Two-year analysis of CodeBreaK 100 phase I/II trial: achieved goals of an ongoing challenge

Introduction

KRAS mutation is the most frequent oncogenic driver in non-small cell lung cancer (NSCLC), observed in up to 30% of patients with non-squamous NSCLC (1), with a higher prevalence in Western population (2). The majority of KRAS mutations occur in codons 12 and 13, with the KRAS glycine to cysteine substitution (G12C) being the most common variant, accounting for 39% of cases (3), and associated with a history of smoking, higher tumour mutational burden and concurrent genomic alterations such as STK11, KEAP1, SMARCA4 and ATM (4). The biological and clinical heterogeneity associated with KRAS mutations has posed significant challenges in developing effective targeted therapies, leading to this mutated oncogene being considered “undruggable” for decades (5). Cytotoxic chemotherapy with docetaxel, with or without antiangiogenic therapy (6,7) has been the standard of care second line treatment for patients with advanced KRAS-mutant NSCLC previously treated with platinum-based therapy and/or immune checkpoint inhibitors (6). The promising results of the CodeBreaK 100 phase I/II trial challenged this trend, by introducing the first KRAS G12C inhibitor sotorasib as a novel treatment option for this subset of patients (8). In this Editorial Commentary, we analyse the most recent updates on the long-term efficacy, safety, and correlated features about this clinical trial.

The CodeBreaK 100 phase I/II and the CodeBreaK 200 phase III trials

The multicenter, single-group, open-label CodeBreaK 100 was the pivotal phase I–II trial that explored the safety and efficacy of sotorasib as second-line treatment for patients bearing the KRAS G12C mutation (8), and it is also the study investigating KRAS inhibitors with the longest follow-up period, reaching the 2 years landmark with the latest update (9).

Sotorasib is a potent covalent inhibitor of the G12C-mutated KRAS isoform that binds to the cysteine residue of the protein, holding it in the inactive form (10). As of February 2022, the CodeBreaK 100 trial enrolled 174 patients: 48 in the phase I and 126 in the phase II. Key inclusion criteria were aged 18 years and older, a diagnosis of locally advanced or metastatic NSCLC carrying the KRAS G12C mutation, having experienced disease progression after prior treatments, and an Eastern Cooperative Oncology Group performance status score of 0 to 1. Among the key exclusion criteria were active untreated brain metastases and the receipt of therapeutic or palliative radiation therapy within 2 weeks before the initiation of sotorasib therapy. The median treatment duration was 5.6 months (range, 0.2–35.9 months), with 13 patients remaining on treatment at the data cut-off date. Median number of prior lines of treatment was 2.0 and almost all patients had been previously exposed to programmed death (ligand)-1 (PD-1/PD-L1) checkpoint inhibition, either alone or in combination with platinum-based chemotherapy. In this subset of heavily pre-treated population, sotorasib achieved an objective response rate (ORR) of 41% [95% confidence interval (CI): 33.3–48.4%] and a disease control rate (DCR) of 84% (95% CI: 77.3–88.9%). Importantly, 72.8% and 50.6% of the responders maintained the disease response at the 6- and 12-month landmarks, respectively, clearly highlighting the potential long-term benefits of the treatment. Median progression free survival (PFS) and overall survival (OS) were 6.3 (range, 5.3–8.2) months and 12.5 (range, 10–17.8) months, respectively, with a 12- and 24-month survival estimates of 51% and 33%. Although evaluated on a small subgroup of patients with central nervous system (CNS) measurable disease (n=16), the intracranial DCR was 88%. Treatment-related adverse events (TRAEs) were observed in 70% of patients, with diarrhea (30%) and elevated levels of liver enzymes (18%) being the most common TRAEs; 20% of patients experienced grade 3 TRAEs and 1% experienced grade 4 TRAEs, but with no fatal TRAEs. Long-term clinical benefit with sotorasib was observed across varying PD-L1 expression levels and it was associated with low baseline circulating tumor DNA (ctDNA; P=0.01), while those with early progression were significantly more likely to be enriched with KEAP1 co-mutations (odds ratio 0.22, 95% CI: 0.06–0.87) (8,9).

The results gathered in CodeBreaK 100 trial have been confirmed in the CodeBreaK 200 phase III trial, which compared sotorasib to docetaxel as second-line treatment of patients with KRAS G12C positive NSCLC showing an improved median PFS of 5.6 vs. 4.5 months, with PFS rates at 12 months of 24.8% and 10.1%, respectively. The CodeBreaK 200 failed to show any improvement in OS, which was a secondary endpoint, however the 26% crossover rate to sotorasib and the receipt of other KRAS G12C inhibitors as following treatment for patients from the control arm need to be taken into account in interpreting this result. Safety was consistent with the previous findings: the most common ≥ G3 TRAEs were diarrhea (12%) and increased alanine transaminase (ALT) (8%) and aspartate transaminase (AST) (5%). Taken together, these results confirm sotorasib as the new second line standard of care for patients with KRAS G12C positive advanced NSCLC (11).

