Trends in Colorectal Cancer Screening from the National Health Interview Survey: Analysis of the Impact of Different Modalities on Overall Screening Rates.

Colorectal cancer is the second leading cause of cancer-related mortality in adults in the United States. Despite compelling evidence of improved outcomes in colorectal cancer, screening rates are not optimal. This study aimed to characterize colorectal cancer screening trends over the last two decades and assess the impact of various screening modalities on overall colorectal cancer screening rates. Using National Health Interview Survey data from 2005 to 2021, we examined colorectal cancer screening [colonoscopy, multitarget stool DNA (mt-sDNA), fecal occult blood test (FOBT)/fecal immunochemical test, sigmoidoscopy, CT colonography] rates among adults ages 50-75 years (n = 85,571). A pseudo-time-series cross-sectional (pseudo-TSCS) analysis was conducted including a random effects generalized least squares regression model to estimate the relative impact of each modality on changes in colorectal cancer screening rates. Among 50 to 75 year olds, the estimated colorectal cancer screening rate increased from 47.7% in 2005 to 69.9% in 2021, with the largest increase between 2005 and 2010 (47.7%-60.7%). Rates subsequently plateaued until 2015 but increased from 63.5% in 2015 to 69.9% in 2018. This was primarily driven by the increased use of mt-sDNA (2.5% in 2018 to 6.6% in 2021). Pseudo-TSCS analysis results showed that mt-sDNA contributed substantially to the increase in overall screening rates (77.3%; P < 0.0001) between 2018 and 2021. While colorectal cancer screening rates increased from 2005 to 2021, they remain below the 80% goal. The introduction of mt-sDNA, a noninvasive screening test may have improved overall rates. Sustained efforts are required to further increase screening rates to improve patient outcomes and offering a range of screening options is likely to contribute to achieving this goal. PREVENTION RELEVANCE: This retrospective study highlights the importance of convenient stool-based colorectal cancer screening options to achieve the national goal of 80% for overall colorectal cancer screening rates. Empowering screening-eligible individuals with a choice for their colorectal cancer screening tests is imperative.

Tunable PhenoCycler imaging of the murine pre-clinical tumour microenvironments.

BACKGROUND: The tumour microenvironment (TME) consists of tumour-supportive immune cells, endothelial cells, and fibroblasts. PhenoCycler, a high-plex single cell spatial biology imaging platform, is used to characterize the complexity of the TME. Researchers worldwide harvest and bank tissues from mouse models which are employed to model a plethora of human disease. With the explosion of interest in spatial biology, these panoplies of archival tissues provide a valuable resource to answer new questions. Here, we describe our protocols for developing tunable PhenoCycler multiplexed imaging panels and describe our open-source data analysis pipeline. Using these protocols, we used PhenoCycler to spatially resolve the TME of 8 routinely employed pre-clinical models of lymphoma, breast cancer, and melanoma preserved as FFPE. RESULTS: Our data reveal distinct TMEs in the different cancer models that were imaged and show that cell-cell contacts differ depending on the tumour type examined. For instance, we found that the immune infiltration in a murine model of melanoma is altered in cellular organization in melanomas that become resistant to αPD-1 therapy, with depletions in a number of cell-cell interactions. CONCLUSIONS: This work presents a valuable resource study seamlessly adaptable to any field of research involving murine models. The methodology described allows researchers to address newly formed hypotheses using archival materials, bypassing the new to perform new mouse studies.

CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial.

C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non-small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles. Primary endpoints were investigator-assessed objective response rate (RECIST v1.1) and safety. Of 105 patients (CRPC, n=40; MSS CRC, n=40; NSCLC, n=25), 3 had a partial response (2 CRPC, 1 MSS CRC) for ORRs of 5%, 2.5%, and 0%, respectively. Median progression-free survival was 1.8-2.4 months without evidence of a dose-response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. Dose-limiting toxicities occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg; events included grade 4 neutropenia and grade 3 transaminase elevation, hepatitis, and pneumonitis. Treatment-related adverse events occurred in 70/105 patients (67%) and led to treatment discontinuation in 7/105 (7%). Maximal reductions from baseline in absolute neutrophil count were 44.5%-48.2% (cycle 1) and 37.5%-44.2% (cycle 2) and occurred within 6-12 hours postdose in both groups. Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in this study. Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925).

