 2021

Approved indications: Locally advanced or metastatic non-small cell lung cancer with MET exon 14 jump mutation

Oscitinib is the third generation, irreversible oral EGFR-TKI that effectively and selectively inhibits EGFR-sensitive mutations and EGFR-T790M-resistant mutations and has been shown to be effective in patients with NSCLC brain metastases.

Trade name: Tagrisso

Common name: Osimertinib [Ossi (hysteretinib) ]

R&D code: AZD9291

Target: EGFR

First approval in the United States: November 2015

First approval in China: March 2017

Approved indications: Non-small cell lung cancer with EGFR mutation

Recommended dose: 80 mg once daily, with or without meals

< h1 class="pgc-h-arrow-right" data-track="25" > clinical data</h1>

TATTON is a phase IB, multi-arm, open-label, multicenter study divided into four parts (A-D) to assess the safety, tolerability, and antitumor activity of osimertinib plus volitinib (increasing the dose of the study drug) in patients with advanced NSCLC mutations who progress after EGFR-TKI treatment. Part C of this study includes study doses and dose extension cohorts.

In the monotherapy cohort, patients with advanced solid malignancies take 400 mg of goulitinib orally once daily, gradually increasing to 600 mg once daily.

In the cohort of combination therapy, patients with advanced EGFR mutation NSCLC receive oral osetinib 80 mg once daily and volitinib 400 mg once daily.

The main objective of the study was the safety and tolerability of woritinib in combination or without osetinib and to determine the combined dose for further clinical evaluation. The second objective of the monotherapy and combination therapy groups is to characterize the pharmacokinetic (PK) characteristics of volitinib and / or osetinib and their metabolites in a stable state after a single and multiple doses.

Secondary objectives of the combination group include an initial assessment of antineoplastic activity by assessing tumor response, including objective response rate (ORR), duration of response (DoR), changes in tumor size, and progression-free survival (PFS).

From 19 February 2015 to 22 August 2019, 17 patients received monotherapy with voulitinib and 12 patients received wolitinib in combination with osimertinib.

In the monotherapy group, the majority of patients had histology (71%) and metastatic disease (71%); 9 patients (53%) received more than three previous anti-cancer treatment regimens; 11 (65%) patients had received first- and second-generation EGFR-TKI treatment, while all patients (100%) received cytotoxic chemotherapy, of which 15 (88%) received platinum-based dual chemotherapy.

In the combination group, the majority of patients had histology of lung adenocarcinoma (100%) and metastatic disease (67%). 50% of patients received a previous anti-cancer regimen; all patients (100%) received first- and second-generation EGFR-TKIs according to eligibility criteria; and seven (58%) patients received cytotoxic chemotherapy.

The data showed that none of the 17 patients with advanced solid tumors in the monotherapy group had an objective response. Nine (53%) patients were stable (SD) ≥ 6 weeks, and 8 (47%) patients had disease progression (PD); the median PFS was 2.6 months, the 6-month PFS rate was 12.7%, and the 12-month PFS rate was 6.3%.

In patients with EGFR mutation NSCLC in the combination therapy group, the objective response rate (ORR) was 42%, 5 out of 12 patients had partial response (PR), and 7 (58%) patients were stable (SD) ≥ 6 weeks.

Of the five PR patients, 3 (60%) still responded after 3 months and 2 (40%) responded after 12 months; the maturity of the response data was 60%; the median PFS was 5.5 months; and the median DoR was 3.1 months.

<h1 class="pgc-h-arrow-right" data-track="49" > pharmacokinetics</h1>

Volitinib is rapidly absorbed and eliminated with an average half-life of 3.30-4.93 hours, no accumulation after multiple doses, similar to PK parameters after monotherapy and after combination with osimertinib.

<h1 class="pgc-h-arrow-right" data-track="53" > security</h1>

In the monotherapy group, 16 (94%) patients reported at least one adverse reaction (AE) during the study period. The most common adverse reactions were nausea (59%) and vomiting (41%). Seven patients (41%) reported adverse reactions of ≥3, including elevated ALT (18%), elevated AST (18%), drug allergy (6%), drug-induced liver injury (6%), lung infection (6%), maculopapular rash (6%), neutropenia (6%), fever (6%), and elevated white blood cells (6%).

In the combination treatment group, all patients reported at least one adverse reaction during the study period. The most common adverse effects were diarrhea (50%) and fever (42%). Four patients (33%) reported adverse reactions of ≥ 3, including anaphylactic shock, dental caries, bile duct stones, and skin reactions. Six patients (50%) discontinued the drug due to adverse reactions, including anaphylactic shock (8%), headache (8%), skin reactions (8%), myalgia (8%), peripheral edema (8%), and fever (17%).

<h1 class="pgc-h-arrow-right" data-track="59" > conclusion</h1>

These preliminary data suggest that there is acceptable safety for woritinib monotherapy or combination of osimertinib, suggesting that it may be a potential treatment option for patients with advanced solid tumors and advanced NSCLC with EGFR mutations who have progressed after previous treatment with EGFR-TKI.

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