Discussion

Following the results achieved in clinical trials, a deeper comprehension of the biological and clinical features associated with the efficacy and side effects of sotorasib has become necessary. Ongoing research endeavours are currently focused on refining patient selection criteria and elucidating the mechanisms of resistance through the exploration of biomarkers and ctDNA. Additionally, investigations are underway to better understand sotorasib’s activity within the CNS and to assess its safety and optimal therapeutic sequences. All these efforts aim to optimize the therapeutic potential of this innovative treatment approach.

Biomarkers

The role of biomarkers has been investigated in an exploratory analysis of the CodeBreaK 200 trial. The most prevalent co-alterations detected in key genes included TP53 (57.1%), STK11 (37.5%), and KEAP1 (25.9%). Additionally, a baseline concomitant alteration of STK11 and KEAP1 was present in 17.4% of patients. Sotorasib retained superior median PFS and ORR compared to docetaxel, irrespective of the key co-alteration analyzed, and showed improved PFS over docetaxel, regardless of PD-L1 expression (12). These results mirrored those obtained in the CodeBreaK 100 trial, where the co-mutational status and the PD-L1 expression did not influence outcomes, except for KEAP1, as patients with this type of co-mutation had a significantly higher likelihood of experiencing early progression during treatment (8). However, literature data (13) suggests that the KEAP1 co-mutation plays a negative prognostic role rather than a predictive one.

An additional exploratory analysis of the CodeBreaK 200 was performed to identify baseline genomic alterations associated with long-term benefit (PFS of at least 6 months) vs. early disease progression (PFS of less 3 months), highlighting a significantly shorter median PFS with sotorasib than docetaxel [2.8 months (95% CI: 1.6–3.4) and 7.5 months (95% CI: 3.0–NE), respectively] in patients with KRAS G12C and NOTCH1 co-altered tumors (12). Taking into account the limits of the small dataset, NOTCH1 exhibited an early progression signal with sotorasib, suggesting a potential negative predictive role of this genomic alteration that warrants further investigation.

Recently, Negrao et al. presented a genomic profiling analysis from a large multicentric cohort of 424 patients with KRAS G12C tumors treated with sotorasib (n=353) and adagrasib (n=71). Co-alterations of KEAP1, SMARCA4 and CDKN2A were identified as independent determinants of poor clinical outcomes with KRAS G12C inhibitors. Taken together, they captured almost 50% of early progressors (defined as median PFS ≤3), the median PFS for patients carrying at least one of these co-mutations resulted in 2.8 vs. 5.9 months in the wild-type population (hazard ratio 2.51, P<0.001), while the median OS was 6.9 vs. 13 months (hazard ratio 2.05, P<0.001). Interestingly, the presence of mutations in the DNA damage repair genes (DDR) was associated with improved PFS (5.9 vs. 4.6 in DDR wild type), suggesting a possible role of this co-alteration in predicting better outcomes (14). The authors concluded that the identification of these co-alterations could be used as a predictor of clinical outcomes, but further studies are needed in order to clarify whether the solely identification of the co-mutations profile could be predictive of worse or better treatment response to KRAS G12C inhibitors.

ctDNA

In an effort to investigate the role of ctDNA in predicting outcomes to sotorasib, a recent study was performed on patients enrolled in CodeBreaK 100 using plasma samples collected at baseline and at pre-specified timepoints during treatment. Patients without detectable baseline plasma KRAS G12C mutation showed a significant improvement in PFS (11.5 vs. 4.1 months) and OS (18.6 vs. 8.1 months). A subset of responders and non-responders showed a transient drop in ctDNA, followed by a progressive increase, while undetectable ctDNA at C2D1 was associated with longer PFS (8.3 vs. 4.4 months). Notably, among the small group of patients achieving complete response (n=4), 75% had undetectable mutations of any kind at baseline versus 12% of non-complete responders (15). Promising results were gathered on the assessment of plasmatic mutational load, particularly focusing on G12C plasmatic detection, both at baseline and during treatment. These findings confirm the prognostic value of ctDNA and its dynamic changes in patients treated with sotorasib, and suggest a possible strategy of early sotorasib initiation when the co-mutational burden is low. Consistently with these findings, higher baseline plasma tumour burden was demonstrated to be a negative prognostic factor, independent of treatment arm [odds ratio, 3.54 (95% CI: 1.83–6.85) per tertile increase; P=0.0001] also in the CodeBreaK 200 exploratory analysis (12).

