Two phase III trials presented at the 2023 ASCO Annual Meeting explored treatments under study for patients with non–small cell lung cancer (NSCLC). In an exploratory analysis of the CodeBreaK 200 trial, the KRAS inhibitor sotorasib was compared with docetaxel chemotherapy in subsets of patients with KRAS G12C–mutated NSCLC.1 In the LUNAR trial, investigators compared the addition of tumor treating fields therapy to standard immunotherapy or chemotherapy in patients with metastatic NSCLC who experienced disease progression after platinum-based chemotherapy.2
CodeBreaK 200: Sotorasib vs Docetaxel
Sotorasib—the first KRAS inhibitor to be approved for the treatment of NSCLC—was found to be superior to docetaxel in the majority of key prespecified subsets of patients with pretreated KRAS G12C–mutated NSCLC in an exploratory analysis of the CodeBreaK 200 trial.1 Results of the trial were published in The Lancet to coincide with this presentation at the ASCO meeting.3
Co-alterations in key genes included TP53, STK11, and KEAP1. In the overall population, these mutations were detected in 57% and 26% of patients treated with sotorasib and docetaxel, respectively.
Sotorasib demonstrated a progression-free survival benefit over docetaxel across all key co-alteration subgroups, including those with STK11-, TP53-, and KEAP1-altered as well as other mutations. Similar results were observed regarding overall response benefit, and response to sotorasib was superior to docetaxel across all major co-alteration–defined subgroups of patients.
At a median follow-up of 17.7 months, sotorasib achieved a 34% reduction in the risk of disease progression or death vs docetaxel, meeting the primary endpoint of the trial. The median progression-free survival with sotorasib was 5.6 months vs 4.5 months with docetaxel. The 12-month progression-free survival rates were 24.8% and 10.1%, respectively.
Sotorasib also improved progression-free survival vs docetaxel, regardless of the level of PD-L1 expression. In patients with less than 1% PD-L1 expression (n = 57), median progression-free survival was 8.3 months with sotorasib vs 5.9 months with docetaxel. Median progression-free survival was 4.6 months and 3.0 months, respectively, in those with PD-L1 expression between 1% and 49%. In patients with PD-L1 expression of 50% or higher, median progression-free survival was 5.7 months vs 5.4 months, respectively.
“In the first randomized, molecularly defined analysis of the KRAS G12C inhibitor vs docetaxel, sotorasib demonstrated consistent clinical benefit vs docetaxel across most co-alteration–defined subgroups,” said lead author Ferdinandos Skoulidis, MD, PhD, MRCP, of The University of Texas MD Anderson Cancer Center, Houston. “Several novel hypothesis-generating findings were observed in this study. Specifically, patients harboring tumors with additional KRAS co-alterations were more refractory to either sotorasib or docetaxel. And, in a small subset of patients harboring tumors with NOTCH1 co-mutations, sotorasib was associated with worse outcomes.”
In the first randomized, molecularly defined analysis of the KRAS G12C inhibitor vs docetaxel, sotorasib demonstrated consistent clinical benefit vs docetaxel across most co-alteration–defined subgroups.— Ferdinandos Skoulidis, MD, PhD, MRCP
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The phase III CodeBreaK 200 trial enrolled 345 patients with locally advanced/unresectable or metastatic KRAS G12C–mutated NSCLC who received one or more previous treatments (including platinum-based chemotherapy and an immune checkpoint inhibitor). Patients were randomly assigned 1:1 to receive oral sotorasib at a daily dose of 960 mg (n = 171) or intravenous docetaxel at 75 mg/m2 every 3 weeks (n = 174).
Of the 345 patients in the intent-to-treat population, baseline tissue next-generation sequencing data were available for 226 patients, and plasma next-generation sequencing data were available for 294 patients. The biomarker-evaluable population for the current analysis totaled 318 patients. At baseline, co-alterations were well balanced across the treatment arms. Beyond TP53, STK11, and KEAP1, other additional co-alterations of interest included EGFR (21%); NTRK1, NTRK2, and NTRK3 (19%); MET (12%); ALK (11%); RET (7%); ROS1 (5%); and BRAF (5%).
“The first conclusion is that these alterations were quite frequent. However, the prevalence of clinically actionable co-alterations in oncogenic drivers was considerably lower,” Dr. Skoulidis said.
In an exploratory analysis, NOTCH1 was the most likely co-alteration to be associated with early disease progression or long-term benefit. The co-existence of NOTCH1 was associated with early disease progression and shorter progression-free survival in the sotorasib arm and long-term benefit in the docetaxel arm.
“A higher baseline plasma tumor burden was associated with greater odds of early disease progression and a lower likelihood of long-term clinical benefit with either sotorasib or docetaxel,” he continued. “We conclude that baseline blood plasma tumor burden is negatively prognostic, independent of the treatment arm.”
