Targeting KRAS G12C in NSCLCShaping the Future Standard of Care

The treatment landscape for KRAS G12C–mutant NSCLC has evolved considerably in recent years, with KRAS G12C inhibitors becoming part of the standard of care for locally advanced or metastatic NSCLC in the second-line setting. Despite this progress, targeted therapies are not available in the first-line setting.

KRAS is a common oncogenic driver in non–small cell lung cancer (NSCLC), present in 25% to 33% of patients.1,2 KRAS G12C is the most common KRAS variant, occurring in approximately 41% of patients with KRAS-mutant NSCLC.1

The treatment landscape for KRAS G12C–mutant NSCLC has evolved considerably in recent years, with KRAS G12C inhibitors becoming part of the standard of care for locally advanced or metastatic NSCLC in the second-line setting.3 Although KRAS was traditionally considered “undruggable,” recent phase III studies have demonstrated improved progression-free survival (PFS) with the KRAS G12C inhibitors sotorasib and adagrasib compared with docetaxel in patients with locally advanced or metastatic NSCLC who have received at least one prior systemic therapy, leading to their U.S. Food and Drug Administration (FDA) approval in this setting.3,4-7

While patients with advanced KRAS G12C–mutant NSCLC who show disease progression after prior systemic therapy are eligible for targeted therapies, targeted therapies are not available in the first-line setting, and treatment for previously untreated patients follows nondriver alteration guidelines.8,9 The current recommendation for previously untreated patients with advanced KRAS G12C–mutant NSCLC remains largely based on PD-L1 status.8

It is critical to develop next-generation KRAS G12C inhibitors with greater clinical activity than existing approved agents that can be brought up to the first-line setting and be safely and effectively combined with immune checkpoint blockade. Jonathan Riess, MD, MS

“Patients with KRAS G12C–mutant NSCLC continue to face major unmet needs driven by limited response rates and durability of response with currently approved KRAS G12C–directed inhibitors and a lack of effective treatment options after progression,” said Jonathan Riess, MD, MS, Director of Thoracic Oncology and Director of Early Phase Therapeutics at UC Davis Comprehensive Cancer Center.

In the first-line setting, patients with advanced KRAS G12C–mutant NSCLC are offered standard treatment with immune checkpoint inhibitor therapy with or without chemotherapy.8,9 In a retrospective analysis of patients with KRAS G12C–mutant advanced NSCLC treated with first-line pembrolizumab-based regimens, less than 40% received second-line therapy.10 This real-world evidence highlights the significant unmet need for more effective first-line treatments.

“It is critical to develop next-generation KRAS G12C inhibitors with greater clinical activity than existing approved agents that can be brought up to the first-line setting and be safely and effectively combined with immune checkpoint blockade,” Dr. Riess stated.

Biology of KRAS G12C–Mutant NSCLC

Oncogenic Signaling in KRAS G12C–Mutant NSCLC

KRAS is a small GTPase that cycles between active GTP-bound and inactive GDP-bound conformations (Figure 1).3,11 Oncogenic KRAS mutations reduce intrinsic GTP hydrolysis and sustain downstream signaling through the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, thereby promoting cell proliferation, survival, invasion, and metastasis.3,12,13

Although KRAS G12C is an oncogenic driver that predominantly accumulates in the active, GTP‑bound conformation, the mutant protein continues to cycle through the GDP-bound state, making it amenable to pharmacological inhibition.3,12,13 This residual cycling enables the activity of small-molecule KRAS G12C inhibitors, which bind the mutant cysteine and irreversibly lock KRAS G12C in its inactive, GDP‑bound form, thereby suppressing downstream signaling.3,12 Additional mechanisms of action for KRAS G12C inhibitors, including distinct binding modes, are under investigation.3

Figure 1

Figure 1. Intracellular Signaling Pathways of KRAS G12C (A), Mechanism of Action for KRAS G12C Inhibitors (B), and Interconversion Between KRAS-GTP and KRAS-GDP Bound States (C)

Adapted from Zhang et al.16 Licensed under the Creative Commons Attribution (CC BY) License: http://creativecommons.org/licenses/by/4.0/.

Abbreviations: GDP = guanosine diphosphate; GTP = guanosine triphosphate; KRAS = Kirsten rat sarcoma viral oncogene homolog; NSCLC = non–small cell lung cancer.

In preclinical models, inhibition of KRAS G12C suppresses downstream RAF/MEK/ERK and PI3K/AKT/mTOR signaling, leading to reduced cell proliferation, increased apoptosis, and induction of cell death in KRAS G12C–mutant tumor cells.12,13 KRAS‑mutant NSCLC exhibits increased production of pro‑tumorigenic inflammatory cytokines (eg, IL‑6) driven by KRAS‑dependent signaling pathways, including MAPK and IL‑1β/TBK1/NF‑κB signaling.14 These cytokine‑mediated autocrine and paracrine loops activate STAT3 and other survival pathways that promote tumor growth.14 Inhibition of KRAS G12C suppresses downstream pathways such as RAF, reducing tumor‑promoting signaling.14

Tumor Immune Microenvironment in KRAS G12C–Mutant NSCLC

Oncogenic KRAS mutations, including KRAS G12C, are associated with alterations in the tumor microenvironment (TME), including immune suppression and metabolic reprogramming, which contribute to immune escape.15,16 Analysis of samples from patients with lung adenocarcinoma showed that oncogenic KRAS G12C upregulates CD47, an anti-phagocytic signal.17 This upregulation occurs through PI3K/STAT3 signaling, which suppresses miR-34a and thereby releases CD47 from post-transcriptional repression. The result is reduced macrophage phagocytosis, which may help tumor cells avoid innate immune clearance.17 KRAS G12C also shapes the myeloid compartment in the TME. In NSCLC mouse models, treatment with an SHP2 inhibitor resulted in recruitment of S100A8hi granulocytic myeloid-derived suppressor cells that suppressed Klrg1+ CD8+ effector T-cell function via CXCR2 ligand signaling.18 Combining SHP2 inhibition with CXCR2 inhibition reversed this, increasing cytotoxic T-cell infiltration and improving survival in mice harboring KRAS-mutant NSCLC.18 In addition, retrospective analysis of samples from patients with NSCLC showed that patients with KRAS G12C mutations had higher levels of PD-L1 than those with KRAS non-G12C mutations, which could enhance T-cell exhaustion through PD-1/PD-L1 signaling on T cells.19

Benjamin Levy, MD, Associate Professor at Johns Hopkins School of Medicine, emphasized that the immunogenic properties of KRAS G12C set it apart from other oncogenic drivers. “KRAS G12C is different from alterations like EGFR and ALK, where checkpoint inhibitors are generally not considered a productive strategy,” said Dr. Levy. “We know that KRAS G12C is immunomodulatory—that the mutation lends itself to immune remodeling and changes the immune microenvironment in ways that make these tumors evade the immune system; however, these tumors respond to immunotherapeutic approaches.”

