Comprehensive Genomic Profiling (CGP)-Informed Personalized Molecular Residual Disease (MRD) Detection: An Exploratory Analysis from the PREDATOR Study of Metastatic Colorectal Cancer (mCRC) Patients Undergoing Surgical Resection.

A majority of patients with metastatic colorectal cancer (mCRC) experience recurrence post curative-intent surgery. The addition of adjuvant chemotherapy has shown to provide limited survival benefits when applied to all patients. Therefore, a biomarker to assess molecular residual disease (MRD) accurately and guide treatment selection is highly desirable for high-risk patients. This feasibility study evaluated the prognostic value of a tissue comprehensive genomic profiling (CGP)-informed, personalized circulating tumor DNA (ctDNA) assay (FoundationOne®Tracker) (Foundation Medicine, Inc., Cambridge, MA, USA) by correlating MRD status with clinical outcomes. ctDNA analysis was performed retrospectively on plasma samples from 69 patients with resected mCRC obtained at the MRD and the follow-up time point. Tissue CGP identified potentially actionable alterations in 54% (37/69) of patients. MRD-positivity was significantly associated with lower disease-free survival (DFS) (HR: 4.97, 95% CI: 2.67−9.24, p < 0.0001) and overall survival (OS) (HR: 27.05, 95% CI: 3.60−203.46, p < 0.0001). Similarly, ctDNA positive status at the follow-up time point correlated with a marked reduction in DFS (HR: 8.78, 95% CI: 3.59−21.49, p < 0.0001) and OS (HR: 20.06, 95% CI: 2.51−160.25, p < 0.0001). The overall sensitivity and specificity at the follow-up time point were 69% and 100%, respectively. Our results indicate that MRD detection using the tissue CGP-informed ctDNA assay is prognostic of survival outcomes in patients with resected mCRC. The concurrent MRD detection and identification of actionable alterations has the potential to guide perioperative clinical decision-making.

Comparative Genomic Analysis of Intrahepatic Cholangiocarcinoma: Biopsy Type, Ancestry, and Testing Patterns.

BACKGROUND: At diagnosis, the majority of patients with intrahepatic cholangiocarcinoma (IHCC) present with advanced disease and a poor prognosis. Comprehensive genomic profiling (CGP) early in the disease course may increase access to targeted therapies and clinical trials; however, unresolved issues remain surrounding the optimal biopsy type to submit for CGP. PATIENTS AND METHODS: Mutational frequencies between primary tumor biopsies (Pbx), metastatic biopsies (Mbx), and liquid biopsies (Lbx) in 1,632 patients with IHCC were compared. RESULTS: Potentially actionable alterations were found in 52%, 34%, and 35% of patients in the Pbx, Mbx, and Lbx cohorts, respectively. In Pbx, Mbx, and Lbx, FGFR2 rearrangements were found in 9%, 6%, and 4%, and IDH1 mutations were identified in 16%, 5%, and 9% patients, respectively. Moreover, alterations in FGFR2 and IDH1 were significantly associated with distinct ancestries, including 2.1-fold enrichment for FGFR2 rearrangements in patients with African ancestry and 1.5-fold enrichment for IDH1 mutations in patients with admixed American (Hispanic) ancestry. Finally, the publication of biomarker-driven clinical trials in IHCC correlated with changing CGP testing patterns. Significant correlations between patient characteristics and IHCC trial disclosures were observed, including a significant decrease from time between biopsy and CGP testing, and more frequent testing of primary versus metastatic samples. CONCLUSION: Overall, because of the high likelihood of identifying actionable genomic alterations, CGP should be considered for the majority of patients with inoperable IHCC, and Lbx and Mbx can be considered as part of the diagnostic suite. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling (CGP) should be considered for all patients with intrahepatic cholangiocarcinoma (IHCC) or suspected IHCC, as actionable alterations were commonly found in multiple genes and a wide variety of FGFR2 fusion partners were identified. The disclosure of IHCC trial data correlated with increased use of CGP, an encouraging trend that moves new therapeutic options forward for rare cancers with a rare biomarker. Although tissue from the primary lesion may identify actionable alterations at higher rates, CGP of a liquid biopsy or metastatic site can be considered, particularly if the primary tissue block is exhausted.

Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor microenvironment. Synergizing cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade with chemotherapy could overcome these barriers. Here we present results of a phase Ib trial combining ipilimumab and gemcitabine in advanced PDAC. MATERIALS AND METHODS: This was a single-institution study with a 3 + 3 dose-escalation design. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included determining the toxicity profile, objective response rate (ORR), median progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-one patients were enrolled, 13 during dose escalation and 8 at the MTD. The median age was 66 years, 62% were female, 95% had stage IV disease, and 67% had received at least one prior line of therapy. The primary objective to establish the MTD was achieved at doses of ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2 . The most common grade 3 or 4 adverse events were anemia (48%), leukopenia (48%), and neutropenia (43%). The ORR was 14% (3/21), and seven patients had stable disease. Median response duration for the three responders was 11 months, with one response duration of 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61-4.83 months), and median OS was 6.90 months (95% CI, 2.63-9.57 months). CONCLUSION: Gemcitabine and ipilimumab is a safe and tolerable regimen for PDAC with a similar response rate to gemcitabine alone. As in other immunotherapy trials, responses were relatively durable in this study. IMPLICATIONS FOR PRACTICE: Gemcitabine and ipilimumab is a safe and feasible regimen for treating advanced pancreatic cancer. Although one patient in this study had a relatively durable response of nearly 20 months, adding ipilimumab to gemcitabine does not appear to be more effective than gemcitabine alone in advanced pancreatic cancer.

Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial.

Importance: In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). Objective: To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. Design, Setting, and Participants: Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). Interventions: mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. Results: Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). Conclusions and Relevance: Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01516216.

Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study.

BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. METHODS: We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. RESULTS: We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. INTERPRETATION: To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. FUNDING: National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Immuno-oncology and Its Opportunities for Interventional Radiologists: Immune Checkpoint Inhibition and Potential Synergies with Interventional Oncology Procedures.

Immunotherapy, specifically the use of immune checkpoint inhibitors, offers a new approach to fighting cancer. Although the results of treatment with immune checkpoint inhibition alone have been remarkable for certain cancers, these results are not universal. Preclinical and early clinical studies indicate the potential for synergistic effects when immune checkpoint inhibition is combined with immunogenic local therapies such as ablation and embolization. This review offers an overview of immunology as it relates to immune checkpoint inhibition and the possibilities for synergy when combined with interventional radiology treatments.

The Parity Paradigm: Can Legislation Help Reduce the Cost Burden of Oral Anticancer Medications?

Over the last decade, there has been increased development and use of oral anticancer medications, which sometimes leads to high cost sharing for patients. Drug parity laws require insurance plans to cover oral anticancer medications with the same cost sharing as intravenous/injected chemotherapy or have a capped limit on out-of-pocket costs. There are currently 36 enacted state laws (plus the District of Columbia) addressing drug parity, but no federal laws. In this policy perspective piece, we discuss the history, opportunities, and limitations of drug parity laws in oncology. We also discuss the implications of provisions of the Affordable Care Act and other proposed policy reforms on financing oral chemotherapy.

Radioembolization as a Treatment Strategy for Metastatic Colorectal Cancer to the Liver: What Can We Learn from the SIRFLOX Trial?

OPINION STATEMENT: In the setting of liver metastases from colorectal cancer (CRC), radioembolization with yttrium-90 has been used to treat chemotherapy refractory disease with a growing interest to establish its efficacy in prospective trials combined with first- and second-line chemotherapy. SIRFLOX is an ongoing, multi-center, phase 3 randomized trial comparing first-line chemotherapy alone or in combination with yttrium-90 radioembolization in patients with CRC who have isolated liver metastases or liver-dominant metastases. Preliminary results from SIRFLOX demonstrate that radioembolization combined with first-line chemotherapy is safe and feasible. There was no significant difference in median overall progression-free survival (PFS) between the combined radioembolization-chemotherapy and chemotherapy-only arms (10.7 versus 10.2 months). Although the trial did not meet its primary endpoint of improved median PFS, there was a significant increase in the median hepatic PFS (20.5 versus 12.6 months; p = 0.02) favoring the combination arm. Thus, combining radioembolization with chemotherapy in the first-line setting may be most effective for liver-limited metastatic CRC. Since radioembolization targets liver disease, it is plausible that the trial failed to achieve an improvement in PFS given that 40 % of the SIRFLOX population had extra-hepatic disease. It is also possible that the overall median PFS may be a poor surrogate endpoint, and other endpoints like overall survival still needs to be delineated in this setting. In addition, it is crucial to document improvement or delay in time to deterioration in quality of life symptom endpoints in this population. SIRFLOX is the first of three prospective studies that assess the efficacy of adding radioembolization to first-line chemotherapy, and the combined data from these trials will provide the necessary power for an overall survival analysis. The final results of SIRFLOX will be eagerly awaited to determine if the increased hepatic PFS in preliminary data will translate to increased overall survival benefit.

