Early Changes in Circulating Cell-Free KRAS G12C Predict Response to Adagrasib in KRAS Mutant Non–Small Cell Lung Cancer Patients
Open accessPublished version of a preprint
Abstract
Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here, we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: Between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared with clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA >90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with patients with incomplete ctDNA clearance (60.6% vs. 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 vs. 5.4 months) and progression-free survival (HR, 0.3). Conclusions: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.
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- Findingown data
At cycle 2, 38 of 39 evaluable patients (97.4%) had some reduction in plasma KRAS G12C.
“a decrease of any magnitude was observed in 97.4% (38/39) of evaluable patients (Figure 2C and D).”
Quote in the paperSubstantial claim - Findingown data
Five patients did not reach complete plasma ctDNA clearance at cycle 2 or cycle 4.
“Five patients never achieved complete clearance of plasma ctDNA at either cycle 2 or 4.”
Quote in the paperNot a substantial claim - Findingown data
Cycle 4 complete ctDNA clearance was linked to longer mPFS (9.8 vs 4.3 months; p=0.01, HR 0.3).
“and mPFS (9.8 vs 4.3 months; p-value 0.01, HR 0.3).”
Quote in the paperSubstantial claim - Findingown data
Disease burden, measured as sum of diameters, showed only a weak correlation with baseline KRAS G12C allelic fraction.
“However, the correlation between disease burden (sum of diameters) to KRAS G12C AF% at baseline was weak (Supplemental figure 2).”
Quote in the paperNot a substantial claim - Findingown data
Baseline KRAS G12C detection sensitivity in Cohort A patients with confirmed tissue KRAS G12C mutation was 75.5% (40/53).
“Sensitivity for KRAS G12C detection at baseline for Cohort A patients with a confirmed KRAS G12C mutation by tumor tissue test was 75.5% (40/53)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Awad, 2021, Acquired resistance to KRASG12C inhibition in cancer, N Engl J Med source
Not checked in the free run.
- Findingown data
Two patients whose KRAS G12C ctDNA had not cleared by cycle 2 later achieved complete or near-complete (>95%) clearance by cycle 4.
“two patients that exhibited incomplete clearance of KRASG12C ctDNA at cycle 2 continued to deepen to achieve complete or near complete (>95%) clearance at cycle 4.”
Quote in the paperNot a substantial claim - Findingown data
At cycle 2, 34 patients showed more than 95% reduction in plasma KRAS G12C.
“By cycle 2, 34 patients had a >95% clearance of their plasma KRASG12C”
Quote in the paperSubstantial claim - Findingown data
Cycle 2 complete ctDNA clearance was associated with a higher objective response rate than incomplete clearance (60.6% vs 33.3%).
“Patients with complete ctDNA clearance at cycle 2 showed improved ORR (cleared: 60.6% (20/33) vs. non-cleared: 33.3% (2/6))”
Quote in the paperSubstantial claim - Findingown data
For most complete sample sets, KRAS G12C ctDNA reached its greatest reduction from baseline by cycle 2.
“We found that the maximal response in KRAS G12C ctDNA levels in most complete sample sets was observed between baseline and cycle 2”
Quote in the paperSubstantial claim - Findingown data
By C2D1, 33 of 39 evaluable patients (84.6%) had complete plasma clearance of KRAS G12C.
“84.6% (33/39) of patients achieving complete KRASG12C plasma clearance by C2D1.”
Quote in the paperSubstantial claim - Findingown data
At cycle 4, 29 of 36 evaluable patients (80.6%) had a complete plasma response.
“80.6% (29/36) achieved a complete plasma response at cycle 4.”
Quote in the paperSubstantial claim - Findingown data
For 24 C1D1 specimens with both ddPCR and NGS results, concordance between the two methods for KRAS G12C allelic fraction was excellent across all levels, with r2 > 0.95.
“Concordance for ddPCR and NGS results was excellent across all AF% levels with a r2 > 0.95 (Supplemental figure 1).”
Quote in the paperSubstantial claim - Findingown data
Pretreatment KRAS G12C ctDNA levels did not predict clinical response according to RECIST 1.1.
“Evaluation of the correlation of baseline KRASG12C ctDNA levels and clinical response utilizing RECIST 1.1 indicated that KRASG12C baseline ctDNA levels were not a predictive marker for clinical response (Figure 2B).”
Quote in the paperSubstantial claim - Findingcitation
Among Cohort A, the subset evaluable for longitudinal KRAS G12C ctDNA response had a slightly higher ORR (56.4%, 22/39) than the overall cohort (50.5%, 48/95).
“This subset of patients that were evaluable for longitudinal KRASG12C ctDNA response in Cohort A exhibited a slightly higher ORR (56.4%, 22/39 cycle ctDNA response evaluable) compared to Cohort A overall (50.5%, 48/95 RECIST 1.1 evaluable patients)19”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Jänne, 2022, Adagrasib in non–small cell lung cancer harboring a KRASG12C mutation, New Engl J Medicine source
Not checked in the free run.
