Complete morphologic response to gilteritinib in ALK-rearranged acute myeloid leukemia.

The cytogenetic abnormality inv(2)(p23q13) in acute myeloid leukemia (AML) results in a fusion of RANBP2 with ALK. This fusion makes ALK constitutively active and acts as a driver for the proliferation of AML cell lines. Gilteritinib, a FLT3 inhibitor approved in AML, also can inhibit ALK among other receptor tyrosine kinases. A 75-year-old-woman with a history of essential thrombocythemia (ET) and a presumed germline DDX41 mutation developed ALK-fusion positive AML and despite standard therapies was transfusion-dependent and globally declining. The patient has been on gilteritinib with an ongoing response of more than one year with near normal blood counts and no evidence of AML. The fact that she was found to harbor a presumed germline DDX41 alteration may account for why she developed, and yet survived, two myeloid neoplasms (ET and AML). Additionally, this demonstrates that gilteritinib is clinically active as an ALK inhibitor, and could be considered for use in any AML patient presenting with an inv(2(p23q13)) translocation. Finally, it is an example of using a disease-agnostic, precision medicine approach to arrive at a beneficial treatment.

Reverse repurposing: Potential utility of cancer drugs in nonmalignant illnesses.

Growth and immune process dysregulation can result in both cancer and nonmalignant disease (hereditary or acquired, with and without predisposition to malignancy). Moreover, perhaps unexpectedly, many nonmalignant illnesses harbor genomic alterations indistinguishable from druggable oncogenic drivers. Therefore, targeted compounds used successfully to treat cancer may have therapeutic potential for nonmalignant conditions harboring the same target. MEK, PI3K/AKT/mTOR, fibroblast growth factor receptor (FGFR), and NRG1/ERBB pathway genes have all been implicated in both cancer and noncancerous conditions, and several cognate antagonists, as well as Bruton's tyrosine kinase inhibitors, JAK inhibitors, and CD20-directed antibodies, have established or theoretical therapeutic potential to bridge cancer and benign diseases. Intriguingly, pharmacologically tractable cancer drivers characterize a wide spectrum of disorders without malignant potential, including but not limited to Alzheimer's disease and a variety of other neurodegenerative conditions, rheumatoid arthritis, achondroplastic dwarfism, and endometriosis. Expanded repositioning of oncology agents in order to benefit benign but serious medical illnesses is warranted.

If it's a target, it's a pan-cancer target: Tissue is not the issue.

Cancer is traditionally diagnosed and treated on the basis of its organ of origin (e.g., lung or colon cancer). However, organ-of-origin diagnostics does not reveal the underlying oncogenic drivers. Fortunately, molecular diagnostics have advanced at a breathtaking pace, and it is increasingly apparent that cancer is a disease of the genome. Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for NTRK fusions; selpercatinib, RET fusions; dabrafenib plus trametinib, BRAFV600E mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid neoplasms). There are emerging targets as well, including but not limited to ALK, BRCA and/or homologous repair deficiency, ERBB2 (HER2), IDH1/2, KIT, KRASG12C, NRG1, and VHL. Many tissue-agnostic approvals center on rare/ultra-rare biomarkers (often < 1 % of cancers), necessitating screening hundreds of tumors to find a single one harboring the cognate molecular alteration. Approval has generally been based on small single-arm studies (<30-100 patients) with high response rates (>30 % to > 75 %) of remarkable durability. Because of biomarker rarity, single-gene testing is not practical; next generation sequencing of hundreds of genes must be performed to obtain timely answers. Resistance to biomarker-driven therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for customized drug combinations matched to the complex molecular alteration portfolio in each tumor. Future investigation should expand tissue-agnostic therapeutics to encompass both hematologic and solid malignancies and include biomarkers beyond those that are DNA-based.

Cancer Care in the Era of Artificial Intelligence.

This JAMA Oncology Patient Page explains artifical intelligence and what patients should know about how it can be used in oncology.

LAG-3 transcriptomic expression correlates linearly with other checkpoints, but not with clinical outcomes.