Cost estimates and economic implications of expanded RAS testing in metastatic colorectal cancer.

BACKGROUND: In colorectal cancer (CRC), evidence shows that expanding RAS testing to analyze more mutations may better predict benefit from anti-EGFR therapy. The economic implications of expanding RAS testing for metastatic CRC were analyzed. MATERIALS AND METHODS: Estimates of standard KRAS exon 2 testing were based on the Centers for Medicare and Medicaid Services (CMS) 2014 Diagnostic Laboratory Fee Schedule, and expanded RAS testing was estimated using a sensitivity analysis done with various potential cost scenarios (1, 2, 10, and 30 times the cost of the standard KRAS test). The cost estimates for cetuximab and panitumumab were based on the CMS payment allowance limits for Medicare Part B. RESULTS: A total of 28,692 patients with metastatic CRC were estimated to be eligible annually for RAS testing. For cetuximab, the societal cost of standard KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 billion versus $816 million if the cost of the tests were the same. If the cost of the expanded RAS test were 30 times the cost of the standard test, then the societal cost of standard KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 billion versus $980 million, a continued savings of more than $184 million annually. Similar savings were seen with panitumumab. CONCLUSION: The increased societal cost of expanded RAS testing versus standard approved KRAS exon 2 testing was inconsequential when compared with the amount of money saved by not treating the additional 18% of patients who harbor additional RAS mutations (beyond exon 2) with anti-EGFR therapy.

Phase II Trial of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevacizumab in Patients With Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204.

LESSONS LEARNED: The 5-year oncologic outcomes from the trial regimen were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy.Due to the lack of an improvement in the pathologic complete response rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study. BACKGROUND: The addition of bevacizumab to chemotherapy improves overall survival for metastatic colorectal cancer. We initiated a phase II trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy (RT) followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab for locally advanced rectal cancer. The purpose of this report is to describe the 5-year oncologic outcomes of this regimen. METHODS: In a phase II Simon two-stage design study, we evaluated preoperative treatment with capecitabine (825 mg/m(2) b.i.d. Monday-Friday), oxaliplatin (50 mg/m(2) weekly), bevacizumab (5 mg/kg on days 1, 15, and 29), and RT (50.4 Gy). Surgery was performed by 8 weeks after RT. Beginning 8-12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles (oxaliplatin stopped after 9 cycles). The primary endpoint was a pathologic complete response (path-CR) rate of 30%. Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled between 2006 and 2010. RESULTS: Of 57 enrolled patients, 53 were eligible and included in the analysis. Forty-eight (91%) patients completed preoperative therapy, all of whom underwent curative surgical resection. Nine patients (17%) achieved path-CR. There were 29 worst grade 3 events, 8 worst grade 4 events, and 2 patient deaths, 1 of which was attributed to study therapy. Twenty-six patients (54%) began adjuvant chemotherapy. After a median follow-up period of 41 months, the 5-year overall survival (OS) rate for all patients was 80%. Only 2 patients experienced cancer recurrence: 1 distant (liver) and 1 loco-regional (pelvic lymph nodes), respectively. Both of these patients are still alive. The 5-year relapse-free survival rate was 81%. CONCLUSION: Despite the path-CR primary endpoint of this trial not being reached, the 5-year OS and recurrence-free survival rates were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy. Because of the lack of an improvement in the path-CR rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study.

