Mirati Therapeutics...announced the United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) granted conditional marketing authorization approval for KRAZATI® (adagrasib) as a monotherapy indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with KRASG12C mutation and have progressive disease after prior therapy with, or intolerance to, platinum-based chemotherapy and/or anti-PD-1/PD-L1 immunotherapy.

KRAZATI is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy.

For patients with advanced NSCLC and a KRAS G12C mutation who have received prior systemic therapy with chemotherapy and anti–programmed death (ligand)-1 therapy, clinicians may offer treatment (monotherapy) with adagrasib…

Non-Small Cell Lung Cancer….KRAS G12C Mutation...Subsequent therapy...Adagrasib

Mirati Therapeutics, Inc...announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to adagrasib for the potential treatment of patients with non-small cell lung cancer (NSCLC) who harbor the KRASG12C mutation following prior systemic therapy.

...- Histologically or cytologically confirmed diagnosis of NSCLC with KRAS G12C mutation....

...KRASG12C-mutation by local testing (by tissue or ctDNA)....

...- Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation (phase 2 must be either Non-Small Cell Lung Cancer or Colorectal Cancer)...

...1.Histologically confirmed diagnosis of NSCLC (squamous or nonsquamous) with KRAS G12C mutation and 2. ...

...MRTX0902 and adagrasib combination therapy: KRAS G12C mutation....

...- Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation...

...- KRASG12C-mutated solid malignancy determined by a sponsor-approved assay using either tumor tissue or ctDNA....

...Cohort A* (closed): Has an untreated and unresectable or metastatic NSCLC with histologically confirmed (squamous or nonsquamous) KRASG12C mutation and histologically confirmed PD-L1 TPS ≥1%....

...- Histologically or cytologically confirmed stage IV NSCLC- KRASG12C-mutation by local testing (by tissue or ctDNA)- Prior treatment with at least one line of systemic therapy for NSCLC (e.g., platinum-based doublet chemotherapy and/or immune-checkpoint inhibition or both).- Life expectancy ≥12 weeks- Measurable disease according to RECIST v1.1- Age ≥18 years with ECOG PS 2 (cohort 1), or age ≥70 years with ECOG PS 0-1 (cohort 2)- Adequate haematological, renal and liver function- Negative pregnancy test for patients of childbearing potential- Ability to comply with the trial protocol, in the investigator's judgment.-Written informed consent for protocol treatment must be signed and dated by the patient and the investigator prior to any trial-related intervention, including the submission of mandatory biomaterial. ...

...- Phase 2: Histologically confirmed diagnosis of unresectable or metastatic NSCLC with KRAS G12C mutation and any PD-L1 TPS...

...- Have advanced NSCLC or metastatic NSCLC (NSCLC that started in the lungs and then spread to other parts of the body) with the KRAS G12C mutation....

...- Histologically confirmed diagnosis of solid tumor malignancy (Phase 1) or NSCLC (Phase 2) with KRAS G12C mutation...

...- Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation (phase 1b must be either Non-Small Cell Lung Cancer or Colorectal Cancer)...

Mirati Therapeutics...announced that following a re-examination procedure, the Company has received a positive opinion from the European Medicine Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) on KRAZATI® (adagrasib) as a targeted treatment option for adult patients with KRASG12C -mutated advanced non-small cell lung cancer (NSCLC) and disease progression after at least one prior systemic therapy....KRYSTAL-1 is an open-label Phase 1/2 multiple-expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anti-cancer therapies in patients with advanced solid tumors harboring the KRASG12C mutation.

We evaluated adagrasib in patients with KRASG12C–mutated NSCLC and untreated CNS metastases from the KRYSTAL-1 trial...Adagrasib demonstrated an IC objective response rate of 42%, disease control rate of 90%, progression-free survival of 5.4 months, and median overall survival of 11.4 months.

Pts with previously treated KRASG12C-mutated NSCLC received ada 600 mg orally BID….ORR by blinded independent central review (BICR) was 42.9%, disease control rate 79.5%, median PFS 6.5 months (95% CI 4.7–8.4) and, with longer follow-up (cutoff 15 Jan 2022), median OS 12.6 months (95% CI 9.2–19.2)....Ada showed promising efficacy and manageable tolerability in previously treated pts with KRASG12C-mutated NSCLC.

In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C -mutated non-small-cell lung cancer (NSCLC)….Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2)....In patients with previously treated KRASG12C -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals.

In the phase II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib yielded an overall response rate of 43% and a disease control rate of 80% in patients with previously treated KRASG12C-mutant non-small cell lung cancer. After a median follow up of 12.9 months, overall survival was 11.7 months. The drug also shrank brain metastases in 33% of patients who had them.

Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM ({greater than or equal to}40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival....In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain....These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM.

Patients with advanced KRASG12C-mutant solid tumors were treated with adagrasib...Of these 20 patients, the primary diagnosis was KRASG12C-mutant non–small-cell lung cancer (NSCLC; n = 16), KRASG12C-mutant CRC (n = 2), and KRASG12C-mutant mucinous appendiceal carcinoma (n = 2), respectively. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non-small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response.

79 pts with pretreated NSCLC were treated with adagrasib 600 mg BID (phase I/Ib and phase II)….Among the 51 pts evaluable for clinical activity, 45% (23/51) had a partial response (PR) and 26 pts had stable disease (SD)….Adagrasib is tolerable and has demonstrated clinical activity in pts with previously treated KRASG12C-mutant NSCLC.

In a phase 1/2 multi-expansion cohort trial (KRYSTAL-1), adagrasib was evaluated in patients with advanced solid tumors harboring KRAS G12C mutations....Pooled data on responses to adagrasib showed an ORR of 43% in the 14 evaluable patients treated with the single agent in the phase 1/1b, which included PRs in 43% and SD in 57%, for a DCR of 100%.

Among the 51 patients evaluable for clinical activity (14 from Phase 1/1b; 37 from Phase 2), 45% of patients had an objective response (23/51 which includes 5 patients who had an unconfirmed partial response and remain on treatment). Disease control rate was 96% (49/51) of patients....Adagrasib is tolerable and demonstrates durable clinical activity in patients with previously treated KRAS G12C-mutant NSCLC.

...phase I trial 17 patients with solid tumors bearing KRAS G12C mutations….The initial MRTX849 dose of 150 mg once daily was escalated to doses up to 1,200 mg daily….Of the 12 evaluable patients, six had metastatic NSCLC and three had partial responses...treatment with MRTX849 was well tolerated...

In contrast to the LLC 46 NRAS KO model, orthotopic lung tumors established with the mKRC.1 cell line exhibited a significant single-agent anti-tumor response to MRTX-849...

...treatment with MRTX849 resulted in potent tumor regression and significant survival extension in another intracranial KRAS G12C model of NSCLC…