We know that KRAS G12C is immunomodulatory—that the mutation lends itself to immune remodeling and changes the immune microenvironment in ways that make these tumors evade the immune system; however, these tumors respond to immunotherapeutic approaches.Benjamin Levy, MD

In preclinical studies, KRAS inhibitors have been shown to remodel the TME toward an immune‑responsive state, providing a scientific rationale for combining inhibitors and immunotherapy.15,16 Inhibition of KRAS G12C in mouse models was found to shift the TME toward a pro-inflammatory state, increasing T-cell infiltration, interferon signaling, and chemokine production, and showing synergy with anti–PD-L1 therapy.20 In another preclinical study, inhibition of G12C in mice with KRAS G12C–mutant tumors reduced the numbers of immunosuppressive myeloid cells in tumors and increased the numbers of M1-polarized macrophages, dendritic cells, and CD4+ and CD8+ T cells.21 In addition, a comparison of biopsy samples from G12C inhibitor–naive and G12C inhibitor–treated patients with NSCLC showed that tumors from G12C inhibitor–treated patients had higher levels of CXCL1 and CXCL6 than those from G12C inhibitor–naive patients, further supporting the notion that targeting KRAS G12C mutations could modulate the tumor immune microenvironment.18

Co-Mutations in KRAS G12C–Mutant NSCLC

KRAS G12C mutations in NSCLC often co-occur with other mutations that may have a clinical impact. A next-generation sequencing study of samples from 772 patients with KRAS-mutant NSCLC showed that the most common co-mutations among the 352 patients with KRAS G12C were TP53 (43%), STK11 (28%), and KEAP1 (23%).19 In the PD‑L1 ≥ 50% subgroup, STK11 and KEAP1 co‑mutations were low and similar between G12C and non‑G12C tumors (STK11: 11% vs 8%; KEAP1: 11% vs 12%).19 Although the frequencies of co‑mutations were similar between G12C and non‑G12C tumors, KRAS G12C–mutant tumors exhibited a more immunogenic molecular phenotype, characterized by greater tumor mutational burden and higher PD‑L1 expression.19

Real-world data from patients with advanced KRAS G12C–mutant NSCLC treated with KRAS G12C inhibitor monotherapy (N = 424; 21 centers in the U.S./EU) suggest that co-mutations in KEAP1, SMARCA4, and CDKN2A are associated with poor outcomes.22 Mutations in KEAP1, SMARCA4, or CDKN2A were collectively present in 32% of patients with KRAS G12C–mutant NSCLC, were enriched among patients with early disease progression (PFS ≤ 3 months), and were associated with poor PFS and overall survival (OS).22 Although enriched in early progression, STK11 co-mutations alone were not associated with objective response rate (ORR), PFS, or OS.22 Mutations in DNA damage response genes (BRCA1/2, ATM, ATR, CHEK1/2, PALB2, RAD50/51 family) were associated with longer PFS.22 Co-mutations in TP53 (present in 45.7% of patients) were not associated with outcomes.22

“These co-alterations are more prognostic right now than they are predictive,” Dr. Levy said. “When STK11 or KEAP1 co-mutations occur alongside KRAS G12C, they tend to portend worse outcomes, not only with KRAS G12C inhibitors, but also with immunotherapeutic approaches. But given the pace of development of novel KRAS G12C therapies, I don’t think we are ready to stratify trials or select patients based on co-alterations occurring alongside KRAS G12C mutations.”

Co-mutations may also modulate the TME in KRAS G12C–mutant NSCLC.15 KRAS G12C–mutant tumors with concurrent TP53 mutations tend to show a hot immune phenotype characterized by higher PD-L1 expression and greater cytotoxic T-cell infiltration.23 ORR in this subgroup after treatment with immune checkpoint inhibitors (ICIs) is typically 35.7%.23 By contrast, KRAS/LKB1 co-mutations are associated with a cold TME, characterized by sparse T-cell infiltration, low PD-L1 expression, and ICI response rates below 10%.24,25

CNS Involvement in KRAS G12C–Mutant NSCLC

Central nervous system (CNS) metastases are common in patients with KRAS G12C–mutant NSCLC.26 A population-based study of the Swedish Lung Cancer Registry showed that among patients with advanced NSCLC, CNS metastasis was more common in patients with KRAS G12C mutations than in those with other KRAS mutations or wild-type KRAS. In addition, a higher proportion of patients with KRAS G12C mutations presented with CNS involvement as the sole site of distant metastasis compared to KRAS-other and KRAS–wild-type subgroups.26

Outcomes for patients with KRAS-mutant NSCLC (including those with KRAS G12C mutations) who have CNS metastases are worse than those without CNS involvement.27,28 Real-world data suggest that current standard-of-care systemic treatments for first-line KRAS G12C–mutant NSCLC (ie, immunotherapy with or without chemotherapy) show modest intracranial responses in patients with NSCLC, creating the need for treatments with CNS penetrance and intracranial efficacy.29

There remains an unmet need for more CNS-penetrant KRAS G12C inhibitors.Jonathan Riess, MD, MS

Dr. Riess acknowledged that existing KRAS G12C inhibitors have shown some intracranial activity,27,28 but underscored the limitations. “There has been modest activity shown with KRAS G12C inhibitors, such as with adagrasib showing intracranial response rates that generally track with systemic activity,” he noted. “However, there remains an unmet need for more CNS-penetrant KRAS G12C inhibitors.”