Impact of Medicare Part D on out-of-pocket drug costs and medical use for patients with cancer.

BACKGROUND: Medicare Part D was designed to reduce out-of-pocket (OOP) costs for Medicare beneficiaries, but to the authors' knowledge the extent to which this occurred for patients with cancer has not been measured to date. The objective of the current study was to examine the impact of Medicare Part D eligibility on OOP cost for prescription drugs and use of medical services among patients with cancer. METHODS: Using the Medical Expenditure Panel Survey (MEPS) for the years 2002 through 2010, a differences-in-differences analysis estimated the effects of Medicare Part D eligibility on OOP pharmaceutical costs and medical use. The authors compared per capita OOP cost and use between Medicare beneficiaries (aged ≥65 years) with cancer to near-elderly patients aged 55 years to 64 years with cancer. Statistical weights were used to generate nationally representative estimates. RESULTS: A total of 1878 near-elderly and 4729 individuals with Medicare were included (total of 6607 individuals). The mean OOP pharmaceutical cost for Medicare beneficiaries before the enactment of Part D was $1158 (standard error, ±$52) and decreased to $501 (standard error, ±$30), a decline of 43%. Compared with changes in OOP pharmaceutical costs for nonelderly patients with cancer over the same period, the implementation of Medicare Part D was associated with a further reduction of $356 per person. Medicare Part D appeared to have no significant impact on the use of medications, hospitalizations, or emergency department visits, but was associated with a reduction of 1.55 in outpatient visits. CONCLUSIONS: Medicare D has reduced OOP prescription drug costs and outpatient visits for seniors with cancer beyond trends observed for younger patients, with no major impact on the use of other medical services noted.

Twelve-year experience of radioembolization for colorectal hepatic metastases in 214 patients: survival by era and chemotherapy.

PURPOSE: The aim of this study was to analyze the safety, treatment characteristics and survival outcomes of Yttrium-90 (Y90) radioembolization for unresectable colorectal carcinoma (CRC) liver metastases refractory to standard of care therapy. METHODS: A total of 214 patients with CRC metastases were treated with Y90 radioembolization over 12 years. Toxicity was assessed using National Cancer Institute common terminology criteria. Overall survival was analyzed from date of diagnosis of primary cancer, hepatic metastases and from the first Y90. Uni/multivariate analyses were performed. Substratification by era of chemotherapeutics was performed. RESULTS: Most patients were male (60 %) and <65 years old (61 %). Of them, 98 % had been exposed to chemotherapy. Grade 3 lymphocyte, bilirubin, albumin, ALP and AST toxicities were observed in 39 %, 11 %, 10 %, 8 % and 4 % of patients, respectively. Grade 4 lymphocyte and ALP toxicities were observed in 5 % and 3 % of patients, respectively. Median overall survival was 43.0, 34.6, and 10.6 months from date of diagnosis of primary cancer, hepatic metastases and first Y90, respectively. Survival was significantly longer in patients: (1) who received ≤2 cytotoxic drugs (n = 104) than those who received 3 (n = 110) (15.2 vs. 7.5 months, p = 0.0001); and (2) who received no biologic agents (n = 52) compared with those that did (n = 162) (18.6 vs. 9.4 months, p = 0.0001). Multivariate analyses identified ≤2 cytotoxic agents, no exposure to biologics, ECOG 0, tumor burden <25 %, lack of extrahepatic disease and albumin >3 g/dL as independent predictors of survival. CONCLUSION: In this largest metastatic CRC series published to date, Y90 radioembolization was found to be safe; survival varied by prior therapy. Further studies are required to further refine the role of Y90 in metastatic CRC.

Concurrent Tissue and Circulating Tumor DNA Molecular Profiling to Detect Guideline-Based Targeted Mutations in a Multicancer Cohort.

