Lung Cancer and Coughing Up Blood: When to See a Doctor
Integrating RECIST And Clinician Approaches Boosts NSCLC Research
Outcomes among patients with stage IV non–small cell lung cancer as evaluated within clinical trials via Response Evaluation Criteria in Solid Tumors (RECIST) and clinician response criteria in observational studies were compared for their concordance and reliability.
A 2-pronged approach in the non–small cell lung cancer (NSCLC) space that includes evaluating patient therapeutic outcomes via Response Evaluation Criteria in Solid Tumors (RECIST) for clinical trials and clinician-anchored approaches in observational studies can better serve future research purposes vs each individual method, experts have concluded in a new study published in JAMA Network Open.1
Data are lacking on how RECIST- and clinician-based end points might be used to bolster confidence in each other in regard to response- and progression-based measures, with particular weight placed on the ability of observational end points to be interpreted in the context of clinical trial response. Patient-level data from the IMpower 132 trial (conducted April 7, 2016, to May 31, 2017) and the nationwide Flatiron Health electronic health record (HER)-derived deidentified advanced NSCLC (advNSCLC) database (data collected January 1, 2011, to March 31, 2022) were used for the present analysis. IMpower 132 evaluated atezolizumab plus platinum-based chemotherapy of carboplatin or cisplatin plus pemetrexed vs carboplatin or cisplatin and pemetrexed in chemotherapy-naïve patients who have stage IV NSCLC.2
"Fundamental differences exist between methods used in clinical trials and routine clinical care to determine response and progression in patients with solid tumors," the study authors wrote. "Further exploration of replicating RECIST end points using clinician-documented end points can further inform and increase confidence in the use of these outcome variables."
There were 769 patients in this analysis; IMpower 132 inclusion/exclusion criteria were used to select patients for the observational cohort, and then all patients were randomized to first-line carboplatin or first-line cisplatin and pemetrexed. Main outcomes of interest were response rates, duration of response, and progression-free survival. Patients in the observational cohort (n = 494) were slightly older than patients in the trial cohort (n = 275), at a median (IQR) of 67 (60-74) years vs 63 (56-68) years and this group had more female patients (46.2% vs 32.7%). Most patients in each group were White (71.3% and 70.5%, respectively).
Clinical trial and electronic health record data were used this this analysis of the comparability of patient outcomes in the NSCLC space between clinical trial data and clinician assessmentsImage Credit: ipopba-stock.Adobe.Com
Overall, there were more response assessments seen for the trial patients vs the observational patients, but the 3 principal outcomes were comparable between the groups. More of the patients in the observational cohort had an ECOG performance status score of 1, meaning they were ambulatory but had some physical restrictions.3 Mean (SD) follow-up was longer in the observational cohort vs the trial cohort, 17.9 (19.7) months vs 15.8 (11.7) months, but there were fewer in the former group with at least 1 response assessment vs the latter group: 77.6% vs 93.1%. The patients in the observation cohort also had a higher percentage of patients with progressive disease: 17.8% vs 12.9%.
For platinum-based chemotherapy, there were significant differences in receipt of carboplatin plus pemetrexed as first-line induction therapy vs cisplatin plus pemetrexed:
Also, 54.9% of patients in the trial group received first-line maintenance therapy vs 32.8% of the observational group.
The unweighted OR was 1.28 (95% CI, 0.95-1.73), according to EHR data, while the weight OR was 1.09 (95% CI, 0.71-1.67) in the primary analysis, "suggesting comparable odds of response between the cohorts."
The median EHR-derived duration of response was 5.59 months overall in the observational cohort vs 6.9 months in the trial cohort (HR, 1.12; 95% CI, 0.82-1.54). PFS measures were closer: 5.3 months vs 5.4 months (HR, 0.98; 955 CI, 0.81-1.19).
Sensitivity analyses determined that for all outcomes, the ORs of response were comparable between the trial and observational cohorts after weighting.
The study authors note that their findings are strong because they echo previous analyses,4,5 add new knowledge, and are robust in that no difference was observed between the trial duration of response and the EHR-derived duration of response.
Potential limitations on these findings are that the investigators could not apply all trial criteria to the observational cohort, that the observational cohort was missing data on race, ethnicity, and PD-L1 status, and that the patients treated in the trial had a strict response assessment protocol, whereas the patients in the observational group were assessed as part of their routine care with varying frequency.
"This study provides valuable insight into the relationships and methodological considerations for interpreting clinical outcomes between trial and observational cohorts," the authors concluded. "The analytic approach could be extended to evaluate whether end points remain comparable in other disease settings."
References
1. Lu Y, Langerman SS, McCain E, et al. Response- and progression-based end points in trial and observational cohorts of patients with NSCLC. JAMA Netw Open. 2024;7(5):e249286. Doi:10.1001/jamanetworkopen.2024.9286
2. A study of atezolizumab in combination with carboplatin or cisplatin + pemetrexed compared with carboplatin or cisplatin + pemetrexed in participants who are chemotherapy-naive and have stage iv non-squamous non-small cell lung cancer (NSCLC) (IMpower 132). ClinicalTrials.Gov. Updated November 21, 2023. Accessed May 8, 2024. Https://www.Clinicaltrials.Gov/study/NCT02657434
3. ECOG performance status scale. ECOG-ACRIN Cancer Research Group. Accessed May 8, 2024. Https://ecog-acrin.Org/resources/ecog-performance-status/
4. Ton TGN, Pal N, Trinh H, et al. Replication of overall survival, progression-free survival, and overall response in chemotherapy arms of non-small cell lung cancer trials using real-world data. Clin Cancer Res. 2022;28(13):2844-2853. Doi:10.1158/1078-0432.CCR-22-0471
5. Huang Bartlett C, Mardekian J, Cotter MJ, et al. Concordance of real-world versus conventional progression-free survival from a phase 3 trial of endocrine therapy as first-line treatment for metastatic breast cancer. PLoS One. 2020;15(4):e0227256. Doi:10.1371/journal.Pone.0227256
Glecirasib Shows Promising Efficacy In KRAS-Mutated NSCLC
Glecirasib, a highly selective covalent oral inhibitor of KRAS G12C, demonstrated promising efficacy in patients with previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC), according to a phase II trial from China.