Targeting KRAS G12C Mutations in Advanced NSCLC

Approved KRAS G12C Inhibitors in Pretreated NSCLC

KRAS G12C inhibitors sotorasib and adagrasib are FDA-approved for the treatment of patients with locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.3,4-7 Sotorasib and adagrasib are both first-generation inhibitors that work by irreversibly trapping KRAS in its inactive GDP-bound (RAS OFF) state.3 Next-generation inhibitors, including RAS OFF agents with improved potency and pharmacological profiles (eg, divarasib, olomorasib, calderasib) and novel RAS ON inhibitors that covalently bind the active GTP-bound form of KRASG12C, are under investigation.3

Sotorasib

Sotorasib was approved on the basis of the phase I/II CodeBreaK 100 trial.3 In the 2-year pooled analysis of CodeBreaK 100, sotorasib treatment resulted in an ORR of 41%, a median duration of response (DOR) of 12.3 months, a median PFS of 6.3 months, and a median OS of 12.5 months. Any-grade treatment-related adverse events (TRAEs) were reported in 70% (121/174) of patients, with grade 3 in 20% (34/174), and grade 4 in 1% (2/174); TRAEs led to treatment reduction or interruption in 22% (39/174) and treatment discontinuation in 6% (11/174).30

In the randomized phase III CodeBreaK 200 trial, sotorasib improved PFS compared with docetaxel (HR = 0.66 [95% CI = 0.51–0.86]; P = .0017) but did not show a significant OS advantage (HR = 1.01 [95% CI = 0.77–1.33]).7

Adagrasib

Adagrasib was approved on the basis of the single-arm phase II KRYSTAL-1 expansion cohort trial.3 Among 116 previously treated patients, the confirmed ORR was 42.9%, the median DOR was 8.5 months, the median PFS was 6.5 months, and the median OS was 12.6 months. Among 33 patients with previously treated stable CNS metastases, intracranial confirmed ORR was 33.3%.31 Any-grade TRAEs occurred in 97.4% (113/116) of the patients, and grade ≥ 3 TRAEs in 44.8% (52/116). Treatment discontinuation due to TRAEs occurred in 6.9% of patients (8/116).31

In the confirmatory, randomized, open-label, phase III KRYSTAL-12 trial, adagrasib demonstrated a significant improvement in PFS compared with docetaxel in patients with previously treated KRAS G12C–mutant advanced NSCLC (median PFS 5.5 vs 3.8 months; HR = 0.58 [95% CI = 0.45–0.76]; P < 0.0001).6 The ORR was higher with adagrasib than with docetaxel (32% vs 9%; P < 0.0001), with a median DOR of 8.3 vs 5.4 months, respectively.6 Grade ≥ 3 TRAEs occurred in 47% of patients treated with adagrasib and 46% of those treated with docetaxel; no new safety signals were identified.6

Ongoing Phase III Trials of Targeted Therapies in the First-Line Setting

Table 1 summarizes ongoing phase III trials evaluating KRAS G12C inhibitors in combination with immunotherapy, chemotherapy, or both in the first-line treatment of advanced NSCLC.

Table 1

Table 1. Ongoing Phase III Trials of First-Line KRAS G12C Inhibitors in Advanced NSCLC

Explore current phase III studies by investigational agent, eligibility profile, and trial endpoints.

Sotorasib

CodeBreaK 20232,33(NCT05920356)

Interventions and Doses

  • Arm A: Sotorasib (960 mg QD orally) + carboplatin + pemetrexed
  • Arm B (comparator): Pembrolizumab + carboplatin + pemetrexed (IV chemotherapy administered Q3W)

Key Inclusion/Exclusion Criteriaa

  • Inclusion: Advanced/metastatic KRAS G12C–mutant NSCLC; PD-L1 TPS < 1%; nonsquamous histology; treatment-naive for metastatic disease
  • Exclusion: Prior therapy with a KRAS G12C inhibitor; symptomatic (treated or untreated) CNS metastases; mixed histology

Primary and Key Secondary Endpoints

  • Primary: PFS (Blinded Independent Central Review per RECIST v1.1)
  • Key secondary: OS, ORR

Adagrasib

KRYSTAL-734,35(NCT04613596)

Interventions and Doses

  • Arm A: Adagrasib (400 mg BID orally) + pembrolizumab (200 mg IV Q3W, up to 35 cycles)
  • Arm B (comparator): Pembrolizumab (200 mg IV Q3W, up to 35 cycles)

Key Inclusion/Exclusion Criteriaa

  • Inclusion: Unresectable, locally advanced or metastatic KRAS G12C–mutant NSCLC (squamous or nonsquamous); PD-L1 TPS ≥ 50%
  • Stratification: CNS metastasis history; region (Asia Pacific vs non–Asia Pacific); ECOG PS 0 vs 1
  • Exclusion: Prior systemic therapy for metastatic NSCLC; radiation to the lung > 30 Gy within 6 months prior to the first dose of study treatment

Primary and Key Secondary Endpoints

  • Co-primary: PFS by BICR and OS
  • Key secondary: Safety/tolerability, ORR, DOR, adagrasib PK, health-related QoL

Adagrasib

KRYSTAL-436,37(NCT06875310)

Interventions and Doses

  • Arm A: Adagrasib (400 mg BID orally) + pembrolizumab (200 mg IV Q3W, up to 24 months) + pemetrexed (500 mg/m2) + cisplatin (75 mg/m2) or carboplatin (AUC 5 mg/mL/min) IV Q3W (4 cycles)
  • Arm B (comparator): Placebo + pembrolizumab + pemetrexed + cisplatin or carboplatin (same doses/schedule)

Key Inclusion/Exclusion Criteriaa

  • Inclusion: Treatment-naive, locally advanced/metastatic nonsquamous KRAS G12C–mutant NSCLC; any PD-L1 expression level; ECOG PS 0 or 1; patients with stable, asymptomatic brain metastases including untreated brain metastases ≤ 20 mm eligible
  • Stratification: PD-L1 TPS (< 1% vs 1%–49% vs ≥ 50%); presence of brain metastases (yes vs no)
  • Exclusion: Prior systemic therapy for advanced/metastatic NSCLC; squamous histology

Primary and Key Secondary Endpoints

  • Co-primary: PFS per RECIST v1.1 by BICR; OS
  • Key secondary: ORR, DOR, safety, patient-reported outcomes

Olomorasib

SUNRAY-01 Part A38,39(NCT06119581)

Interventions and Doses

  • Arm A: Olomorasib (oral BID) + pembrolizumab (IV Q3W)
  • Arm B (comparator): Placebo + pembrolizumab (IV Q3W)