Importance: Tissue-based next-generation sequencing (NGS) of solid tumors is the criterion standard for identifying somatic mutations that can be treated with National Comprehensive Cancer Network guideline-recommended targeted therapies. Sequencing of circulating tumor DNA (ctDNA) can also identify tumor-derived mutations, and there is increasing clinical evidence supporting ctDNA testing as a diagnostic tool. The clinical value of concurrent tissue and ctDNA profiling has not been formally assessed in a large, multicancer cohort from heterogeneous clinical settings. Objective: To evaluate whether patients concurrently tested with both tissue and ctDNA NGS testing have a higher rate of detection of guideline-based targeted mutations compared with tissue testing alone. Design, Setting, and Participants: This cohort study comprised 3209 patients who underwent sequencing between May 2020, and December 2022, within the deidentified, Tempus multimodal database, consisting of linked molecular and clinical data. Included patients had stage IV disease (non-small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer) with sufficient tissue and blood sample quantities for analysis. Exposures: Received results from tissue and plasma ctDNA genomic profiling, with biopsies and blood draws occurring within 30 days of one another. Main Outcomes and Measures: Detection rates of guideline-based variants found uniquely by ctDNA and tissue profiling. Results: The cohort of 3209 patients (median age at diagnosis of stage IV disease, 65.3 years [2.5%-97.5% range, 43.3-83.3 years]) who underwent concurrent tissue and ctDNA testing included 1693 women (52.8%). Overall, 1448 patients (45.1%) had a guideline-based variant detected. Of these patients, 9.3% (135 of 1448) had variants uniquely detected by ctDNA profiling, and 24.2% (351 of 1448) had variants uniquely detected by solid-tissue testing. Although largely concordant with one another, differences in the identification of actionable variants by either assay varied according to cancer type, gene, variant, and ctDNA burden. Of 352 patients with breast cancer, 20.2% (71 of 352) with actionable variants had unique findings in ctDNA profiling results. Most of these unique, actionable variants (55.0% [55 of 100]) were found in ESR1, resulting in a 24.7% increase (23 of 93) in the identification of patients harboring an ESR1 mutation relative to tissue testing alone. Conclusions and Relevance: This study suggests that unique actionable biomarkers are detected by both concurrent tissue and ctDNA testing, with higher ctDNA identification among patients with breast cancer. Integration of concurrent NGS testing into the routine management of advanced solid cancers may expand the delivery of molecularly guided therapy and improve patient outcomes.

Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy.

INTRODUCTION: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. METHODS: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15-180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. RESULTS: The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). CONCLUSIONS: xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

Phase 2 study of preoperative radiation with concurrent capecitabine, oxaliplatin, and bevacizumab followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal cancer: ECOG 3204.

BACKGROUND: Recent studies have demonstrated the feasibility of combining oxaliplatin with 5-fluorouracil (5-FU) or capecitibine and radiation therapy. The addition of bevacizumab to chemotherapy improves overall survival for metastatic disease. We initiated a phase 2 trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy followed by surgery and postoperative 5-FU, leucovorin, oxaliplatin (FOLFOX) and bevacizumab for locally advanced rectal cancer. METHODS: Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled. Preoperative treatment was capecitabine (825 mg/m(2) twice daily from Monday to Friday), oxaliplatin (50 mg/m(2) weekly), bevacizumab (5 mg/kg on days 1, 15, 29), and radiation therapy (50.4 Gy). Surgery was performed by 6 weeks after neoadjuvant therapy. Beginning 8 to 12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles. RESULTS: Fifty-four of 57 enrolled patients were eligible. Forty-nine (91%) patients completed preoperative therapy and underwent surgery. Nine patients (17%; 90% confidence interval, 9%-27%) achieved pathologic complete response. Thirty-two patients (59%) experienced pathologic tumor downstaging, and 53% and 15% of patients experienced worst grade 3 and grade 4 acute toxicity, respectively. Forty-seven percent of patients who underwent surgery experienced a surgical complication. CONCLUSIONS: The primary endpoint of a 30% pathologic complete response rate was not reached; however, the majority of patients experienced pathologic downstaging with this regimen. Increased wound-healing delays and complications may have been related to the addition of bevacizumab, oxaliplatin, or both. Continued observation of these patients will establish the long-term morbidity and efficacy of this combined modality approach.

Health care disparities in the treatment of colorectal cancer.