Colorectal cancer screening uptake and adherence by modality at a large tertiary care center in the United States: a retrospective analysis.

OBJECTIVE: Real-world data is crucial to inform existing opportunistic colorectal cancer (CRC) prevention programs. This study aimed to assess CRC screening adherence and utilization of various screening modalities within a Primary Care network over a three-year period (2017-2019). METHODS: A retrospective review of individuals aged 50-75 years at average CRC risk, with at least one clinic visit in the previous 24 months. The primary outcome, CRC screening adherence (overall and by modality) was examined among the entire eligible population and newly adherent individuals each calendar year. The final sample included 107,366 patients and 218,878 records. RESULTS: Overall CRC screening adherence increased from 71% in 2017 to 78% in 2019. For "up-to-date" individuals, colonoscopy was the predominant modality (accounting for approximately 74%, versus 4% of adherence for non-invasive options). However, modality utilization trends changed over time in these individuals: mt-sDNA increased 10.2-fold, followed by FIT (1.6-fold) and colonoscopy (1.1-fold). Among newly adherent individuals, the proportion screened by colonoscopy and FOBT decreased over time (89% to 80% and 2.4% to 1.2%, respectively), while uptake of FIT and mt-sDNA increased (7.7% to 11.5% and 0.9% to 6.8%, respectively). Notably, FIT and mt-sDNA increases were most evident in age and race-ethnicity groups with the lowest screening rates. CONCLUSIONS: In an opportunistic CRC screening program, adherence increased but remained below the national 80% goal. While colonoscopy remained the most utilized modality, new colonoscopy uptake declined, compared with rising mt-sDNA and FIT utilization. Among minority populations, new uptake increased most with mt-sDNA and FIT.

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.

Patterns of colorectal cancer screening and adherence rates among an average-risk population enrolled in a national health insurance provider during 2009-2018 in the United States.

While colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States (US), outcomes can be improved through timely screening. Despite the benefits and widespread availability of screening tests, adherence to recommended screening strategies is low. The study aimed to provide recent evidence regarding screening rates and adherence to screening recommendations among adults at average risk for CRC in a commercially insured and Medicare Advantage population. De-identified administrative data from a large US research database were examined to determine screening rates for the years 2009 through 2018. The study population included adults aged 50-75 years and annual study population counts ranged from 1,390,594 in 2009 to 1,654,544 in 2018. Incident screening rates were found to be relatively stable across the study years (approximately 15 %) with adherence lowest in the youngest age group (ages 50-54 years). Colonoscopies accounted for approximately 50 % of all screening tests performed, while there was a substantial increase in the use of home-based screening tests over the study timeframe. The use of the fecal immunochemical test increased from 17.2 % in 2009 to 28.9 % in 2018 and the multi-target stool DNA test increased from 0.4 % in 2015 to 9.0 % in 2018. Overall though, CRC screening and adherence rates remain relatively low among adults at average risk for CRC in the US. Improving adherence rates with CRC screening recommendations among individuals at average risk for CRC is required to improve health outcomes.

Two Cases of Durable and Deep Responses to Immune Checkpoint Inhibition-Refractory Metastatic Melanoma after Addition of Camu Camu Prebiotic.