Immune checkpoint inhibitors have revolutionized the treatment landscape for patients with cancer. Multi-omics, including next-generation DNA and RNA sequencing, have enabled the identification of exploitable targets and the evaluation of immune mediator expression. There is one FDA-approved LAG-3 inhibitor and multiple in clinical trials for numerous cancers. We analyzed LAG-3 transcriptomic expression among 514 patients with diverse cancers, including 489 patients with clinical annotation for their advanced malignancies. Transcriptomic LAG-3 expression was highly variable between histologies/cancer types and within the same histology/cancer type. LAG-3 RNA levels correlated linearly, albeit weakly, with high RNA levels of other checkpoints, including PD-L1 (Pearson's R2 = 0.21 (P < 0.001)), PD-1 (R2 = 0.24 (P < 0.001)) and CTLA-4 (R2 = 0.19 (P < 0.001)); when examined for Spearman correlation, significance did not change. LAG-3 expression (dichotomized at ≥ 75th (high) versus < 75th (moderate/low) RNA percentile level) was not a prognostic factor for overall survival (OS) in 272 immunotherapy-naïve patients with advanced/metastatic disease (Kaplan Meier analysis; P = 0.54). High LAG-3 levels correlated with longer OS after anti-PD-1/PD-L1-based checkpoint blockade (univariate (P = 0.003), but not multivariate analysis (hazard ratio, 95% confidence interval = 0.80 (0.46-1.40) (P = 0.44))); correlation with longer progression-free survival showed a weak univariate trend (P = 0.13). Taken together, these results suggest that high LAG-3 levels in and of themselves do not predict resistance to anti-PD-1/PD-L1 checkpoint blockade. Even so, since LAG-3 is often co-expressed with PD-1, PD-L1 and/or CTLA-4, selecting patients for combinations of checkpoint blockade based on immunomic co-expression patterns is a strategy that merits exploration.

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer.

BACKGROUND: Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions. MAIN BODY: Approximately 0.15-0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS. CONCLUSION: Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.

15 years of patient-reported outcomes in clinical trials leading to GU cancer drug approvals: a systematic review on the quality of data reporting and analysis.

Background: Standardized, high-quality PRO data reporting is crucial for patient centered care in the field of oncology, especially in clinical trials that establish standard of care. This study evaluated PRO endpoint design, conduct and reporting methods in FDA approved drugs for GU malignancies. Methods: A systematic review of the FDA archives identified GU cancer drug approvals from Feb 2007 to July 2022. ClinicalTrials.gov and PubMed were used to retrieve relevant data. PRO data was screened, and analytic tools, interpretation methods in the published papers and study protocols were reviewed. Compliance with PRO reporting standards were assessed using PRO Endpoint Analysis Score (PROEAS), a 24-point scoring scale from Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium (SISAQOL). Findings: We assessed 40 trial protocols with 27,011 participants, resulting in 14 renal cell cancer (RCC), 16 prostate cancer (PC), and 10 urothelial cancer (UC) approvals. PRO data was published for 27 trials, with 23 PRO publications (85%) focusing solely on PRO data, while 4 (15%) included PRO data in the original paper. Median time between primary clinical and secondary paper with PRO data was 10.5 months (range: 9-25 months). PROs were not planned as primary endpoints for any study but 14 (52%) reported them as secondary, 10 (37%) as exploratory outcomes, and 3 (11%) lacked any clarity on PRO data as endpoint. Mean PROEAS score of all GU cancers was 11.10 (range: 6-15), RCC (11.86, range: 6-15), UC (11.50, range: 9-14), and PC (10.56, range: 6-15). None met all the SISAQOL recommendations. Interpretation: Low overall PROEAS score and delays in PRO data publication in GU cancer drug trials conducted in the past decade emphasize the need for improvement in quality of design and conduct of PRO endpoint in future trials and accelerated publication of PRO endpoints, using standardized analysis, and prespecified hypothesis driven endpoint. These improvements are essential for facilitating interpretation and application of PRO study findings to define patient care. Funding: None.

Pan-cancer analysis of TIM-3 transcriptomic expression reveals high levels in pancreatic cancer and interpatient heterogeneity.

BACKGROUND: T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor, dampens immune function. TIM-3 antagonists have entered the clinic. METHODS: We analyzed TIM-3 transcriptomic expression in 514 diverse cancers. Transcript abundance was normalized to internal housekeeping genes and ranked (0-100 percentile) to a reference population (735 tumors; 35 histologies [high≥75 percentile rank]). Ninety tumors (17.5%) demonstrated high TIM-3 expression. RESULTS: TIM-3 expression varied between and within tumor types. However, high TIM-3 expression was more common in pancreatic cancer (20/55 tumors, 36.4%; odds ratio, 95% confidence interval (pancreatic vs. other tumors) = 3.176 (1.733-5.818; p < 0.001, multivariate]). High TIM-3 also significantly and independently correlated with high PD-L1 (p = 0.014) and high CTLA-4 (p < 0.001) transcriptomic expression (multivariate). CONCLUSIONS: These observations indicate that TIM-3 RNA expression is heterogeneous, but more common in pancreatic cancer and in tumors exploiting PD-L1 and CTLA-4 checkpoints. Clinical trials with patient selection for matched immune-targeted combinations may be warranted.