OPINION STATEMENT: Treatment of colorectal carcinoma remains challenging, especially in patients with recurrent or metastatic disease. Despite advances in screening and treatment of this cancer, health care disparities remain one of the major yet amendable factors that can lead to differences in outcomes. As clinicians, we need to be aware of such disparities to better tailor our screening and treatment interventions for our patients. Knowing that socioeconomic status, educational status, and personal beliefs contribute to racial disparities in this disease, as clinicians we should strive to know our patients and their beliefs to help minimize this discrepancy. Additionally, we need to maintain and advance our knowledge by keeping up with all clinical and translational research in the field and create strategies to increase enrollment of racial minorities in clinical trials. While conventional chemotherapies continue to play a vital role, it is becoming more and more evident that treatment strategies need to be personalized. Understanding the molecular biology of cancer has changed the landscape of new therapies. Future research needs to be directed towards understanding genetic, biological, and pharmacogenetic and genomic contributors to the development of disease and treatment responses.

Assessment of Tumor Mutational Burden and Outcomes in Patients With Diverse Advanced Cancers Treated With Immunotherapy.

Importance: There are few studies assessing the association of tumor mutational burden (TMB) and clinical outcomes in a large cohort of patients with diverse advanced cancers. Objective: To clinically validate a TMB biomarker from a next-generation sequencing targeted gene panel assay. Design, Setting, and Participants: A prespecified cohort study using the deidentified clinicogenomic Tempus database of patients sequenced between 2018 and 2022, which contained retrospective, observational data originating from 300 cancer sites including 199 community sites and 101 academic sites. Patients with advanced solid tumors across 8 cancer types and more than 20 histologies, sequenced with Tempus xT who were treated with immune checkpoint inhibitors (ICIs) in the first-line or second-line setting were included. Data were analyzed from September 2018 to August 2022. Exposure: Treatment with US Food and Drug Administration (FDA)-approved antiprogrammed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) ICI and/or in combination with a cytotoxic T-lymphocyte-associated protein-4 ICI. Main Outcomes and Measures: The primary outcome was the association of tumor mutational burden (TMB) binary category (high [≥10 mut/mb] vs low) with overall survival (OS) in patients treated with ICIs. Secondary outcomes were progression-free survival (PFS), and time to progression (TTP). Results: In the evaluable cohort of 674 patients, the median (IQR) age was 69.4 (28.6-89.8) years, 271 patients (40.2%) were female, and 435 patients (64.5%) were White. The most common advanced cancers were non-small cell lung cancer (330 patients [49.0%]), followed by bladder cancer (148 patients [22.0%]), and head and neck squamous cell carcinoma (96 patients [14.8%]). Median (IQR) follow-up was 7.2 (3.2-14.1) months. High TMB (TMB-H) cancers (206 patients [30.6%]) were significantly associated with longer OS than low TMB (TMB-L) cancers (hazard ratio [HR], 0.72; upper confidence bound [UCB], 0.91; P = .01). In a prospective subset of 403 patients treated with ICIs after TMB testing, TMB-H cancers (135 patients [33.5%]) were significantly associated with longer OS (HR, 0.61; UCB, 0.84; P = .005), PFS (HR, 0.62; UCB, 0.82; P = .003), and TTP (HR, 0.67; UCB, 0.92; P = .02) than TMB-L cancers. An overall survival benefit was seen regardless of the type of ICI used (pembrolizumab, 339 patients; HR, 0.67; UCB, 0.94; P = .03), other ICIs (64 patients; HR, 0.37; UCB, 0.85; P = .03), and after adjusting for PD-L1 and microsatellite stability status (403 patients; HR = 0.67; UCB, 0.92; P = .02). Conclusions and Relevance: In this cohort study of patients with advanced solid tumors treated with ICIs in diverse clinics, TMB-H cancers were significantly associated with improved clinical outcomes compared with TMB-L cancers.

Exploring Barriers to Pediatric Cancer Clinical Trials: The Role of a Networked, Just-in-Time Study Program.