Camu camu (CC) is a prebiotic that selectively stimulates growth and activity of beneficial gut microbiota. Work in murine models demonstrated that castalagin, the active compound in CC, preferentially binds to beneficial gut microbiome bacteria, promoting a stronger CD8+T cell anti-cancer response. We present two patients with metastatic melanoma whose cancer progressed on immune checkpoint inhibitors (ICIs) and developed clinically significant immune-related adverse events (irAEs). They were rechallenged with ICIs in combination with CC. The first patient is a 71-year-old woman with metastatic melanoma, whose ICI treatment was complicated by immune-related pneumonitis and colitis. Upon progression on maintenance nivolumab, CC was added to nivolumab, leading to a near complete response (CR). The second patient is a 90-year-old man with recurrent unresectable melanoma, treated with nivolumab, complicated by immune-related rash and diabetes. He developed new subcutaneous calf lesions and a metastatic popliteal lymph node. CC was added to nivolumab. One month later, the patient experienced a CR. Both patients have been on nivolumab and CC with durable responses for more than a year, with minimal irAEs. These two cases suggest that CC may modulate the microbiome, synergizing with ICIs to produce deep, durable responses with minimal irAEs.

Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma.

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.

Assessing Skin Cancer Risk Factors, Sun Safety Behaviors and Melanoma Concern in Atlantic Canada: A Comprehensive Survey Study.

BACKGROUND: The incidence of cutaneous melanoma (CM) is increasing at an alarming rate in Canada and elsewhere around the world. Significant regional differences in CM incidence have been identified in Atlantic provinces. The goal of this study is to compare ultraviolet exposure, sun protective behaviours, level of worry and baseline CM knowledge in provinces with a high versus low incidence of CM as well, as between various demographic groups. METHODS: A cross-sectional survey study was conducted in Atlantic provinces between July 2020 and August 2022. All participants aged ≥ 16 years with a completed survey were eligible. Survey responses were summarized using frequency counts, percentages, and means. Two-sided Z-tests for equality of proportions and logistic regression models were used to compare the survey results between geographic and demographic groups. RESULTS: In total, 7861 participants were included (28.0% men; mean age 61.3 years; response rate 28%). Our results (gender- and age-adjusted odds ratio, 95% confidence interval) show that high-incidence provinces for CM (Prince Edward Island and Nova Scotia) had significantly more sunburns (OR 2.00, 1.72-2.31), total sun exposure (OR 2.05, 1.68-2.50), recreational sun exposure (OR 1.95, 1.61-2.35) and tans (OR 1.77, 1.53-2.05) than individuals in low-incidence provinces (Newfoundland and Labrador). However, individuals in high-incidence provinces displayed more protective behaviors: there were less tanning bed users (OR 0.82, 0.71-0.95), they checked their skin more frequently for new moles (OR 1.26, 1.06-1.51) and practiced more sun protection overall. Additional analyses are presented based on education, income, sexual orientation and gender. DISCUSSION: These findings suggest that future efforts aimed at reducing the CM burden in Atlantic Canada should be tailored for target geographic and/or demographic groups. LIMITATIONS: the study participants are not representative of the population in Atlantic Canada due to recruitment strategies.

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation.

BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).

Healthcare costs, resource utilization, and productivity loss associated with colorectal cancer screening.

OBJECTIVES: To evaluate healthcare costs, resource utilization, associated costs, and lost productivity for colorectal cancer (CRC) screening in an average-risk population. METHODS: This retrospective cohort study identified average-risk individuals (50-75 years) with claims in the Optum Research Database for CRC screening test between 1 January 2014 to 31 December 2018. Index date was defined as the first date of a claim for colonoscopy, fecal immunochemical test (FIT), guaiac-based fecal occult blood test (FOBT) or multi-target stool DNA test (mt-sDNA). Screening costs were evaluated with descriptive statistics and multivariable analyses, adjusting for patient characteristics and index screening costs. RESULTS: In total, 903,831 individuals were identified by test groups: mt-sDNA (n = 29,614), FIT (n = 254,002), guaiac-based FOBT (n = 112,757) and colonoscopy (n = 507,458). Adjusted costs for index screening were, colonoscopy ($3,029), mt-sDNA ($752), FIT ($45), and (FOBT ($153). Adjusted costs across the six months following the index screening were $146 for colonoscopy, $329 for mt-sDNA, $306 for FIT, and $412 for FOBT. Colonoscopy had the highest costs for lost productivity. CONCLUSIONS: Screening colonoscopy had the highest productivity loss and healthcare costs up-front, suggesting potential cost benefits for noninvasive screening modalities. The more frequent screening interval required for FIT and FOBT resulted in a higher yearly cost than colonoscopy or mt-sDNA.