Key Inclusion/Exclusion Criteriaa

  • Inclusion: Stage IIIB–IIIC or stage IV KRAS G12C–mutant NSCLC not suitable for curative-intent surgery or radiation; known PD-L1 status (≥ 50%); patients with asymptomatic brain metastases (lesions ≤ 1.5 cm) or previously treated, radiographically and clinically stable brain metastases are eligible
  • Exclusion: Prior systemic therapy for advanced/metastatic NSCLC; history of pneumonitis/interstitial lung disease; clinically significant active cardiovascular disease or malabsorption syndrome

Primary and Key Secondary Endpoints

  • Primary: PFS per RECIST v1.1 (blinded independent review)
  • Key secondary: OS, ORR, DOR, safety

Olomorasib

SUNRAY-01 Part B38,39(NCT06119581)

Interventions and Doses

  • Arm A: Olomorasib + pembrolizumab + pemetrexed + platinum
  • Arm B (comparator): Placebo + pembrolizumab + pemetrexed + platinum

Key Inclusion/Exclusion Criteriaa

  • Inclusion: Stage IIIB–IIIC or stage IV KRAS G12C–mutant NSCLC not suitable for curative-intent surgery or radiation; known PD-L1 status (0%–100%); nonsquamous histology (per pemetrexed label); patients with asymptomatic brain metastases (lesions ≤ 1.5 cm) or previously treated, radiographically and clinically stable brain metastases are eligible
  • Exclusion: Prior systemic therapy for advanced/metastatic NSCLC; history of pneumonitis/interstitial lung disease; clinically significant active cardiovascular disease or malabsorption syndrome

Primary and Key Secondary Endpoints

  • Primary: PFS per RECIST v1.1 (blinded independent review)
  • Key secondary: OS, ORR, DOR, safety

Calderasib

KANDLELIT-00440,41(NCT06345729)

Interventions and Doses

  • Arm A: Calderasib (100 mg oral QD) + pembrolizumab (200 mg IV Q3W)
  • Arm B (comparator): Placebo + pembrolizumab (200 mg IV Q3W)

Key Inclusion/Exclusion Criteriaa

  • Inclusion: Histologically or cytologically confirmed stage IV NSCLC; confirmed KRAS G12C mutation; PD-L1 TPS ≥ 50%; ECOG PS 0 or 1
  • Stratification: ECOG PS (0 vs 1); presence of CNS metastases (yes vs no); prior immunotherapy in the neoadjuvant/adjuvant setting (yes vs no)
  • Exclusion: Active CNS metastases and/or carcinomatous meningitis; prior systemic anticancer therapy for their locally advanced or metastatic NSCLC; radiation therapy to the lung that is > 30 Gy within 6 months of start of study intervention; radiotherapy within 2 weeks of start of study intervention

Primary and Key Secondary Endpoints

  • Co-primary: PFS per RECIST v1.1 by BICR, OS
  • Key secondary: ORR, DOR, safety

Calderasib

KANDLELIT-00742,43(NCT07190248)

Interventions and Doses

  • Arm A: Calderasib (100 mg oral QD) + SC pembrolizumab (790 mg SC Q6W)
  • Arm B (comparator): Pembrolizumab (790 mg SC Q6W) + pemetrexed (500 mg/m2) + carboplatin (AUC 5 mg/mL/min) or cisplatin (75 mg/m2) Q3W

Key Inclusion/Exclusion Criteriaa

  • Inclusion: Advanced or metastatic nonsquamous KRAS G12C–mutant NSCLC; any PD-L1 TPS; ineligible for curative resection or chemoradiation; ECOG PS of 0 or 1
  • Stratification: PD-L1 TPS (< 1% vs 1%–49% vs ≥ 50%); ECOG PS (0 vs 1), presence/history of treated CNS metastases (yes vs no); geographic region (East Asia vs North America/Western Europe/Australia/New Zealand vs rest of world)
  • Exclusion: Prior systemic therapy for advanced or metastatic NSCLC; active autoimmune disease; active CNS metastases or interstitial lung disease

Primary and Key Secondary Endpoints

  • Primary: PFS per RECIST v1.1 by BICR in patients with PD-L1 TPS ≥ 1%
  • Key secondary: PFS in all patients, OS, ORR, DOR, safety

Divarasib

KRAScendo 244,45(NCT06793215)

Interventions and Doses

  • Arm A: Divarasib (oral QD) + pembrolizumab (IV Q3W)
  • Arm B (comparator): Pembrolizumab (IV Q3W) + pemetrexed (IV Q3W) + carboplatin or cisplatin (IV Q3W; 4 cycles of platinum-based chemotherapy)

Key Inclusion/Exclusion Criteriaa

  • Inclusion: Advanced or metastatic nonsquamous KRAS G12C–mutant NSCLC; previously untreated for advanced/metastatic disease; known PD-L1 expression status; ECOG PS 0 or 1; measurable disease per RECIST v1.1; asymptomatic, stable, treated CNS metastases eligible
  • Stratification: PD-L1 TPS (< 1% vs 1%–49% vs ≥ 50%); ECOG PS (0 vs 1); history of CNS metastases (yes vs no)
  • Exclusion: Prior therapy with a KRAS G12C inhibitor or pan-KRAS/RAS inhibitor; prior systemic immunotherapy or immune checkpoint inhibitors; symptomatic, untreated, or actively progressing CNS metastases; known concomitant second oncogenic driver with available targeted treatment

Primary and Key Secondary Endpoints

  • Co-primary: PFS by BICR per RECIST v1.1; OS
  • Key secondary: ORR and DOR by BICR; patient-reported symptoms and functioning (EORTC QLQ-LC13, QLQ-C30); safety
Trial Name (Identifier) Interventions and Doses Key Inclusion/Exclusion Criteriaa Primary and Key Secondary Endpoints
CodeBreaK 202 (NCT05920356)32,33Sotorasib

Arm A: Sotorasib (960 mg QD orally) + carboplatin + pemetrexed

Arm B (comparator): Pembrolizumab + carboplatin + pemetrexed (IV chemotherapy administered Q3W)

Inclusion: Advanced/metastatic KRAS G12C–mutant NSCLC; PD-L1 TPS < 1%; nonsquamous histology; treatment-naive for metastatic disease