LUNAR: Potential Role of Tumor Treating Fields Therapy
The addition of tumor treating fields to standard-of-care immunotherapy or chemotherapy improved overall survival vs the standard of care alone in patients with metastatic NSCLC following disease progression on or after platinum-based chemotherapy, according to data from the phase III LUNAR trial.2
The study met its primary endpoint, reducing the risk of death by 26% (P = .035). Median overall survival in the intent-to-treat population was 13.2 months with tumor treating fields plus the standard of care vs 9.9 months with the standard of care alone. With the addition of tumor treating fields, the 1-year and 3-year overall survival rates were 53% and 18%, respectively, with 42% and 7% in the control group.
“Tumor treating fields therapy should be considered part of the standard of care for metastatic NSCLC following disease progression after platinum-based chemotherapy,” said lead author Ticiana Leal, MD, of the Winship Cancer Institute of Emory University School of Medicine, Atlanta. “Tumor treating fields therapy is a potentially paradigm-shifting treatment modality.”
Tumor treating fields therapy should be considered part of the standard of care for metastatic NSCLC following disease progression after platinum-based chemotherapy.— Ticiana Leal, MD
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Tumor treating fields exert physical forces on electrically charged intracellular components in dividing cancer cells disrupting mitosis. This leads to downstream effects such as immunogenic cell death, triggering a systemic antitumor immune response.
“Tumor treating fields therapy is a noninvasive anticancer treatment modality,” she added. Dr. Leal explained that the electric fields are generated by a portable, at-home medical device and delivered to the tumors through two pairs of arrays applied to the chest with local regional delivery. Tumor treating fields therapy is currently approved for the treatment of glioblastoma and malignant pleural mesothelioma.
Median overall survival among patients treated with an immune checkpoint inhibitor was 18.5 months with the addition of tumor treating fields, compared with 10.8 months for the standard of care alone—translating to a 37% reduced risk of death (P = .03). Among patients treated with docetaxel, median overall survival was 11.1 months vs 8.7 months, respectively, for a nonsignificant 19% reduction in the risk of death.
According to histology, patients with nonsquamous histology had a median overall survival of 12.6 months with tumor treating fields, compared with 9.9 months with the standard of care (nonsignificant). Those with squamous histology had a median overall survival of 13.9 months compared with 10.1 months, respectively (P = .05). Median progression-free survival with the addition of tumor treating fields was comparable and not statistically significant between the two arms: 4.8 months vs 4.1 months, respectively.
The number of complete responses was quite low, noted Dr. Leal. However, all five complete responses occurred in patients receiving an immune checkpoint inhibitor, and four of them were in the arm receiving tumor treating fields therapy.
Most device-related adverse events were grade 1 or 2 dermatitis. These events resolved in 87% of cases after a median duration of 3 weeks.
“The LUNAR trial is the first study in more than 7 years to show a significant improvement in overall survival in metastatic NSCLC after platinum chemotherapy. I am heartened by this progress and the potential of this innovative therapy to help many patients with metastatic lung cancer in need of new treatment choices following platinum therapy, without added systemic toxicity,” Dr. Leal said.
In the global, randomized phase III LUNAR study, 276 patients were randomly assigned 1:1 to receive either tumor treating fields plus the standard of care—which included investigator’s choice of an immune checkpoint inhibitor or docetaxel—or the standard of care alone. Patients were followed every 6 weeks and remained on therapy until disease progression or intolerable toxicities.
Baseline demographics were comparable across both study arms. Overall, median patient age was 64 years (range, 22–86 years), and most patients were male (65%). Nearly all patients (96%) had an Eastern Cooperative Oncology Group performance status of 0 or 1.
DISCLOSURE: Dr. Skoulidis reported financial relationships with BioNTech, Moderna Therapeutics, the European Society for Medical Oncology, McGill Universite de Montreal, Moving Innovation and Technology, Physician’s Education Resource, RV Mais, Amgen, BeiGene, Calithera Biosciences, Guardant Health, Intellisphere, Medscape, Navire, Novartis, and Tango Therapeutics; and has received institutional funding from AIMM Therapeutics, Amgen, Boehringer Ingelheim, Merck, Mirati Therapeutics, Novartis, and Pfizer. Dr. Leal reported financial relationships with Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Daiichi Sankyo/AstraZeneca, Eisai, EMD Serono, Genentech, Janssen, Jazz Pharmaceuticals, Eli Lilly, Merck, Mirati Therapeutics, Novocure, Regeneron, Roche, and Takeda; and has received institutional funding from Pfizer.
REFERENCES
1. Skoulidis F, De Langen A, Paz-Ares LG, et al: Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus docetaxel in patients with pretreated KRAS G12C–mutated advanced non–small cell lung cancer. 2023 ASCO Annual Meeting. Abstract 9008. Presented June 3, 2023.
2. Leal T, Kotecha R, Ramlau R, et al: Tumor treating field therapy with standard of care in metastatic non-small cell lung cancer following platinum failure: Randomized, phase 3 LUNAR study. 2023 ASCO Annual Meeting. Abstract LBA9005. Presented June 4, 2023.
3. 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.
