Amgen...announced that LUMAKRAS® (sotorasib) has been approved in Japan for the treatment of KRAS G12C-mutated positive, unresectable, advanced and/or recurrent non-small cell lung cancer (NSCLC) that has progressed after systemic anticancer therapy.

Amgen (NASDAQ: AMGN) today announced that the European Commission (EC) has granted conditional marketing authorization for LUMYKRAS® (sotorasib), a first-in-class KRASG12C inhibitor, for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation and who have progressed after at least one prior line of systemic therapy.

Amgen today announced that Health Canada has approved LUMAKRASTM (sotorasib) for the treatment of adult patients with KRAS G12C-mutated locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy.

The UK's Medicines and Healthcare Products Regulatory Agency (MHRA) on Friday approved Amgen's sotorasib (Lumakras) for advanced non-small cell lung cancer patients whose tumors harbor a KRAS G12C mutation.

The Ministry of Health and Prevention has recently approved the registration and use of Amgen’s lung cancer drug Lumakras...The drug is prescribed to adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received at least one previous cancer therapy.

LUMAKRAS 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, clinicians may offer treatment (monotherapy) with sotorasib...

NICE has today (Thursday, 3 March) published its final appraisal document on sotorasib (also known as Lumykras and made by Amgen), a once-a-day tablet, which is being recommended for people with the KRAS G12C gene mutation of non-small-cell lung cancer who have progressed on, or are intolerant to, platinum-based chemotherapy and/or immunotherapy.

Non-Small Cell Lung Cancer: KRAS G12C mutation positive…Sotorasib

We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries....Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs.

In this global, open-label phase 3 trial, 345 patients (pts) with KRAS G12C-mutated NSCLC who progressed after prior platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to oral sotorasib (960 mg daily) or intravenous docetaxel (75 mg/m2 every 3 weeks)....In this first, randomized phase 3 trial for a KRASG12C inhibitor, oral sotorasib demonstrated superior PFS and ORR compared to intravenous docetaxel and had a more favorable safety profile.

Amgen...announced that the global Phase 3 CodeBreaK 200 trial evaluating once daily oral LUMAKRAS® (sotorasib) met its primary endpoint of progression-free survival (PFS), demonstrating statistical significance and superiority over standard of care chemotherapy, intravenous docetaxel. The first randomized clinical trial for a KRASG12C inhibitor assessed the efficacy and safety of LUMAKRAS in 345 previously treated patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) who had received at minimum, prior platinum-based doublet chemotherapy and checkpoint inhibitor therapy.

Amgen (NASDAQ:AMGN) today announced that the U.S. Food and Drug Administration (FDA) has granted Priority Review for sotorasib for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), following at least one prior systemic therapy.

Amgen today announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for its investigational KRASG12C inhibitor, sotorasib, for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with KRAS G12C mutation, as determined by an FDA-approved test, following at least one prior systemic therapy.

...Pathologically documented, previously treated, locally-advanced and unresectable or metastatic NSCLC with KRAS p.G12C mutation...

Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib expanded access program between April 2021 to February 2022….The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached), with a 1-year mortality rate of 48.5%.

Median rwPFS was 4.2 ms [95%CI 3.3;4.9], and median OS was 9.3 ms [95%CI 7.9 ;12.3]. Objective response rate (ORR) was 34.3% [95%CI 28.4; 40.1] and disease control rate (DCR) was 64.2%....Our IFCT-2102 study confirms the effectiveness of sotorasib in pretreated KRAS G12C-NSCLC pts, and its safety profile is manageable with hepatic grade 3 or 4 TRAEs occurring in 7% of pts.

...we report real-world efficacy and tolerability data from NSCLC patients who received sotorasib within the Italian expanded access program (EAP)....Overall, response rate was 26% and disease control rate 66%. Median PFS was 6.1 months (95% CI: 5.6 – 9.1)….Real-world data from the Italian EAP confirm the activity and tolerability of sotorasib in pre-treated patients with KRAS p.G12C-mutated advanced NSCLC.

...objective responses were seen in 37.4% of patients with KRAS G12C positive advanced NSCLC taking 960mg sotorasib orally per day.

The combination of sotorasib, pemetrexed and carboplatin showed promising clinical activity in KRAS G12C-mutated advanced NSCLC in both the 1L and 2L setting. This combination was safe and tolerable, with incidences of grade 3-4 TRAEs largely consistent with other platinum doublet-based approaches.

A total of 128 patients from 72 different VA medical centers received sotorasib for KRAS G12C-mutated advanced NSCLC between June 2021 and February 2023....Among the 92 patients assessed for response, ORR was 34% and disease control rate 71%. The median time to response was 2.4 months and median duration of response 4.0 months.

Among 105 patients with advanced KRAS G12C-mutant NSCLC treated with sotorasib, treatment led to a 5.3-month median rwPFS, 12.6-month median OS, and 28% real-world response rate.

Pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to sotorasib (960 mg daily; n=171) or docetaxel (75 mg/m2 every 3 weeks; n=174)….With a median follow-up of 20.0 months, the median systemic PFS by RECIST 1.1 in the FAS was 6.1 months versus 4.5 months (HR 0.57 [95% CI: 0.30, 1.07], P=0.045) for sotorasib versus docetaxel, respectively....These results suggest IC activity with sotorasib to complement the overall PFS benefit observed with sotorasib versus docetaxel.

This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib….Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%.

