The New England Journal of Medicine JUNE 24, 2021

Sotorasib in KRAS G12C–Mutated Non-Small-Cell Lung Cancer

Ferdinandos Skoulidis, Bob T. Li, Gregory J. Dy, et al.

Bottom Line

The CodeBreaK 100 trial demonstrated that sotorasib, a first-in-class KRAS G12C inhibitor, provides durable clinical benefit and an objective response rate of 37.1% in heavily pretreated patients with KRAS G12C–mutated advanced non-small-cell lung cancer.

Key Findings

1. In the phase 2 cohort, sotorasib achieved an objective response rate (ORR) of 37.1% (95% CI, 28.6 to 46.2), with 4 complete responses and 42 partial responses observed among 124 patients.

2. The median duration of response (DoR) was 11.1 months, indicating significant durability of treatment effect in this pretreated population.

3. Median progression-free survival (PFS) was 6.8 months, and median overall survival (OS) reached 12.5 months.

4. The disease control rate (DCR) was 80.6%, demonstrating stable disease or better for the vast majority of participants.

5. Sotorasib exhibited a manageable safety profile, with 69.8% of patients experiencing any-grade treatment-related adverse events and 19.8% experiencing grade 3 or higher events.

Study Design

Design

Phase 1/2 Trial

Open-Label

Sample

124

Patients

Duration

15.3 mo

Median

Setting

Multicenter, international

Population Patients with locally advanced or metastatic non-small-cell lung cancer harboring the KRAS G12C mutation who had previously received platinum-based chemotherapy and/or immune checkpoint inhibitor therapy.

Intervention Sotorasib 960 mg orally once daily.

Comparator None (Single-arm trial)

Outcome Objective response rate (ORR) as assessed by blinded independent central review.

Study Limitations

• The study was a single-arm, open-label trial without a randomized control group, which limits the ability to compare outcomes directly against current standards of care.

• The study population was heterogeneous regarding prior therapies, including various combinations of platinum-based chemotherapy and immune checkpoint inhibitors.

• As an early-phase trial, the sample size for some subgroups was relatively small, potentially affecting the precision of survival and duration estimates.

• The trial focused on a specific molecular subset, and the long-term toxicity profile warrants continued surveillance.

Clinical Significance

This trial established sotorasib as the first targeted therapy for the KRAS G12C mutation in NSCLC, overcoming a long-standing therapeutic hurdle in oncology and providing a vital, FDA-approved treatment option for patients who have exhausted standard systemic therapies.

Historical Context

The KRAS oncogene was identified over four decades ago, but for years it was considered 'undruggable' due to the protein's lack of obvious binding pockets. Sotorasib’s success in CodeBreaK 100 marked a paradigm shift, proving that direct inhibition of KRAS G12C is clinically achievable and provides meaningful benefits for lung cancer patients.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the specific biochemical mechanism that allows sotorasib to target the KRAS G12C mutation, and why was KRAS considered 'undruggable' for decades prior to this discovery?

Key Response

Sotorasib is a small molecule that specifically and irreversibly binds to the cysteine residue at position 12 (G12C) in the Switch-II pocket of the KRAS protein. This pocket is only present in the inactive, GDP-bound state. KRAS was historically considered undruggable because it lacked deep, high-affinity binding pockets for small molecules and has an extremely high affinity for its natural substrate, GTP, making competitive inhibition difficult.

Resident

A patient with metastatic NSCLC harboring the KRAS G12C mutation has progressed after treatment with carboplatin/pemetrexed and pembrolizumab. Based on the CodeBreaK 100 trial, what are the most common Grade 3/4 toxicities you should monitor for when starting this patient on sotorasib?

Key Response

In the CodeBreaK 100 trial, sotorasib was generally well-tolerated, but the most common treatment-related adverse events (TRAEs) of Grade 3 or higher were elevations in alanine aminotransferase (ALT) (6.3%) and aspartate aminotransferase (AST) (5.9%), followed by diarrhea (4.0%). Monitoring liver function tests (LFTs) is a critical part of the management protocol.

Fellow

The CodeBreaK 100 study performed exploratory analyses on co-mutations such as STK11, KEAP1, and TP53. How did the presence of these co-mutations, particularly STK11, influence the clinical response to sotorasib, and how does this compare to their impact on traditional immunotherapy?