CNS activity

The development of CNS metastases is a common event in patients with NSCLC and is associated with poor prognosis and decreased quality of life (16). In contrast to other oncogene addictions, such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocations, where tyrosine kinase inhibitors induce potent and long-lasting intracranial responses (17,18), there is still limited data regarding the intracranial activity of sotorasib. Patients with baseline asymptomatic and stable brain metastases were allowed to enter the CodeBreaK 100 trial, accounting approximately for the 20% of the study population (8). Among them, only 16 patients had measurable CNS disease, of whom, 3 (19%) developed a complete response and 11 (69%) had stable disease, leading to an intracranial DCR of 88% (9). The median PFS and OS of patients with brain metastases enrolled in the CodeBreaK 100 trial were 5.3 and 8.3 months respectively (19). In the post-hoc analysis from the CodeBreaK 200 trial sotorasib demonstrated delayed time to CNS recurrence and longer CNS-specific PFS vs. docetaxel in patients with stable or treated CNS lesions. ORR in individuals with measurable lesions (≥10 mm) was double with sotorasib (33.3%) compared with docetaxel (15.4%). The concordance between systemic and intracranial disease control was higher in the sotorasib arm (88%) than in docetaxel arm (54%) and the median duration of treatment was 6.8 months for patients receiving sotorasib vs. 3.0 months with docetaxel (20).

These initial results suggest a substantial activity of sotorasib in improving CNS outcomes in patients with KRAS G12C positive NSCLC, nevertheless, patients with active, untreated CNS metastases were excluded from the CodeBreaK trials leaving unanswered question on the reproducibility in clinical practice.

Safety

Sotorasib exhibited a manageable safety profile both in the pivotal trial and in the subsequent studies investigating the molecule. Diarrhea, nausea and increased transaminases were the most common ≥ G3 TRAEs registered, with a median time to onset in the CodeBreaK 100 population ranging from 6 weeks for diarrhea to 9 weeks for the hepatotoxicity. A trend towards increased hepatotoxicity was observed in patient with an interval between the discontinuation of checkpoint inhibitors and the initiation of sotorasib ≤3 months (8). These data have been confirmed in the first multicentric retrospective real-world study investigating sotorasib in KRAS G12C NSCLC, where 15 out of 16 patients who experienced a ≥ G3 TRAE with sotorasib, had already received an anti-PD(L)1 antibody, whereas only 1 among the 19 patients who were anti-PD-(L)1 naive developed a G3 TRAE (21). No significant correlations were found between the previous development of an immune-related adverse event (IRAE) and the consequent toxicity to sotorasib (16% and 20% of G3+ in the no-previous IRAEs and the previous IRAEs subgroups, respectively). However, there was a clear association between the last administration of anti-PD(L)1 therapy and the development of sotorasib-related TRAEs, as similarly highlighted in the CodeBreaK 100, where nearly the 95% of TRAE-related discontinuations and ≥ G3 TRAEs, occurred in patients with a restricted interval between the two treatments (set as less than 3 months). Notably, almost all G3+ toxicities (13 out of 15) were hepatotoxicity, and almost a third of the patients, had a significant improvement to grade 0-following steroids administration (8,21). The first safety report of the phase Ib CodeBreaK 100/101 trial investigating the combination of sotorasib plus either atezolizumab or pembrolizumab, further reinforced data on early hepatotoxicity from the combination therapy (22,23).

Data gathered from clinical trials address hepatotoxicity after early anti-PD(L)1 therapy as an important topic to discuss, especially considering that KRAS inhibitors have currently been approved only for second-or-later-line treatment.

Conclusions

The CodeBreaK 100 and CodeBreaK 200 trials established sotorasib as a new standard of care for the second line treatment of patients with advanced KRAS G12C positive NSCLC, paving the way for the development of other KRAS G12C inhibitors, including agents in advanced stage of development such as adagrasib (24) and new emerging molecules (25). However, research efforts are still necessary to optimize patients’ selection through tissue and ctDNA-based biomarkers and to improve the safety profile of combination therapies.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-18/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-18/coif). A.C. reports personal fees from MSD, AstraZeneca, BMS, Oncoc4, IQVIA, Roche, GSK, Ardelis Health, Access Infinity, EISAI, and Pierre-Fabre, which are outside this work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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