Exclusion: Prior therapy with a KRAS G12C inhibitor; symptomatic (treated or untreated) CNS metastases; mixed histology

Primary: PFS (investigator assessed per RECIST v1.1)

Key secondary: OS, ORR
KRYSTAL-7 (NCT04613596)34,35Adagrasib

Arm A: Adagrasib (400 mg BID orally) + pembrolizumab (200 mg IV Q3W, up to 35 cycles)

Arm B (comparator): Pembrolizumab (200 mg IV Q3W, up to 35 cycles)

Inclusion: Unresectable, locally advanced or metastatic KRAS G12C–mutant NSCLC (squamous or nonsquamous); PD-L1 TPS ≥ 50%

Stratification: CNS metastasis history; region (Asia Pacific vs non–Asia Pacific); ECOG PS 0 vs 1

Exclusion: Prior systemic therapy for metastatic NSCLC; radiation to the lung > 30 Gy within 6 months prior to the first dose of study treatment

Co-primary: PFS by BICR and OS

Key secondary: Safety/tolerability, ORR, DOR, adagrasib PK, health-related QoL
KRYSTAL-4 (NCT06875310)36,37Adagrasib

Arm A: Adagrasib (400 mg BID orally) + pembrolizumab (200 mg IV Q3W, up to 24 months) + pemetrexed (500 mg/m2) + cisplatin (75 mg/m2) or carboplatin (AUC 5 mg/mL/min) IV Q3W (4 cycles)

Arm B (comparator): Placebo + pembrolizumab + pemetrexed + cisplatin or carboplatin (same doses/schedule)

Inclusion: Treatment-naive, locally advanced/metastatic nonsquamous KRAS G12C–mutant NSCLC; any PD-L1 expression level; ECOG PS 0 or 1; patients with stable, asymptomatic brain metastases including untreated brain metastases ≤ 20 mm eligible

Stratification: PD-L1 TPS (< 1% vs 1%–49% vs ≥ 50%); presence of brain metastases (yes vs no)

Exclusion: Prior systemic therapy for advanced/metastatic NSCLC; squamous histology

Co-primary: PFS per RECIST v1.1 by BICR; OS

Key secondary: ORR, DOR, safety, patient-reported outcomes
SUNRAY-01 Part A (NCT06119581)38,39Olomorasib

Arm A: Olomorasib (oral QD) + pembrolizumab (IV Q3W)

Arm B (comparator): Placebo + pembrolizumab (IV Q3W)

Inclusion: Stage IIIB–IIIC or stage IV KRAS G12C–mutant NSCLC not suitable for curative-intent surgery or radiation; known PD-L1 status (≥ 50%); patients with asymptomatic brain metastases (lesions ≤ 1.5 cm) or previously treated, radiographically and clinically stable brain metastases are eligible

Exclusion: Prior systemic therapy for advanced/metastatic NSCLC; history of pneumonitis/interstitial lung disease; clinically significant active cardiovascular disease or malabsorption syndrome

Primary: PFS per RECIST v1.1 (blinded independent review)

Key secondary: OS, ORR, DOR, safety
SUNRAY-01 Part B (NCT06119581)38,39Olomorasib

Arm A: Olomorasib + pembrolizumab + pemetrexed + platinum

Arm B (comparator): Placebo + pembrolizumab + pemetrexed + platinum

Inclusion: Stage IIIB–IIIC or stage IV KRAS G12C–mutant NSCLC not suitable for curative-intent surgery or radiation; known PD-L1 status (0%–100%); nonsquamous histology (per pemetrexed label); patients with asymptomatic brain metastases (lesions ≤ 1.5 cm) or previously treated, radiographically and clinically stable brain metastases are eligible

Exclusion: Prior systemic therapy for advanced/metastatic NSCLC; history of pneumonitis/interstitial lung disease; clinically significant active cardiovascular disease or malabsorption syndrome

Primary: PFS per RECIST v1.1 (blinded independent review)

Key secondary: OS, ORR, DOR, safety
KANDLELIT-004 (NCT06345729)40,41Calderasib

Arm A: Calderasib (100 mg oral QD) + pembrolizumab (200 mg IV Q3W)

Arm B (comparator): Placebo + pembrolizumab (200 mg IV Q3W)

Inclusion: Histologically or cytologically confirmed stage IV NSCLC; confirmed KRAS G12C mutation; PD-L1 TPS ≥ 50%; ECOG PS 0 or 1

Stratification: ECOG PS (0 vs 1); presence of CNS metastases (yes vs no); prior immunotherapy in the neoadjuvant/adjuvant setting (yes vs no)

Exclusion: Active CNS metastases and/or carcinomatous meningitis; prior systemic anticancer therapy for their locally advanced or metastatic NSCLC; radiation therapy to the lung that is > 30 Gy within 6 months of start of study intervention; radiotherapy within 2 weeks of start of study intervention

Co-primary: PFS per RECIST v1.1 by BICR, OS

Key secondary: ORR, DOR, safety
KANDLELIT-007 (NCT07190248)42,43Calderasib

Arm A: Calderasib (100 mg oral QD) + SC pembrolizumab (790 mg SC Q6W)

Arm B (comparator): Pembrolizumab (790 mg SC Q6W) + pemetrexed (500 mg/m2) + carboplatin (AUC 5 mg/mL/min) or cisplatin (75 mg/m2) Q3W

Inclusion: Advanced or metastatic nonsquamous KRAS G12C–mutant NSCLC; any PD-L1 TPS; ineligible for curative resection or chemoradiation; ECOG PS of 0 or 1

Stratification: PD-L1 TPS (< 1% vs 1%–49% vs ≥ 50%); ECOG PS (0 vs 1), presence/history of treated CNS metastases (yes vs no); geographic region (East Asia vs North America/Western Europe/Australia/New Zealand vs rest of world)

Exclusion: Prior systemic therapy for advanced or metastatic NSCLC; active autoimmune disease; active CNS metastases or interstitial lung disease

Primary: PFS per RECIST v1.1 by BICR in patients with PD-L1 TPS ≥ 1%

Key secondary: PFS in all patients, OS, ORR, DOR, safety
KRAScendo 2 (NCT06793215)44,45Divarasib

Arm A: Divarasib (oral QD) + pembrolizumab (IV Q3W)

