Tarlox and Sotorasib in Patients With KRAS G12C Mutations

  • End date
    Dec 1, 2024
  • participants needed
  • sponsor
    Medical University of South Carolina
Updated on 21 April 2022
platelet count
cancer chemotherapy
lung carcinoma


This is a Phase IB dose expansion trial with safety lead-in evaluating the safety, clinical activity/efficacy of the combination of tarloxotinib and sotorasib in patients with KRAS G12C mutation who have progressed on any small molecule targeting KRAS G12C mutant Non-Small Cell lung cancer.


KRAS acts as a key protein in transducing signals from cell surface receptors, such as receptor tyrosine kinases (RTKs) into cells to initiate a network of cytoplasmic and nuclear signaling cascades that mediate key processes, such as cell cycle entry and cell survival that regulate normal tissue homeostasis. Due to the central importance of KRAS in mediating critical cellular processes, there are significant interconnected signaling feedback pathways that protect normal cells from uncontrolled proliferation and cell death. These signaling feedback pathways are also activated by tumor cells upon inhibition of mutated KRAS, which may result in intrinsic or acquired resistance to small molecule KRAS G12C inhibitors. Pre-clinical studies in non-small cell lung cancer (NSCLC) have shown that a key pathway that may be activated upon KRAS inhibition is the upstream ERBB RTKs, which provides the rationale for dual KRAS and ERBB blockade in overcoming resistance mechanisms in KRAS mutated NSCLC.

Lung cancer is the second most common cancer and the leading cause of cancer death in the United States. There were approximately 247,270 new cases of lung cancer that occurred in 2020. Prior studies have reported that lung cancer resulted in more deaths than breast cancer, prostate cancer, colorectal cancer, and leukemia combined in men ≥40 years old and women ≥60 years old. The past decade has seen a revolution of new advances in the management of non-small cell lung cancer (NSCLC) with remarkable progresses in screening, diagnosis, and treatment. The advances in systemic treatment have been driven primarily by the development of molecularly targeted therapeutics, immune-checkpoint inhibitors and anti-angiogenic agents, all of which have transformed this field with significantly improved patient outcomes. Despite these advances, most patients with advanced NSCLC have incurable disease, particularly after failure of a platinum-based chemotherapy regimen and check point inhibitors.

One of the earliest identified molecular drivers of NSCLC is the GTPase transductor protein called KRAS. It is a member of the RAS family of oncogenes and at the apex of multiple signaling pathways central to tumor cell proliferation. KRAS mutant lung cancers have worse outcomes in both early stage and advanced metastatic settings, illustrating the critical need for novel agents targeting KRAS-driven NSCLC. KRAS G12C mutations are present in ~15% of lung adenocarcinomas and 0-8% of other cancers. The missense mutation at codon 12 interferes with the GTPase, activating protein mediated GTP hydrolysis and shifting the equilibrium between the signaling-competent KRAS-GTP and signaling incompetent KRAS-GDP in favor of the GTP bound state. This process links upstream cell surface receptors such as the ERBB family (EGFR, HER-2, HER-3, HER-4) to downstream pathways such as RAF/MEK/ERK and PI3K/AKT/mTOR which leads to uncontrolled cell proliferation and survival.

Attempts to identify small molecular inhibitors of KRAS have been unsuccessful for many years as there was a lack of a clearly defined deep pocket in the structure of RAS outside of the nucleotide binding site and the challenge of targeting the nucleotide binding site due to extraordinarily high affinity of GTP. Recently, several pioneering studies have identified small molecule cysteine-reactive inhibitors that covalently modify the mutant KRAS G12C protein to reveal an allosteric switch II pocket. The induction of the structurally disordered pocket by these small molecule inhibitors converts the GTP preference of naïve KRAS G12C to the inactive GDP bound state, impairing its interaction with downstream effectors.

AMG510/Sotorasib was the first KRAS G12C inhibitor to the enter the clinic. A Phase I/II clinical trial involving 129 patients included 59 patients with KRAS G12C mutated NSCLC who had progressed on prior standard therapies. Patients were enrolled in dose escalation and expansion cohorts to receive daily sotorasib monotherapy (960 mg PO daily). At a median follow up of 12.2 months, approximately 50% of NSCLC patients demonstrated tumor regression with a confirmed objective response rate (ORR) of 37.1% (95% CI 28.6-46.2%) and a disease control rate (DCR) of 80.6% (95% CI 72.6-87.2%). The median time to objective response was 1.4 months and median duration of response was 10 months, with median progression free survival (PFS) of 6.8 months. The FDA has now accepted a new drug application and granted it a priority review for the treatment of patients with KRAS G12C mutant locally advanced or metastatic NSCLC following at least 1 prior systemic treatment, with an expected decision date by August 2021.

Although the results from these early-stage clinical trials showed promise, ~50% of KRAS G12C mutant NSCLC patients failed to respond to therapy and rate of relapse is high calling for the need for novel combinations to overcome intrinsic and acquired resistance mechanisms in this subset of patients.