- Findingown data
Baseline KRAS G12C allelic fraction was higher in patients whose plasma did not clear completely.
“patients with incomplete plasma clearance had higher AF% at baseline (Supplemental figure 3)”
Quote in the paperNot a substantial claim - Findingown data
Cycle 2 complete ctDNA clearance showed a nonsignificant trend toward shorter mPFS than incomplete clearance.
“Patients with complete ctDNA clearance at cycle 2 also exhibit a nonsignificant trend toward shorter mPFS compared to patients with incomplete ctDNA clearance, likely a result of the small sample size in the ‘not-cleared’ cohort.”
Quote in the paperNot a substantial claim - Findingown data
Cycle 2 complete ctDNA clearance was associated with longer survival than incomplete clearance (14.1 vs 8.7 months; p=0.04; HR=0.3).
“and survival (cleared: 14.1 months vs. non-cleared: 8.7 months; p = 0.04; HR=0.3).”
Quote in the paperSubstantial claim - Findingown data
Cycle 4 complete ctDNA clearance was linked to longer overall survival (14.7 vs 5.4 months; P<.001; HR 0.1).
“Complete ctDNA clearance at cycle 4 was associated with both improved survival (14.7 months vs 5.4 months; P-value <.001; HR 0.1)”
Quote in the paperSubstantial claim - Premisecitation
A prior study of 64 colorectal cancer patients given adagrasib alone or with cetuximab found >95% KRAS G12C mutant allele fraction reduction in 55.2% (16/29) of monotherapy and 87.5% (14/16) of combination patients.
“We previously accessed plasma samples collected at baseline and C2D1 for 64 colorectal cancer patients treated on adagrasib with and without cetuximab. 55.2% (16/29) of evaluable patients in the monotherapy and 87.5% (14/16) in the cetuximab cohort achieved a greater than 95% reduction in KRASG12C mutant allele fractions.26”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Yaeger, 2023, Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C, New Engl J Med source
Not checked in the free run.
- Interpretationown data
In advanced NSCLC, ctDNA response may be a useful marker of treatment outcome in some clinical and drug development contexts.
“Our data presented herein support previous studies that ctDNA response has the potential to be a marker of treatment outcome in patients with advanced NSCLC, and as such can be useful in certain clinical and drug development settings.”
Quote in the paperSubstantial claim - Interpretationown data
Early plasma response may serve as a marker of treatment outcome.
“Together these studies support that early plasma response has potential as a marker of treatment outcome.”
Quote in the paperSubstantial claim - Study design and conductown data
Few patients had incomplete ctDNA clearance at cycle 2 or cycle 4.
“the number of patients that had incomplete ctDNA clearance at cycle 2 or cycle 4 was small.”
Quote in the paperNot a substantial claim - Interpretationown data
The findings support using KRAS G12C plasma response at about 3 weeks to estimate the chance of a favorable objective clinical response.
“These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.”
Quote in the paperSubstantial claim
- May combine two claims. 8
- Classified as probably not a substantial claim. 8
May combine two claims.
Findingown dataThe median tumor shrinkage was 46% (range -100% to 0%) among 33 patients with cycle 2 complete ctDNA clearance, versus 19.5% (range 8% to 53%) among 6 patients without complete clearance.
“The median tumor diameter reduction of 33 patients that cleared their ctDNA completely at cycle 2 was 46% (range −100% to 0%), while the median reduction for the 6 patients with incomplete ctDNA clearance at cycle 2 was 19.5% (range 8% to 53%).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOf five patients whose ctDNA fell at cycle 2 then rose at cycle 4, only one had a radiographic increase from baseline; the others were stable or continued to benefit.
“For the 5 patients that initially showed a decrease in ctDNA levels but a subsequent rise at cycle 4, only one patient had a radiographic increase from baseline (−11% to 13%), while the other patients either were either clinically stable (−26% to −26%) or showed continued benefit of treatment 43.5% median decrease (range 27 to 60%).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn five patients, plasma KRAS G12C fell at cycle 2 and then rose at cycle 4.
“Five patients initially showed a decrease in their plasma KRAS G12C at cycle 2 but a subsequent increase in ctDNA levels at cycle 4.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenORR, maximum target lesion size change, and PFS were centrally evaluated with RECIST 1.1.
“Objective response rate (ORR), maximum change in target lesion size, and progression free survival (PFS) were centrally assessed by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenOnly baseline, cycle 2, and cycle 4 specimens were analyzed.
“our study was limited to analysis of baseline, cycle 2 and cycle 4 specimens only.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationRecent data suggest that serial ctDNA analyses may have clinical value because ctDNA clearance in patients receiving systemic chemo- or immunotherapy correlates with progression-free and overall survival.
“recent data suggests that serial analyses may have clinical value as clearance of ctDNA among patients undergoing systemic chemo- or immunotherapy correlate with progression-free and overall survival.13–17”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [13] Bratman, 2020, Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab, Nat Cancer source
Not checked in the free run.