Arm B (comparator): Pembrolizumab (IV Q3W) + pemetrexed (IV Q3W) + carboplatin or cisplatin (IV Q3W; 4 cycles of platinum-based chemotherapy)

Inclusion: Advanced or metastatic nonsquamous KRAS G12C–mutant NSCLC; previously untreated for advanced/metastatic disease; known PD-L1 expression status; ECOG PS 0 or 1; measurable disease per RECIST v1.1; asymptomatic, stable, treated CNS metastases eligible

Stratification: PD-L1 TPS (< 1% vs 1%–49% vs ≥ 50%); ECOG PS (0 vs 1); history of CNS metastases (yes vs no)

Exclusion: Prior therapy with a KRAS G12C inhibitor or pan-KRAS/RAS inhibitor; prior systemic immunotherapy or immune checkpoint inhibitors; symptomatic, untreated, or actively progressing CNS metastases; known concomitant second oncogenic driver with available targeted treatment

Co-primary: PFS by BICR per RECIST v1.1; OS

Key secondary: ORR and DOR by BICR; patient-reported symptoms and functioning (EORTC QLQ-LC13, QLQ-C30); safety

NOTE: The safety and efficacy of the molecules/agents and uses under investigation have not been established. There is no guarantee that pipeline molecules will receive regulatory approval and become commercially available for the uses being investigated. The information provided about new disease states being studied is for scientific information exchange purposes only with commercial intent.

a Not an exhaustive list. For a complete list of inclusion and exclusion criteria, please refer to the ClinicalTrials.gov page for the respective trial.

Abbreviations: AUC = area under the curve; BICR = blinded independent central review; BID = twice daily; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group performance status; GDP = guanosine diphosphate; GTP = guanosine triphosphate; IV = intravenous; NSCLC = non–small cell lung cancer; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death-ligand 1; PFS = progression-free survival; PK = pharmacokinetics; QD = once daily; Q3W = every 3 weeks; Q6W = every 6 weeks; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; S-IIP = switch-II pocket; SC = subcutaneous; TPS = tumor proportion score.

CodeBreaK 202 (ClinicalTrials.gov identifier NCT05920356) is investigating sotorasib (960 mg orally once daily) in combination with carboplatin and pemetrexed, compared with the standard pembrolizumab plus carboplatin and pemetrexed regimen.32,33 The trial enrolls previously untreated patients with advanced or metastatic nonsquamous NSCLC harboring a KRAS G12C mutation and a PD-L1 tumor proportion score (TPS) below 1%. The primary endpoint is investigator-assessed PFS.32,33

Two trials are evaluating adagrasib in the first-line setting for KRAS G12C–mutant advanced NSCLC. KRYSTAL-7 (NCT04613596) enrolls patients with squamous or nonsquamous KRAS G12C–mutant NSCLC with PD-L1 TPS of 50% or higher.34,35 Patients are randomly assigned to adagrasib (400 mg twice daily) plus pembrolizumab or pembrolizumab alone. The co-primary endpoints are PFS and OS.34,35 KRYSTAL-4 (NCT06875310) enrolls patients with treatment-naive, locally advanced or metastatic nonsquamous KRAS G12C–mutant NSCLC regardless of PD-L1 expression level.36,37 Patients are randomly assigned to adagrasib in combination with pembrolizumab and platinum-doublet chemotherapy or placebo plus pembrolizumab and platinum-doublet chemotherapy. The study has dual primary endpoints of PFS and OS.36,37

SUNRAY-01 Part A (NCT06119581) randomly assigns patients with KRAS G12C–mutant NSCLC and PD-L1 TPS of 50% or higher to olomorasib plus pembrolizumab or placebo plus pembrolizumab.38,39 The primary endpoint is PFS. SUNRAY-01 Part B is open to patients with IIIB–IIIC or stage IV KRAS G12C–mutant nonsquamous NSCLC regardless of PD-L1 expression level, and adds pemetrexed and platinum to both arms (olomorasib or placebo, each combined with pembrolizumab, pemetrexed, and platinum-doublet chemotherapy). PFS, as assessed by blinded independent review, is the primary endpoint.38,39 Patients with asymptomatic brain metastases (lesions ≤ 1.5 cm) or previously treated, radiographically and clinically stable brain metastases are eligible for inclusion in both Part A and Part B.38

Two trials evaluate calderasib (100 mg orally once daily). KANDLELIT-004 (NCT06345729) enrolls patients with stage IV KRAS G12C–mutant NSCLC and a PD-L1 TPS of 50% or higher, randomly assigning them to calderasib plus intravenous pembrolizumab or placebo plus pembrolizumab. The co-primary endpoints are PFS and OS.40,41 KANDLELIT-007 (NCT07190248) enrolls patients with advanced or metastatic nonsquamous KRAS G12C–mutant NSCLC regardless of PD-L1 level, and compares calderasib with subcutaneous pembrolizumab against the pembrolizumab plus pemetrexed-platinum chemotherapy regimen. The primary endpoint is PFS in patients with PD-L1 TPS of 1% or higher.42,43

KRAScendo 2 (NCT06793215) is evaluating KRAS G12C inhibitor divarasib in combination with pembrolizumab as a first-line treatment option.44,45 The trial enrolls previously untreated patients with advanced or metastatic nonsquamous KRAS G12C–mutant NSCLC of any PD-L1 level; patients with asymptomatic, stable, treated CNS metastases are also eligible. Patients are randomly assigned 1:1 to divarasib (oral once daily) plus pembrolizumab (IV Q3W) or to pembrolizumab plus pemetrexed and four cycles of platinum-based chemotherapy (carboplatin or cisplatin; IV Q3W). The co-primary endpoints are PFS by blinded independent central review and OS.44,45

Dr. Levy highlighted that tolerability is a potential challenge that the ongoing trials may need to address. “The early signals we’re seeing with these combination approaches are that overall they seem well tolerated, but we have to keep in mind the hepatotoxicity risk and other side effects that we may see,” he said. “The question is which KRAS G12C inhibitor, which immunotherapy, and at what dose and schedule—so that we can extend outcomes and elicit durable responses while ensuring safety.”