Home-run trials for rare cancers: giving the right drug(s) to the right patients at the right time and in the right place.

In oncology clinical trials, many patients spend their final months at a central clinical trial facility far from home for "mandatory" protocol visits/diagnostic testing. Studies suggest that the travel strain may be greatest among patients living in low-income areas and/or participating in early-phase studies. In this regard, rare cancers constitute a special unmet need with limited therapeutic options and few trials. Though individually uncommon, rare cancers as a group constitute ~22% of the cancer burden; the portion of cancer burden may even be greater if biomarker-defined rare subsets of either a single cancer type or a tissue-agnostic subgroup are included. Exacerbating the access issue is the fact that, in addition to the paucity of trials, many centers will not activate existing single-arm trials, often due to accrual concerns, which may further disadvantage this patient group and also jeopardize trial completion. Decentralized clinical trials may resolve some of these challenges by allowing patients to participate from close to home. Decentralized clinical trials can take the form of being site-less, with the coordinating body working remotely and care provided by the home oncologist, or by taking the tack of National Cancer Institute/cooperative groups (e.g., NCI-MATCH genomics matching trial or SWOG1609 [NCI] DART immunotherapy rare cancer trial) using a platform design with multiple cohorts and opening at >1000 sites. Decentralized trials now also have supportive FDA guidance. Importantly, home-run trials permit clinical trial access to underserved groups, including those in rural areas and patients financially unable to travel to a central facility.

Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload.

Antibody-drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components-an antibody, a linker molecule, and a cytotoxic agent ("payload"), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs' effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies.

Challenges and prospects of CSF1R targeting for advanced malignancies.

CSF1R expression modulates tumor-associated macrophages, making CSF1R blockade an appealing immune-modulating therapeutic target. We evaluated the correlation between CSF1R tumor RNA expression and outcome (pan-cancer setting). RNA expression was ranked as a percentile (0-100) using a standardized internal reference population (735 tumors; 35 histologies). Among 514 patients, there was no difference in survival from biopsy between high and low CSF1R expressors (< 50 percentile versus ≥ 50 percentile rank). There was also no significant difference in median progression-free or overall survival (from treatment) based on CSF1R expression in 21 patients who received CSF1R inhibitors (all p values ≥ 0.08). Concurrent upregulation of ≥ 2 additional immune checkpoint markers (e.g. PD-L1, BTLA, CTLA4, LAG3, TIM3) was observed in all tumor samples with CSF1R expression ≥ 50th percentile. Pending further large prospective studies, patients with high tumor CSF1R expression may need treatment that co-targets the specific immune checkpoint pathways activated in order to impact outcome.

Comprehensive Analysis of Human Epidermal Growth Factor Receptor 2 Through DNA, mRNA, and Protein in Diverse Malignancies.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) expression (protein immunohistochemistry [IHC] or gene amplification [copy-number variation, CNV]) predicts anti-HER2 therapy responsiveness, although recently it was shown that even low HER2-expressing breast cancers benefit from trastuzumab-deruxtecan. Little is known about HER2 transcriptomic (mRNA) expression, and comparisons between genomic, mRNA, and protein HER2 assays. METHODS: HER2 status was evaluated using clinical-grade IHC (protein), quantitative reverse transcription polymerase chain reaction (mRNA), and next-generation sequencing (NGS; amplifications). RESULTS: Multi-institutional HER2 testing was performed on 5,305 diverse cancers including non-small-cell lung (n = 1,175), breast (n = 1,040), and colon cancers (n = 566; N = 3,926 tested for CNV; N = 1,848, mRNA; N = 2,533, IHC). Overall, 4.1% (161/3,926) had NGS HER2 amplification; 33.3% (615/1,848) had mRNA overexpression; and 9.3% (236/2,533) were IHC-positive. In 723 patients with all three tests (CNV/mRNA/IHC), various amplification/expression patterns occurred: 7.5% (54/723) had all three HER2 tests positive; 62.8% (454/723) had all three tests negative. Discrepant patterns between amplification and overexpression emerged. For instance, 20% (144/723) of patients had mRNA overexpression alone with negative CNV and IHC. A range in values for only mRNA+ cases occurred in different tumor types (eg, 16.9%, breast; 5%, hepatobiliary). There were 53 patients with various tumors from our institution who had all three assays attempted; 22 tested positive for HER2, and seven received anti-HER2 therapy: two patients achieved response: one (esophageal cancer), complete response (≥42 months); one (cholangiocarcinoma), who only had HER2 mRNA positivity (tissue was inadequate for IHC and CNV assessment), partial response (≥24 months) on HER2-based regimens. CONCLUSION: We demonstrate variability of HER2 (protein and mRNA) expression and amplification using comprehensive assays (CNV, mRNA, and IHC) among diverse cancers. As HER2-targeted therapy indications expand, the relative importance of these modalities merits further evaluation.