- cites [14] Osumi, 2019, Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer, Sci Rep source
Not checked in the free run.
- cites [15] Ricciuti, 2021, Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non–small cell lung cancer (NSCLC), J Immunother Cancer source
Not checked in the free run.
- cites [16] Cabel, 2017, Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study, Ann Oncol source
Not checked in the free run.
- cites [17] Cheng, 2021, Plasma ctDNA response is an early marker of treatment effect in advanced NSCLC, Jco Precis Oncol source
Not checked in the free run.
May combine two claims.
PremisecitationResponse rates were 18.6% for adagrasib alone and 46.6% for adagrasib plus cetuximab.
“Of interest, the response rate for the adagrasib monotherapy cohort was 18.6% and 46.6% for the adagrasib/cetuximab combination cohort.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Yaeger, 2023, Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C, New Engl J Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFor EGFR TKIs, ctDNA increase preceded radiographic progression by a median of just under one month, though over 25% of patients had a lead time exceeding 3 months.
“This is in line with reported lead times of plasma progression versus radiographic progression, which showed the median lead time from ctDNA increase to radiographic progression was just under one month for EGFR TKIs, but greater than 25% of patients had a lead time of over 3 months.36”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Tie, 2022, Circulating tumor DNA analysis guiding adjuvant therapy in Stage II colon cancer, New Engl J Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe study did not aim to monitor patients until clinical progression or to characterize acquired resistance mutations.
“our study was not designed to longitudinally monitor until clinical progression or to characterize acquired resistance mutations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll laboratory personnel were blinded to sample identity.
“All laboratory personal were blinded to sample identity.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFor advanced NSCLC, routine restaging imaging of the chest, abdomen, pelvis, and brain (if CNS symptoms exist) occurs every 6-8 weeks, matching RECIST 1.1 criteria used in trials.
“In advanced NSCLC, restaging scans of the chest, abdomen, pelvis and the brain, if known metastatic lesions symptoms concerning for central nervous system (CNS) involvement are present, are routinely performed every 6–8 weeks; this matches Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1) criteria, used for the assessment of treatment response and progression in clinical trials.11,12”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11] Eisenhauer, 2009, New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eur J Cancer source
Not checked in the free run.
- cites [12] Schwartz, 2016, RECIST 1.1—update and clarification: from the RECIST committee, Eur J Cancer source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAdagrasib is an oral small molecule that selectively and irreversibly inhibits mutant KRAS G12C, and the FDA recently approved it for NSCLC after at least one prior systemic therapy.
“Adagrasib is a selective and irreversible oral small-molecule inhibitor of the mutant KRAS G12C protein18 and was recently approved by the FDA for treatment of NSCLC who have received at least 1 prior systemic therapy19.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [18] Tanaka, 2021, Clinical acquired resistance to KRASG12C inhibition through a novel KRAS Switch-II pocket mutation and polyclonal alterations converging on RAS–MAPK reactivation, Cancer Discov source
Not checked in the free run.
- cites [19] Jänne, 2022, Adagrasib in non–small cell lung cancer harboring a KRASG12C mutation, New Engl J Medicine source
Not checked in the free run.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Clearance of ctDNA of the targeted oncogene has been proposed as a potential pharmacodynamic marker, predictive of response to the matched therapy and of OS.
“Clearance of ctDNA of the targeted oncogene has been proposed as a potential pharmacodynamic marker, predictive of response to the matched therapy and of OS (13, 14).”
From Efficacy and Safety of Adagrasib plus Cetuximab in Patients with <i>KRAS</i> G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [13]
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References 36 · Cited by 23
- Authors
- Paweletz, C. P., Heavey, G. A., Kuang, Y., Durlacher, E., Kheoh, T., Chao, R. C., Spira, A. I., Leventakos, K., Johnson, M. L., Ou, S.-H. I., Riely, G. J., Anderes, K., Yang, W., Christensen, J. G., & Jänne, P. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Mirati Therapeutics (United States) (US)
- Virginia Cancer Specialists (US)
- Mayo Clinic (US)
- Tennessee Oncology (US)
- University of California, Irvine (US)
- Memorial Sloan Kettering Cancer Center (US)
- 1Belfer Center of Applied Cancer Science, Dana–Farber Cancer Institute, Boston, Massachusetts.
- Corresponding author
- Paweletz, Cloud P.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2023-06-06
- Volume
- 29
- Issue
- 16
- Pages
- 3074-3080
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC10527102
- OpenAlex
- W4379515913
- Semantic Scholar
- e779fa4d981c0883bc002321e8aff4cfd4995884
- Cited by
- 23
- References
- 36
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 6 · 2023: 3
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CA240592-02)
- Mirati Therapeutics
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- KRAS G12C, circulating tumor DNA, cell-free DNA, adagrasib, KRAS inhibitors, non-small cell lung cancer, liquid biopsy, treatment response prediction, ctDNA clearance, objective response rate, overall survival, progression-free survival
- MeSH terms
- Acetonitriles, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Piperazines, Pyrimidines, Proto-Oncogene Proteins p21(ras)
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