Conclusions

KRAS G12C mutations are common in NSCLC and, until recently, represented an untreatable oncogenic driver.1,3 The approval of KRAS G12C inhibitors for the treatment of previously treated patients with KRAS G12C–mutant NSCLC represented a shift in the management of NSCLC with targeted therapy.3,4-7 However, the current standard of care for previously untreated patients with KRAS G12C–mutant NSCLC remains immunotherapy with or without chemotherapy, an approach guided by PD-L1 status rather than the molecular profile of the tumor.8,9

Preclinical data suggest that KRAS G12C inhibition remodels the tumor immune microenvironment in ways that could potentiate checkpoint blockade, providing the scientific rationale for the combination strategies now in phase III testing in the first-line setting.15,16 Ongoing phase III trials, including CodeBreaK 202, KRYSTAL-4, KRYSTAL-7, SUNRAY-01 Part A, SUNRAY-01 Part B, KANDLELIT-004, KANDLELIT-007, and KRAScendo 2, are evaluating whether pairing KRAS G12C inhibitors with pembrolizumab, with or without chemotherapy, can improve current first-line outcomes.3 Results from these studies will be critical in determining whether targeted therapy moves earlier in the treatment sequence.3

“In the first-line setting, we need to see significant improvements in PFS and, depending on whether there is crossover, overall survival as well,” Dr. Levy said. “Improved response rates will matter, but just as important will be whether these gains can be achieved in the context of tolerability. This is a journey patients are on, and we need to ensure we are not only controlling the tumor, but also sparing the patient.”

Disclosure

Dr. Riess reported a consulting or advisory role with Daiichi Sankyo, Bristol Myers Squibb/Celgene, Janssen Oncology, Regeneron, Amgen, Merck, Pfizer, GSK, Replimune, Oncohost, Bicycle Therapeutics, ArriVent Biopharma, GSK, Nuvalent, Inc., AstraZeneca, Nuvation Bio, Taiho Pharmaceutical, Veristem, Boehringer Ingelheim, Natera, Foundation Medicine, Revolution Medicines, and Lilly; research funding from Merck, AstraZeneca/MedImmune, Boehringer Ingelheim, Novartis, Revolution Medicines, ArriVent, IO Biotech, Summit Pharmaceuticals, Nuvalent, Inc., Pfizer, Blossom Hill, Prelude Therapeutics, Bicycle Therapeutics, BridgeBio Pharma, and BridgeBio Pharma; and travel, accommodations, or expenses from IO Biotech and GSK.

Dr. Levy reported an advisory board or panel role with AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Janssen, Merck, and Pfizer; and a consulting role with AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Merck, and Pfizer.

