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▎WuXi AppTec content team editor
Nuvalent today announced the initial results
of its ROS1 inhibitor NVL-520 in a phase 1/2 clinical trial.
Data analysis showed that NVL-520 has a good safety profile and tolerability, and shows preliminary efficacy in those patients with ROS1-positive non-small cell lung cancer (NSCLC) who have undergone a large number of pre-treatment, including those with brain metastases and G2032R resistance variants
.
This indicates that NVL-520 is a potential "best-in-class" ROS1 selective inhibitor that may have the potential to overcome the limitations of existing approved or investigational ROS1 tyrosine kinase inhibitors (TKIs)!
Lung cancer is the most common type of cancer and the leading cause of
cancer death.
In 2020 alone, more than 1.
7 million people
died of lung cancer worldwide.
The pathological classification of lung cancer can be roughly divided into two categories: NSCLC and small cell lung cancer (SCLC), of which NSCLC is the highest lung cancer type, accounting for about 80%-85% of
lung cancer cases.
About 1% to 2% of patients with NSCLC carry ROS1 gene rearrangement, a mutated form of the ROS1 gene that often occurs in the NSCLC subtype, and in such patients the ALK, KRAS, and EGFR gene mutations are negative
in their tumors.
NVL-520 is an innovative, selective, brain-permeable ROS1 inhibitor designed to treat cancers that are resistant to existing ROS1 inhibitors, such as those with G2032R, S1986Y/F, L2026M or D2033N mutations
.
Because NVL-520 is brain permeable, it has the potential to improve the treatment of those with metastases to the
brain.
In preclinical trials, NVL-520 was able to selectively inhibit wild-type ROS1 and its resistance-associated variants, while avoiding inhibition of the tropomyosin receptor kinase (TRK) family
, which is structurally similar to ROS1.
Therefore, NVL-520 has the potential to avoid TRK-related CNS adverse effects, allowing patients to receive longer-lasting treatment
.
Such adverse effects are common
in many TRK/ROS1 inhibitors.
The Phase 1/2 trial of ARROS-1 is a "first-in-human" study of NVL-520 that recruits ROS1-positive NSCLC and other solid tumor patients who have previously received upfront treatment
.
Patients were assigned to 5 different cohorts and treated
with NVL-520 of 25, 50, 75, 100, and 125 mg per day.
Before the data deadline of September 13, 2022, there were 21 patients with NSCLC who were able to undergo efficacy review (after one to more than eight months of treatment), and the preliminary analysis results of the data were as follows:
Of all patients with reviewable efficacy, 48% (10/21) achieved a partial response (PR) and 76% (16/21) continued treatment in the trial
.
Of the patients receiving all doses, 53% (9/17) had a remission in those who had previously received at least 2 lines or more of TKIs and at least 1 line of upfront chemotherapy, and 50% (9/18) of those who had previously been treated with lorlatinib or repotrectinib multikinase inhibitors experienced remission
.Of the 9 patients with the ROS1 G2032R resistance mutation, 78% (7/9) experienced a response, including 2 (2/3) patients
who had previously been treated with repotrectinib.
Another 100% (9/9) of patients have tumor shrinkage
.
It is worth noting that all 7 patients with G2032R variant circulating tumor DNA (ctDNA) were not detected with mutated ctDNA
after treatment.
100% (3/3) of patients with measurable (>10 mm) central nervous system metastases achieved partial intracranial remission
.
Remission occurred in 73% (8/11) of patients with a history of CNS metastases, and no CNS disease progression was observed in all patients
.
In addition, NVL-520 demonstrated a favorable safety profile
among all 35 enrolled patients.
Prior to the data cut-off date, no dose-limiting toxicity, treatment-related serious adverse effects, and no adverse effects resulting in dose reduction or trial interruption were observed
.
Most treatment-related adverse effects were low and manageable
.
To date, trials have not reached the maximum tolerated dose
.
"We believe today's preliminary results support Nuvalent's R&D strategy
.
This strategy not only brings encouraging initial results to NVL-520, but also strengthens the development
of all our pipeline drugs.
" I congratulate the Nuvalent team for their tireless efforts and sincerely thank all the patients, caregivers and researchers
who participated in the ARROS-1 trial.
" ”
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.
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