Predicting the Abscopal Effect: Associated Tumor Histologic Subtypes and Biomarkers.

Radiotherapy is a pillar of cancer treatment, which has historically been used primarily to treat localized disease with curative intent. With the increasing role of radiotherapy for metastatic disease and rapid integration of immunotherapy into the standard of care for various cancers, it has been observed that local radiation to one malignant site can lead to shrinkage of tumors at other sites, a phenomenon termed the "abscopal effect." Historically, there was little mechanistic elucidation as to how this phenomenon occurs. However, multiple groups have recently identified associated immuno-prognostic factors, such as high post-radiotherapy absolute lymphocyte count, neoantigens, myeloid-derived suppressor cells, and NK cells. The concomitant use of immunotherapy with radiotherapy has been documented to induce the abscopal effect. As immunotherapies continue to be incorporated into most cancer treatment approaches, understanding which patients are more likely to benefit from an abscopal effect may allow for optimization of both systemic and radiotherapeutic strategies. This review highlights the tumor histologic subtypes and biomarkers of the greatest utility for the recognition and identification of patients likely to benefit from the abscopal effect.

LAG-3 transcriptomic expression patterns across malignancies: Implications for precision immunotherapeutics.

BACKGROUND: Lymphocyte activation gene 3 (LAG-3) or CD223 is a transmembrane protein that serves as an immune checkpoint which attenuates T-cell activation. Many clinical trials of LAG-3 inhibitors have had modest effects, but recent data indicate that the LAG-3 antibody relatlimab, together with nivolumab (anti-PD-1), provided greater benefit than nivolumab alone in patients with melanoma. METHODS: In this study, the RNA expression levels of 397 genes were assessed in 514 diverse cancers at a clinical-grade laboratory (OmniSeq: https://www.omniseq.com/). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) using a reference population (735 tumors; 35 histologies). RESULTS: A total of 116 of 514 tumors (22.6%) had high LAG-3 transcript expression (≥75 percentile rank). Cancers with the greatest proportion of high LAG-3 transcripts were neuroendocrine (47% of patients) and uterine (42%); colorectal had among the lowest proportion of high LAG-3 expression (15% of patients) (all p < 0.05 multivariate); 50% of melanomas were high LAG-3 expressors. There was significant independent association between high LAG-3 expression and high expression of other checkpoints, including programmed death-ligand 1 (PD-L1), PD-1, and CTLA-4, as well as high tumor mutational burden (TMB) ≥10 mutations/megabase, a marker for immunotherapy response (all p < 0.05 multivariate). However, within all tumor types, there was inter-patient variability in LAG-3 expression level. CONCLUSIONS: Prospective studies are therefore needed to determine if high levels of the LAG-3 checkpoint are responsible for resistance to anti-PD-1/PD-L1 or anti-CTLA-4 antibodies. Furthermore, a precision/personalized immunotherapy approach may require interrogating individual tumor immunograms to match patients to the right combination of immunotherapeutic agents for their malignancy.

Agnostic Approvals in Oncology: Getting the Right Drug to the Right Patient with the Right Genomics.

(1) Background: The oncology field has drastically changed with the advent of precision medicine, led by the discovery of druggable genes or immune targets assessed through next-generation sequencing. Biomarker-based treatments are increasingly emerging, and currently, six tissue-agnostic therapies are FDA-approved. (2) Methods: We performed a review of the literature and reported the trials that led to the approval of tissue-agnostic treatments and ongoing clinical trials currently investigating novel biomarker-based approaches. (3) Results: We discussed the approval of agnostic treatments: pembrolizumab and dostarlimab for MMRd/MSI-H, pembrolizumab for TMB-H, larotrectinib and entrectinib for NTRK-fusions, dabrafenib plus trametinib for BRAF V600E mutation, and selpercatinib for RET fusions. In addition, we reported novel clinical trials of biomarker-based approaches, including ALK, HER2, FGFR, and NRG1. (4) Conclusions: Precision medicine is constantly evolving, and with the improvement of diagnostic tools that allow a wider genomic definition of the tumor, tissue-agnostic targeted therapies are a promising treatment strategy tailored to the specific tumor genomic profile, leading to improved survival outcomes.