Key Response

STK11 mutations are often associated with a 'cold' tumor microenvironment and poor response to immune checkpoint inhibitors. Interestingly, sotorasib showed clinical activity across these subgroups, with an objective response rate of 50% in the STK11-mutated/KEAP1-wild-type group, suggesting that sotorasib may overcome some of the primary resistance to immunotherapy seen in STK11-deficient tumors.

Attending

Given the results of CodeBreaK 100 showing a median progression-free survival (PFS) of 6.8 months and a median duration of response of 11.1 months, how does this redefine the treatment sequencing for KRAS G12C-mutated NSCLC compared to standard-of-care docetaxel?

Key Response

Sotorasib provides a more targeted, less toxic alternative to second-line docetaxel (which historically yields ORRs of 7-15% and PFS of ~3-4 months). While sotorasib is now the preferred second-line choice, the relatively short median PFS suggests that acquired resistance is nearly universal, necessitating early consideration of clinical trials or combinations (e.g., with SHP2 or EGFR inhibitors) upon progression.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Sotorasib binds to the inactive (GDP-bound) conformation of KRAS G12C. From a pharmacological perspective, how does the intrinsic rate of nucleotide exchange and the 'upstream' activation of the MAPK pathway by receptor tyrosine kinases (RTKs) act as a bottleneck for this drug's efficacy?

Key Response

Because sotorasib only binds the GDP-bound state, any cellular signal that increases the rate of nucleotide exchange (transitioning KRAS to the GTP-bound active state) reduces the window of opportunity for the drug to bind. Feedback reactivation of RTKs (like EGFR or HER2) can drive KRAS back into the active state, which sotorasib cannot inhibit, representing a major mechanism of adaptive resistance.

Journal Editor

The CodeBreaK 100 trial was a single-arm, Phase 2 study. What are the primary threats to internal validity when using objective response rate (ORR) as the primary endpoint in this setting, and how did the authors attempt to mitigate the risk of investigator bias?

Key Response

Single-arm trials lack a concurrent control to account for the natural history of the disease or patient selection bias. To mitigate investigator bias, the trial utilized a Blinded Independent Central Review (BICR) to assess tumor responses. However, the lack of a randomized comparator means that survival benefits (PFS/OS) remain descriptive until confirmed by Phase 3 data (CodeBreaK 200).

Guideline Committee

Based on the CodeBreaK 100 data, the FDA granted accelerated approval to sotorasib. Should the current NCCN guidelines prioritize sotorasib over docetaxel plus ramucirumab in the second-line setting for KRAS G12C mutations, and what level of evidence (1, 2A, or 2B) is currently supported?

Key Response

NCCN guidelines currently list sotorasib as a 'preferred' subsequent therapy for KRAS G12C-mutated NSCLC (Category 2A). While sotorasib shows superior ORR compared to historical docetaxel data, the Category 2A status reflects that high-quality evidence is based on Phase 2 data; a transition to Category 1 would typically require the results of a randomized Phase 3 trial demonstrating a statistically significant improvement in a primary endpoint like PFS.

Clinical Landscape

Noteworthy Related Trials

2015

CheckMate 017 Trial

n = 272 · NEJM

Tested

Nivolumab

Population

Patients with previously treated advanced squamous non-small-cell lung cancer

Comparator

Docetaxel

Endpoint

Overall survival

Key result: Nivolumab resulted in significantly longer overall survival than docetaxel in patients with advanced NSCLC.

2018

KEYNOTE-042 Trial

n = 1274 · NEJM

Tested

Pembrolizumab

Population

Patients with previously untreated locally advanced or metastatic NSCLC with PD-L1 expression

Comparator

Platinum-based chemotherapy

Endpoint

Overall survival

Key result: Pembrolizumab monotherapy significantly improved overall survival compared to chemotherapy in patients with PD-L1 TPS of 1% or greater.

2021

KRYSTAL-1 Trial

n = 116 · NEJM

Tested

Adagrasib

Population

Patients with KRAS G12C–mutated NSCLC previously treated with chemotherapy and immunotherapy

Comparator

None (single-arm study)

Endpoint

Objective response rate

Key result: Adagrasib demonstrated an objective response rate of 43% and a disease control rate of 80% in previously treated patients.

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