It was previously thought that constitutively active oncogenic KRAS induces growth factor independence. However, recent evidence has suggested that specific KRAS mutant isoforms such as KRAS G12C may be regulated by upstream activation of several receptor tyrosine kinases. The pattern of RTK dependence appears to vary between KRAS G12C mutant cancer but numerous RTKs are involved in the adaptive feedback mechanism to G12C inhibition. This may be mediated through an adaptive RAS pathway activation. Silencing oncogenic KRAS in EGFR/HER dependent cells reduced cellular growth and induced a modest apoptotic signal. The depletion of KRAS expression by mutant specific siRNA was accompanied by a reduction in AKT phosphorylation in the ERBB dependent subset and activation of STAT3, which suggests a feedback loop via STAT3 that re-establishes oncogenic signaling thereby compensating for the loss of AKT survival signals. Pan ERBB inhibition in these KRAS G12C mutated NSCLC lines resulted in a potent suppression of growth and inhibition of receptor signaling and downstream signaling effectors. Thus, sole silencing of oncogenic KRAS may not be an effective therapeutic strategy in KRAS-addicted cancers since upstream events and feedback loops are likely to attenuate or annul the effects of the therapeutic intervention.

These pre-clinical studies provide a solid ground to evaluate the use of pan-ERBB inhibitors in combination with KRAS G12C inhibitors in patients with KRAS mutant lung tumors.

Tarloxotinib is a recently discovered novel prodrug that releases a potent, irreversible pan-ERBB (EGFR, HER2 and HER4) TKI. It is designed to be inactive under normal oxygen conditions but undergoes fragmentations under low oxygen conditions (hypoxia) to release the potent irreversible active metabolite (tarloxotinib-E) that has activity against both normal and mutant versions of the ERBB family. Selective production of tarloxotinib-E under hypoxic conditions generates a therapeutic window where it is selectively activated in hypoxic tumor regions to deliver higher drug delivery to tumor tissue. This reduces systemic exposure which avoids on-target EGFR related toxicities than standard EGFR TKI. In a mouse xenograft model of a human derived EGFR exon 20 insertion, intra-tumoral tarloxotinib-E levels were 20 time higher than skin and 50 times higher than plasma demonstrating selective tumor conversion. This strategy broadens the therapeutic window leading to improved efficacy, while reducing toxicity. Multiple pre-clinical studies have further demonstrated the efficacy of tarloxotinib compared to standard EGFR inhibitors.

Phase I clinical trials to determine the MTD and DLTs of tarloxotinib enrolled 27 patients with locally advanced or metastatic solid tumors. Of the patients that received tarloxotinib as a weekly 1-hour infusion, 6 patients received the drug at the recommended Phase 2 dose of 150 mg/m2 with good tolerance.

The combination of tarloxotinib with sotorasib is poised to provide highly specific tumor inhibition while targeting the vertical KRAS signaling pathway with minimal toxicity. The combination is unlikely to result in clinically relevant drug-drug interaction (DDI) based on absorption, metabolism, elimination or protein-binding. Tarloxotinib is intravenously administered while sotorasib is a small molecule that is administered orally; no absorption interactions are expected.

Condition Non-Small Cell Lung Cancer
Treatment Sotorasib and Tarloxotinib
Clinical Study IdentifierNCT05313009
SponsorMedical University of South Carolina
Last Modified on21 April 2022


Yes No Not Sure

Inclusion Criteria

Histologically confirmed diagnosis of squamous or non-squamous NSCLC with KRAS G12C mutation
Unresectable or metastatic disease
No available treatment with curative intent
Must have previously received treatment with at least a platinum-containing chemotherapy regimen
Must have previously received at least one month trial of sotorasib or a therapy targeting KRAS G12C mutation with documented progression. If sotorasib dose from prior therapy was reduced for toxicity, patients that meet the above criteria are expected to receive study treatment at the reduced dose
Must have measurable or evaluable disease as defined by RECIST 1.1
Age >18 years
Life expectancy of at least 3 months
Recovery from adverse effect of prior therapy at the time of enrollment
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Laboratory values within the screening period
Absolute neutrophile count > 1000/mm3
Platelet count > 100,000 /mm3
Hemoglobin > 8 in the absence of transfusions for at least 2 weeks
Total bilirubin < 1.5 x upper limit of normal (or < 3 x ULN if associated with liver metastases or Gilbert's disease)
Aspartate transaminase (AST) or alanine transaminase (ALT) < 3 x ULN (or < 5x ULN if associated with liver metastases
Creatinine clearance (CrCl) > 60 mL/min
Women of child-bearing potential agrees to use contraception while participating in
the study and for a period of 6 months following termination of study
Completed informed consent process
Willing to comply with clinical trial instructions and requirements

Exclusion Criteria

Active brain metastases. Patients are eligible if brain metastases are asymptomatic measuring no more than 2.0 cm each and confined to the cerebral hemispheres if neurologically stable and must be on a stable or tapering dose of corticosteroids for at least 2 weeks prior to C1D1
History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow pills
Congestive heart failure > NYHA Class 3
QTc > 480 milliseconds or family history of Long QT syndrome
Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be switched to alternative treatment prior to study entry
Pregnancy or breast feeding
Has known activating oncogene-driver mutations, including but not limited to KRAS, ALK, ROS1, RET, BRAF, NTRK1/2/3, MET, EGFR
Previously have received anti-EGFR or anti-HER2 TKIs
Previously have received anti-EGFR or anti-HER2 monoclonal antibodies
Clinically active or symptomatic interstitial lung disease
AST and ALT>3xULN if no hepatic metastases are present; >5xULN if hepatic metastases are present; total bilirubin >1.5xULN; 3xULN with direct bilirubin >1.5 x ULN in the presence of Gilbert's syndrome
Known concurrently malignancy that is expected to require active treatment within 2 years or may interfere with the interpretation of the efficacy and safety outcomes of this study
Infection requiring systemic treatment within 7 days prior to cycle 1 day1
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