References

  1. Biernacka A, Tsongalis PD, Peterson JD, et al: The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma. Cancer Genet 209:195-198, 2016
  2. Jordan EJ, Kim HR, Arcila ME, et al: Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov 7:596-609, 2017
  3. Shaverdashvili K, Burns TF: Advances in the treatment of KRAS G12C mutant non-small cell lung cancer. Cancer 131 Suppl 1:e35783, 2025
  4. KRAZATI (adagrasib) prescribing information. Bristol Myers Squibb Company; Revised March 2026. Available at: https://packageinserts.bms.com/pi/pi_krazati.pdf. Accessed April 17, 2026.
  5. LUMAKRAS (sotorasib) prescribing information. Amgen Inc.; Revised January 2025. Available at: https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Lumakras/lumakras_pi_hcp_english.pdf. Accessed April 17, 2026.
  6. Barlesi F, Yao W, Duruisseaux M, et al: Adagrasib versus docetaxel in KRAS(G12C)-mutated non-small-cell lung cancer (KRYSTAL-12): A randomised, open-label, phase 3 trial. Lancet 406:615-626, 2025
  7. de Langen AJ, Johnson ML, Mazieres J, et al: Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: A randomised, open-label, phase 3 trial. Lancet 401:733-746, 2023
  8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V9.2026. National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed September 23, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  9. Puri S, Leighl NB, Ismaila N, et al: Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO Living Guideline, 2026.3.0. J Clin Oncol 44:e15-e55, 2026
  10. Sheffield K, Puri T, Thoele K, et al: P1.17.49 Real-world outcomes with IO and chemo-IO demonstrate unmet need for 1L KRAS G12C-mutant advanced NSCLC in the US. J Thorac Oncol 20:S234, 2025
  11. Molina-Arcas M, Downward J: Exploiting the therapeutic implications of KRAS inhibition on tumor immunity. Cancer Cell 42:338-357, 2024
  12. Choucair K, Imtiaz H, Uddin MH, et al: Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges. Signal Transduct Target Ther 10:385, 2025
  13. Bhattacharya D, Roman B, Reddy S: Therapeutic advances with KRAS(G12C) inhibitors and combination strategies in non-small cell lung cancer brain metastases. Cancer Gene Ther 33:323-337, 2026
  14. Tani T, Kitajima S, Conway EB, et al: KRAS G12C inhibition and innate immune targeting. Expert Opin Ther Targets 25:167-174, 2021
  15. Tian L, Li H, Cui H, et al: Oncogenic KRAS mutations drive immune suppression through immune-related regulatory network and metabolic reprogramming. Cell Death Dis 16:785, 2025
  16. Zhang F, Wang B, Wu M, et al: Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: A systematic review. Front Immunol 16:1509173, 2025
  17. Hu H, Cheng R, Wang Y, et al: Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47. J Clin Invest 133, 2023
  18. Tang KH, Li S, Khodadadi-Jamayran A, et al: Combined inhibition of SHP2 and CXCR1/2 promotes antitumor T-cell response in NSCLC. Cancer Discov 12:47-61, 2022
  19. Arbour KC, Rizvi H, Plodkowski AJ, et al: Treatment outcomes and clinical characteristics of patients with KRAS-G12C-mutant non-small cell lung cancer. Clin Cancer Res 27:2209-2215, 2021
  20. Canon J, Rex K, Saiki AY, et al: The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575:217-223, 2019
  21. Briere DM, Li S, Calinisan A, et al: The KRAS(G12C) inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. Mol Cancer Ther 20:975-985, 2021
  22. Negrao MV, Araujo HA, Lamberti G, et al: Co-mutations and KRASG12C inhibitor efficacy in advanced NSCLC. Cancer Discov 13:1556-1571, 2023
  23. Gu M, Xu T, Chang P: KRAS/LKB1 and KRAS/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas. Ther Adv Med Oncol 13:17588359211006950, 2021
  24. Skoulidis F, Goldberg ME, Greenawalt DM, et al: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 8:822-835, 2018
  25. Skoulidis F, Byers LA, Diao L, et al: Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 5:860-77, 2015
  26. Isaksson J, Berglund A, Louie K, et al: KRAS G12C mutant non-small cell lung cancer linked to female sex and high risk of CNS metastasis: Population-based demographics and survival data from the National Swedish Lung Cancer Registry. Clin Lung Cancer 24:507-518, 2023
  27. Lamberti G, Aizer A, Ricciuti B, et al: Incidence of brain metastases and preliminary evidence of intracranial activity with sotorasib in patients with KRAS(G12C)-mutant non-small-cell lung cancer. JCO Precis Oncol 7:e2200621, 2023
  28. Negrao MV, Spira AI, Heist RS, et al: Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial with KRAS(G12C)-mutated non-small-cell lung cancer who have untreated CNS metastases. J Clin Oncol 41:4472-4477, 2023
  29. Brown LJ, Khou V, Brown C, et al: First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: A registry study. Front Oncol 14:1305720, 2024
  30. Dy GK, Govindan R, Velcheti V, et al: Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated KRAS G12C-mutated non-small-cell lung cancer: 2-year analysis of CodeBreaK 100. J Clin Oncol 41:3311-3317, 2023
  31. Janne PA, Riely GJ, Gadgeel SM, et al: Adagrasib in non-small-cell lung cancer harboring a KRAS-G12C mutation. N Engl J Med 387:120-131, 2022
  32. Barlesi F, Felip E, Popat S, et al: Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202). J Clin Oncol 42:TPS8653-TPS8653, 2024
  33. A study evaluating sotorasib platinum doublet combination versus pembrolizumab platinum doublet combination as a front‑line therapy in participants with stage IV or advanced stage IIIB/C nonsquamous non‑small cell lung cancers (CodeBreaK 202). ClinicalTrials.gov identifier: NCT05920356. Updated April 24, 2026. Accessed April 28, 2026. https://clinicaltrials.gov/study/NCT05920356.
  34. Garassino MC, Jänne PA, Barlesi F, et al: 1394TiP KRYSTAL-7: A phase III study of first-line adagrasib plus pembrolizumab versus pembrolizumab alone in patients with advanced NSCLC with KRASG12C mutation. Ann Oncol 35:S872-S873, 2024
  35. Phase 2 trial of adagrasib monotherapy and in combination with pembrolizumab and a phase 3 trial of adagrasib in combination in patients with a KRAS G12C mutation (KRYSTAL‑7). ClinicalTrials.gov. identifier: NCT04613596. Updated March 18, 2026. Accessed April 28, 2026. https://clinicaltrials.gov/study/NCT04613596.
  36. Naidoo J, Jänne PA, Griesinger F, et al: P3.18.61 KRYSTAL-4: Phase 3 study of adagrasib plus pembrolizumab and chemotherapy in treatment-naive, advanced KRAG12C-mutated NSCLC. J Thorac Oncol 20:S571-S572, 2025
  37. A study of adagrasib plus pembrolizumab plus chemotherapy vs placebo plus pembrolizumab plus chemotherapy in participants with previously untreated non-squamous non-small cell lung cancer with KRAS G12C mutation (KRYSTAL-4). ClinicalTrials.gov identifier NCT06875310. Updated May 13, 2026. Accessed May 27, 2026. https://clinicaltrials.gov/study/NCT06875310.
  38. Negrao MV, Arbour KC, Burns TF, et al: SUNRAY-01, a pivotal, global study of olomorasib (LY3537982) in combination with pembrolizumab with or without chemotherapy for 1L treatment in KRAS G12C-mutant advanced NSCLC. J Clin Oncol 42:TPS8649-TPS8649, 2024
  39. A study of first-line olomorasib (LY3537982) and pembrolizumab with or without chemotherapy in patients with advanced KRAS G12C-mutant non-small cell lung cancer (SUNRAY-01). ClinicalTrials.gov identifier: NCT06119581. Updated April 20, 2026. Accessed April 28, 2026. https://clinicaltrials.gov/study/NCT06119581.
  40. Cobb PW, Hochmair M, Schuler MHH, et al: 1392TiP Phase III study of pembrolizumab plus MK-1084 vs pembrolizumab plus placebo as first-line treatment for metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation and PD-L1 tumour proportion score (TPS) ≥50%: MK-1084-004. Ann of Oncol 35:S871-S872, 2024
  41. A study of calderasib (MK‑1084) plus pembrolizumab (MK‑3475) in participants with KRAS G12C mutant non‑small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD‑L1) tumor proportion score (TPS) ≥50% (MK‑1084‑004/KANDLELIT‑004). ClinicalTrials.gov identifier: NCT06345729. Updated April 28, 2026. Accessed April 29, 2026. https://clinicaltrials.gov/study/NCT06345729.
  42. Provencio Pulla M, Hochmair MJ, Hughes BGM, et al: 140TiP KANDLELIT-007: Phase III, open-label study of first-line calderasib with subcutaneous pembrolizumab (pembro SC) vs pembro SC plus chemotherapy (chemo) for KRAS G12C-mutant advanced/metastatic nonsquamous NSCLC. ESMO Open 11, 2026
  43. A clinical study of calderasib (MK‑1084) and other treatments for participants with non‑small cell lung cancer (MK‑1084‑007/KANDLELIT‑007). ClinicalTrials.gov identifier: NCT07190248. Updated April 28, 2026. Accessed April 29, 2026. https://clinicaltrials.gov/study/NCT07190248.
  44. Skoulidis F, Solomon BJ, Frost NSW, et al: Krascendo 2: A phase III study of divarasib and pembrolizumab vs pembrolizumab and chemotherapy in patients with previously untreated, advanced or metastatic, KRAS G12C-mutated non-small cell lung cancer (NSCLC). J Clin Oncol 43:TPS8656-TPS8656, 2025
  45. A study evaluating the efficacy and safety of divarasib and pembrolizumab versus pembrolizumab and pemetrexed and carboplatin or cisplatin in participants with previously untreated, KRAS G12C‑mutated, advanced or metastatic non‑squamous non‑small cell lung cancer. ClinicalTrials.gov identifier: NCT06793215. Updated April 13, 2026.  Accessed May 7, 2026. https://clinicaltrials.gov/study/NCT06793215

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