Amgen study 20190436 (study-436) is a global protocol under the sotorasib EAP which allowed compassionate use of sotorasib, a first-in-class KRAS G12C inhibitor, in previously treated patients (pts) with KRAS G12C-mutated aNSCLC….Here we present the median OS data from study-436....Among the subgroups, the median OS was numerically longer in pts with ECOG PS 0 or 1 vs ECOG PS 2; with up to 2 vs > 2 prior lines of anticancer therapies; and in pts with former vs current smoking history (table). The median OS was numerically similar between patients with vs without a history of CNS metastases.

We explored whether the presence of specific mutations and dynamic changes in circulating tumor DNA (ctDNA) would be of prognostic/predictive value for patients (pts) with KRAS G12C mutations on sotorasib....At baseline, 77% of pts (129/168) had detectable plasma KRAS G12C mutations. Lower G12C allele frequency (AF) at baseline correlated with better % change in radiographic Sum of Diameters (SoD) (Spearman’s rho=0.22, p <0.001). Pts without baseline detectable plasma KRAS G12C had a median PFS of 11.5 months as compared to 4.1 months in those with detectable G12C (HR 2.8, p<0.001), and were more likely to respond (HR = 2.76, p <0.001)....At baseline, lower G12C AF and lower number of altered genes were associated with improved outcomes...

We treated 4 patients with sotorasib...Sotorasib showed deffinitve clinical efficacy in NSCLC patients with KRAS G12C mutation.

Among 93 patients with advanced KRAS G12C-mutant NSCLC treated with sotorasib, treatment led to a 26.7% real-world response rate, 5.0 month median rwPFS, and median time on treatment of 6.0 months.

Amgen...today announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending conditional marketing authorization of LUMYKRAS® (sotorasib), known as LUMAKRAS® in the U.S., for the treatment of adults with advanced non-small-cell lung cancer (NSCLC) with KRAS G12C mutation and who have progressed after at least one prior line of systemic therapy. If the European Commission follows the recommendation for approval, LUMYKRAS will be the first targeted therapy available in the European Union (EU) for the KRAS G12C mutation, one of the most prevalent biomarkers in NSCLC.

The phase 1/2 CodeBreaK 100 trial evaluated sotorasib in patients with pretreated advanced non-small cell lung cancer (NSCLC) harboring KRAS p.G12C….Patients from the phase 1/2 CodeBreaK 100 trial receiving 960mg dose were included….Of 13 patients with non-target CNS lesions, 2 had CR, 11 had SD. Of 3 patients with target lesions, 1 had SD, and 2 had PD. Overall, intracranial disease control was achieved in 14 of 16 patients (87.5%) with evaluable BM....Sotorasib demonstrated systemic durable anticancer activity, with a median PFS and OS of 5.3 and 8.3 months in NSCLC patients with stable BM previously treated with radiation or surgery. Intracranial complete responses were observed, with continued intracranial stabilization observed in the majority of patients with evaluable BM.

The phase 1/2 CodeBreaK 100 trial evaluated sotorasib in patients with pretreated advanced non-small cell lung cancer (NSCLC) harboring KRAS p.G12C….Patients from the phase 1/2 CodeBreaK 100 trial receiving 960mg dose were included….Sotorasib demonstrated systemic durable anticancer activity, with a median PFS and OS of 5.3 and 8.3 months in NSCLC patients with stable BM previously treated with radiation or surgery.

In these exploratory analyses of the registrational phase 2 CodeBreaK 100 trial, the clinical benefit of sotorasib in KRASG12C-mutated NSCLC was observed across a range of patient subgroups including patients with low PD-L1 expression level and those with co-occurring STK11 mutation.

An objective response was observed in 46 patients...including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response...The median duration of response was 11.1 months...Disease control occurred in 100 patients...The median progression-free survival was 6.8 months...and the median overall survival was 12.5 months....In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C–mutated NSCLC.

Amgen...announced that its investigational KRASG12C inhibitor sotorasib was granted Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA). The designation is for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy.

This study was included 20 patients with treatment naïve metastatic NSCLC with KRAS G12C...The overall DCR was 88.1%. Of the patients who hPatients were followed on sotorasib for a median of 11.7 months...The overall DCR was 88.1%. Of the patients who had a response to sotorasib, the median DOR was 10.9 months (1.1+ to 13.6), and the median duration of SD was 4.0 months (1.4 to 10.9+). The median PFS was 6.3 months (0.0+ to 14.9).

At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1)….In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C...

We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation….In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months....Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation.

CONTRADICTING EVIDENCE: The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR-wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms...The KRAS G12C mutation is a biomarker of poor prognosis in Chinese NSCLC patients, which could potentially be improved by G12C-specific inhibitors in the future.(296 words).

Early results suggest antitumor activity of single-agent AMG 510 in pts with KRASG12C mutant solid tumors.

...we investigated the additive effect of radiation and KRAS-MEK inhibitors (AMG510 and trametinib) in KRAS-mutated tumors....The four human cancer cell lines with the KRAS G12C mutation had different sensitivities to AMG510, and the CCK-8 assay showed that miapaca2 and H358 cells were more sensitive to AMG510 than the other cell lines (Figure 1B) and were also sensitive to MEKi...

...we tested if anti-EGF VacAbs could improve the antitumor activity of capmatinib, tepotinib and sotorasib in MET amplified, MET Δ14 and KRAS mutant non-small cell lung cancer (NSCLC) cell lines....In combination, anti-EGF VacAbs significantly enhanced the antitumor activity of capmatinib and tepotinib in EBC1 (MET-amplified) and Hs746T (METΔ14), potentiating the blockade of EGFR, Akt and Erk 1/2 phosphorylation. The same effects were observed when combining anti-EGF VacAbs with sotorasib in H2122 and H23 (G12C) cells.