For these patients, the objective response rate (ORR) was 47.9% and median progression-free survival (PFS) was 8.2 months, reported Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, during an American Society of Clinical Oncology (ASCO) virtual plenary.
ASCO discussant Julia Rotow, MD, of Dana-Farber Cancer Institute in Boston, said that compared with adagrasib (Krazati) and sotorasib (Lumakras) -- which are FDA approved as second-line therapies for patients with KRAS G12C-mutated locally advanced or metastatic NSCLC -- "there appears to be a trend towards a better response rate and better progression-free survival with glecirasib."
A comparison across studies showed that patients treated with adagrasib in KRYSTAL-1 achieved an ORR of 43% and a median PFS of 6.5 months. As for sotorasib, the phase II CodeBreak 100 study showed that patients had an ORR of 37.1% and a median PFS of 6.8 months, while in the phase III randomized CodeBreak 200 trial, the ORR was 28.1% and the median PFS was 5.6 months.
"Efficacy [with glecirasib] appears to be trending in the right direction, but is modest and could be from the range of cross-trial variation," Rotow said. "So, ongoing confirmation will be needed."
While plans for FDA approval of glecirasib in NSCLC are unclear, the KRAS inhibitor recently garnered the agency's orphan drug designation for pancreatic cancer, according to drugmaker Jacobio.
The current study included 119 NSCLC patients (79% men, median age 62 years). About 81% had an Eastern Cooperative Oncology Group (ECOG) performance status score of 1, and 94% had received prior PD-1/L1 inhibitors and platinum-based chemotherapy.
With a median follow-up of 10.4 months, 34.2% of patients were still on treatment.
Of the 119 patients in the study, four achieved a complete response to glecirasib, 52 had a partial response, and 45 had stable disease, resulting in a disease control rate of 86.3%.
Six-month and 12-month PFS rates were 56.6% and 40%, respectively. Median overall survival was 13.6 months, with 6- and 12-month rates of 83% and 54.6%, respectively.
As for safety, KRAS inhibitors "are often more toxic than many of our other targeted agents we use in oncogene-driven lung cancer, and here glecirasib does have a distinct side effect profile that is different from sotorasib and adagrasib," Rotow said. "Particularly notable are the rates of hepatic toxicities ... This is something to watch for if we are treating a patient with this agent."
Specifically, there were substantially higher rates of treatment-related adverse events with glecirasib involving blood bilirubin increases (all-grade: 48.7%; ≥grade 3: 6.7%) and alanine aminotransferase and aspartate aminotransferase increases (all-grade: 35.3%; ≥grade 3: 10.9%) compared with what was reported with sotorasib and adagrasib in their respective trials.
However, both Shi and Rotow noted that there was very limited gastrointestinal toxicity seen in the study compared with sotorasib and adagrasib, with just 5.9% of patients experiencing any-grade nausea, 7.6% having vomiting, and 3.4% having diarrhea. Just one patient experienced grade 3 nausea.
Discontinuation and dose-reduction rates in the trial were also slightly lower than those seen in CodeBreak 100, and significantly lower than the rates in KRYSTAL-1. "This likely has to do with the different GI toxicity profiles," Rotow suggested. "This is ... Something that may be an advantage when selecting among agents."
Rotow added that there are multiple unanswered questions surrounding glecirasib, such as whether the agent will have central nervous system activity, and what its role will be in combination therapy.
She also wondered how the agent will compare with other KRAS-targeted strategies now under development, such as the KRAS G12C inhibitor divarasib that has demonstrated response rates over 50%, as well as KRAS inhibitors that have different mechanisms of action, such as the KRAS G12C inhibitor RMC-6291.
"Emerging RAS-targeted therapies continue to offer hope for improved outcomes for patients with KRAS-mutated NSCLC," Rotow said, "hopefully moving response rates from 30%-40% to the over-50% range going forward."
Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.
Disclosures
Shi and co-authors had no disclosures.
Rotow reported consulting fees from Amgen, AstraZeneca, BioAtla, BMS, Daiichi Sankyo, Genentech, G1 Therapeutics, Guardant Health, Janssen, Jazz Pharmaceuticals, Pfizer, Sanofi-Genzyme, Summit Therapeutics, and Takeda, and having contracts for research to her institution with AstraZeneca, BioAtla, Blueprint Medicines, Enliven Therapeutics, Black Diamond, LOXO Oncology, ORIC Pharmaceuticals, AbbVie, and RedCloud Bio.
Primary Source
American Society of Clinical Oncology
Source Reference: Shi Y, et al "A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation" ASCO Virtual Plenary 2024; Abstract 468214.
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