Colorectal cancer (CRC) is a prominent healthcare concern the United States, which accounted for 149,500 new cases and 52,980 deaths in 2021. Screening is effective for diagnosing the condition at earlier more treatable stages, and reducing deaths. However, screening is largely underutilized in part due to perceived cost barriers. This observational study used insurance claims data to calculate healthcare costs, resource use, and lost productivity for CRC screening in an average-risk population aged 50­75 years. A total of 903,831 individuals were identified by test groups: multi-target stool DNA test (mt-sDNA test; 29,614 individuals), fecal immunochemical test (FIT; 254,002 individuals), guaiac-based fecal occult blood test (FOBT; 112,757 individuals) and colonoscopy (507,458 individuals). Adjusted costs for initial screening were $3,029 for colonoscopy, $752 for mt-sDNA, $45 for FIT, and $153 for FOBT. Adjusted colonoscopy-related costs combined across the six months following the initial screening were $146 for the colonoscopy cohort, $329 for mt-sDNA, $306 for FIT, and $412 for FOBT. Colonoscopy had the highest costs for lost productivity. Overall, screening colonoscopy was accompanied by the highest productivity loss and up-front costs, suggesting potential cost benefits for noninvasive screening modalities ­ mt-sDNA, FIT, and FOBT; however, the more frequent screening interval required by FIT and FOBT resulted in a higher estimated average yearly screening cost.

Opportunities and Challenges in Screening for Colorectal Cancer.

Colorectal cancer (CRC) is a leading cause of mortality in the United States. Outcomes are greatly improved if CRC is detected early; hence, screening is currently recommended for adults aged 45 years and older at average risk for the disease. Despite this recommendation and the availability of accurate screening tests, the CRC screening rates are below those recommended. The goal of this study was to identify temporal trends (from 2015 to 2019) in CRC screening rates and the utilization of screening tests recommended for CRC detection among average-risk individuals within the St Elizabeth Healthcare system in Kentucky, United States. The primary population of interest was patients aged 50-75 years (the CRC screening was recommended for this age group at the time of the study). Deidentified data were sourced from patients' electronic health records, and the results showed that screening rates increased significantly from 26% in 2015 to 49% in 2019 (<0.0001). The incidence of any screening test also increased significantly from 2015 to 2019, for those who were due for screening (P < 0.05) and for the entire cohort (P < 0.1). The use of multitarget stool DNA (mt-sDNA) increased 40-fold over the study timeframe (P < 0.05). These study results confirm that CRC screening rates remain suboptimal, although incidence and adherence improved significantly in those aged 50-75 years from 2015 to 2019. The growing adoption and availability of mt-sDNA may be correlated with an increase in overall screening in this average-risk population.

Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial.

Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899 .

Patient and provider factors associated with colorectal cancer screening among average risk health plan enrollees in the US, 2015-2018.