The Research to Accelerate Cures and Equity (RACE) for Children Act mandates that newly developed targeted oncology drugs be tested in children when molecular targets are relevant to pediatric cancers. In its first year, the RACE for Children Act was effective in creating novel drug development opportunities for children with cancer; however, significant barriers to clinical trial enrollment persist. Pediatric cancer clinical trials are impacted by challenges surrounding logistics, complexity, and access. As such, there is potential for a networked and centralized study approach to address these barriers. Here we discuss adapting a just-in-time clinical trial approach for adults to serve the pediatric oncology population. Through innovative patient matching solutions leveraging large, real-world datasets with high computational power, the Tempus Integrated Molecular Evaluation (TIME) for Kids Program aims to address barriers in the development of new therapies. This commentary explores the potential for reducing challenges in developing novel pediatric therapeutics, advancing equity in genomic biomarker testing for precision tailored treatment, and improving outcomes for pediatric oncology patients.

Early circulating tumor DNA dynamics as a pan-tumor biomarker for long-term clinical outcome in patients treated with durvalumab and tremelimumab.

There is an urgent need to identify biomarkers of early response that can accurately predict the benefit of immune checkpoint inhibitors (ICI). Patients receiving durvalumab/tremelimumab had tumor samples sequenced before treatment (baseline) to identify variants for the design of a personalized circulating tumor (ctDNA) assay. ctDNA was assessed at baseline and at 4 and/or 8 weeks into treatment. Correlations between ctDNA changes to radiographic response and overall survival (OS) were made to assess potential clinical benefit. 35/40 patients (87.5%) had personalized ctDNA assays designed, and 29/35 (82.9%) had plasma available for baseline analysis, representing 16 unique solid tumor histologies. As early as 4 weeks after treatment, decline in ctDNA from baseline predicted improved OS (P = 0.0144; HR = 9.98) and ctDNA changes on treatment-supported and refined radiographic response calls. ctDNA clearance at any time through week 8 identified complete responders by a median lead time of 11.5 months ahead of radiographic imaging. ctDNA response monitoring is emerging as a dynamic, personalized biomarker method that may predict survival outcomes in patients with diverse solid tumor histologies, complementing and sometimes preceding standard-of-care imaging assessments.

Molecular residual disease detection in resected, muscle-invasive urothelial cancer with a tissue-based comprehensive genomic profiling-informed personalized monitoring assay.

Introduction: Circulating tumor DNA (ctDNA) detection postoperatively may identify patients with urothelial cancer at a high risk of relapse. Pragmatic tools building off clinical tumor next-generation sequencing (NGS) platforms could have the potential to increase assay accessibility. Methods: We evaluated the widely available Foundation Medicine comprehensive genomic profiling (CGP) platform as a source of variants for tracking of ctDNA when analyzing residual samples from IMvigor010 (ClinicalTrials.gov identifier NCT02450331), a randomized adjuvant study comparing atezolizumab with observation after bladder cancer surgery. Current methods often involve germline sampling, which is not always feasible or practical. Rather than performing white blood cell sequencing to filter germline and clonal hematopoiesis (CH) variants, we applied a bioinformatic approach to select tumor (non-germline/CH) variants for molecular residual disease detection. Tissue-informed personalized multiplex polymerase chain reaction-NGS assay was used to detect ctDNA postsurgically (Natera). Results: Across 396 analyzed patients, prevalence of potentially actionable alterations was comparable with the expected prevalence in advanced disease (13% FGFR2/3, 20% PIK3CA, 13% ERBB2, and 37% with elevated tumor mutational burden ≥10 mutations/megabase). In the observation arm, 66 of the 184 (36%) ctDNA-positive patients had shorter disease-free survival [DFS; hazard ratio (HR) = 5.77; 95% confidence interval (CI), 3.84-8.67; P < 0.0001] and overall survival (OS; HR = 5.81; 95% CI, 3.41-9.91; P < 0.0001) compared with ctDNA-negative patients. ctDNA-positive patients had improved DFS and OS with atezolizumab compared with those in observation (DFS HR = 0.56; 95% CI, 0.38-0.83; P = 0.003; OS HR = 0.66; 95% CI, 0.42-1.05). Clinical sensitivity and specificity for detection of postsurgical recurrence were 58% (60/103) and 93% (75/81), respectively. Conclusion: We present a personalized ctDNA monitoring assay utilizing tissue-based FoundationOne® CDx CGP, which is a pragmatic and potentially clinically scalable method that can detect low levels of residual ctDNA in patients with resected, muscle-invasive bladder cancer without germline sampling.