BACKGROUND: To assess patient and primary care provider (PCP) factors associated with adherence to American Cancer Society (ACS) and United States Preventive Services Task Force (USPSTF) guidelines for average risk colorectal cancer (CRC) screening. METHODS: Retrospective case-control study of medical and pharmacy claims from the Optum Research Database from 01/01/2014 - 12/31/2018. Enrollee sample was adults aged 50 - 75 years with ≥ 24 months continuous health plan enrollment. Provider sample was PCPs listed on the claims of average-risk patients in the enrollee sample. Enrollee-level screening opportunities were based on their exposure to the healthcare system during the baseline year. Screening adherence, calculated at the PCP level, was the percent of average-risk patients up to date with screening recommendations each year. Logistic regression modelling was used to examine the association between receipt of screening and enrollee and PCP characteristics. An ordinary least squares model was used to determine the association between screening adherence among the PCP's panel of patients and patient characteristics. RESULTS: Among patients with a PCP, adherence to ACS and USPSTF screening guidelines ranged from 69 to 80% depending on PCP specialty and type. The greatest enrollee-level predictors for CRC screening were having a primary/preventive care visit (OR = 4.47, p < 0.001) and a main PCP (OR = 2.69, p < 0.001). CONCLUSIONS: Increased access to preventive/primary care visits could improve CRC screening rates; however, interventions not dependent on healthcare system contact, such as home-based screening, may circumvent the dependence on primary care visits to complete CRC screening.

Inhibition of the MNK1/2-eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer.

Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders the translation of mRNAs that code for proteins involved in cell survival. We hypothesized that cancer cells treated with palbociclib use upregulated phosphorylated eIF4E (phospho-eIF4E) to escape the antitumor benefits of this drug. Indeed, we found that pharmacologic or genetic disruption of MNK1/2 activity, the only known kinases for eIF4E, enhanced the ability of palbociclib to decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis of melanoma cells treated with combined MNK1/2 and CDK4/6 inhibitors showed downregulation of proteins with critical roles in cell-cycle progression and mitosis, including AURKB, TPX2, and survivin. We also observed that palbociclib-resistant breast cancer cells have higher basal levels of phospho-eIF4E, and that treatment with MNK1/2 inhibitors sensitized these palbociclib-resistant cells to CDK4/6 inhibition. In vivo we demonstrate that the combination of MNK1/2 and CDK4/6 inhibition significantly increases the overall survival of mice compared with either monotherapy. Overall, our data support MNK1/2 inhibitors as promising drugs to potentiate the antineoplastic effects of palbociclib and overcome therapy-resistant disease.

Efficacy and safety of pembrolizumab monotherapy in patients with advanced thyroid cancer in the phase 2 KEYNOTE-158 study.

BACKGROUND: The authors report results from the thyroid carcinoma cohort of the multicohort phase 2 KEYNOTE-158 study (NCT02628067), which evaluated pembrolizumab monotherapy in patients with previously treated cancers. METHODS: Eligible patients had histologically and/or cytologically confirmed papillary or follicular thyroid carcinoma, failure of or intolerance to prior therapy, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients received pembrolizumab (200 mg) every 3 weeks for up to 35 cycles. The primary end point was objective response rate (ORR) per RECIST v1.1 by independent central review. RESULTS: A total of 103 patients were enrolled and received pembrolizumab. Median duration from first dose to data cutoff (October 5, 2020) was 49.4 (range, 43.9-54.9) months. ORR was 6.8% (95% confidence interval [CI], 2.8%-13.5%), and median duration of response was 18.4 (range, 4.2-47.2+) months. ORR was 8.7% (95% CI, 2.4%-20.8%) among patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 (n = 46) and 5.7% (95% CI, 1.2%-15.7%) among patients with PD-L1 CPS <1 (n = 53). Median overall survival and progression-free survival were 34.5 (95% CI, 21.2 to not reached) and 4.2 (95% CI, 3.9-6.2) months, respectively. Treatment-related adverse events occurred in 69.9% of patients (grade 3-5, 14.6%). CONCLUSIONS: Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in a small subset of patients with advanced thyroid cancer. These results provide evidence of modest antitumor activity in this setting regardless of tumor PD-L1 expression. Future studies evaluating immune checkpoint inhibitors in patients with differentiated thyroid cancer should focus on biomarker-driven patient selection or combination of immune checkpoint inhibitors with other agents, in order to achieve higher response rates than observed in this study.