Complete response to alectinib in ALK-fusion metastatic salivary ductal carcinoma.

The advent of next-generation sequencing (NGS) has allowed for the identification of novel therapeutic targets for patients with uncommon cancers. It is well known that fusion translocations are potent driver of cancer pathogenesis and can render tumors exquisitely sensitive to matching targeted therapies. Here we describe a patient with ALK-fusion positive widely metastatic salivary ductal carcinoma, who achieved a durable complete response from alectinib, a potent and specific ALK tyrosine kinase inhibitor. This case serves as another reminder that ALK-fusions can be targeted regardless of histology and can afford patients dramatic and durable benefit. It also emphasizes the need for insurance coverage for such beneficial therapies. While ALK fusions are exceedingly rare in salivary ductal carcinoma, the presence of multiple other targetable aberrations supports the recommendation for universal NGS testing for such tumors.

Evolution of the Targeted Therapy Landscape for Cholangiocarcinoma: Is Cholangiocarcinoma the 'NSCLC' of GI Oncology?

In the past two decades, molecular targeted therapy has revolutionized the treatment landscape of several malignancies. Lethal malignancies such as non-small cell lung cancer (NSCLC) have become a model for precision-matched immune- and gene-targeted therapies. Multiple small subgroups of NSCLC defined by their genomic aberrations are now recognized; remarkably, taken together, almost 70% of NSCLCs now have a druggable anomaly. Cholangiocarcinoma (CCA) is a rare tumor with a poor prognosis. Novel molecular alterations have been recently identified in patients with CCA, and the potential for targeted therapy is being realized. In 2019, a fibroblast growth factor receptor 2 (FGFR2) inhibitor, pemigatinib, was the first approved targeted therapy for patients with locally advanced or metastatic intrahepatic CCA who had FGFR2 gene fusions or rearrangement. More regulatory approvals for matched targeted therapies as second-line or subsequent treatments in advanced CCA followed, including additional drugs that target FGFR2 gene fusion/rearrangement. Recent tumor-agnostic approvals include (but are not limited to) drugs that target mutations/rearrangements in the following genes and are hence applicable to CCA: isocitrate dehydrogenase 1 (IDH1); neurotrophic tropomyosin-receptor kinase (NTRK); the V600E mutation of the BRAF gene (BRAFV600E); and high tumor mutational burden, high microsatellite instability, and gene mismatch repair-deficient (TMB-H/MSI-H/dMMR) tumors. Ongoing trials investigate HER2, RET, and non-BRAFV600E mutations in CCA and improvements in the efficacy and safety of new targeted treatments. This review aims to present the current status of molecularly matched targeted therapy for advanced CCA.

The abscopal effect in patients with cancer receiving immunotherapy.

Interest in the abscopal effect has been rekindled over the past decade with the advent of immunotherapy. Although purportedly elusive, this phenomenon is being increasingly reported. Venturing further using a multimodality approach with an array of systemic agents and unconventional modalities is direly needed. In this perspective, we describe the fundamentals of abscopal responses (ARs), explore combinations with systemic therapies that hold promise in eliciting ARs, and reconnoiter unconventional modalities that may induce ARs. Finally, we scrutinize prospective agents and modalities that exhibit preclinical ability to elicit ARs and discuss prognostic biomarkers, their limitations, and pathways of abscopal resistance for reproducibility.

Cost Effectiveness of Treatment Sequences in Advanced Renal Cell Carcinoma.

BACKGROUND: The treatment landscape for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years. Without direct comparator trials, factors such as cost effectiveness (CE) are important to guide decision-making. OBJECTIVE: To assess the CE of guideline-recommended approved first- and second-line treatment regimens. DESIGN, SETTING, AND PARTICIPANTS: A comprehensive Markov model was developed to analyze the CE of the five current National Comprehensive Cancer Network-recommended first-line therapies with appropriate second-line therapy for patient cohorts with International Metastatic RCC Database Consortium favorable and intermediate/poor risk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Life years, quality-adjusted life years (QALYs), and total accumulated costs were estimated using a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed. RESULTS AND LIMITATIONS: In patients with favorable risk, pembrolizumab + lenvatinib followed by cabozantinib added $32 935 in costs and yielded 0.28 QALYs, resulting in an incremental CE ratio (ICER) of $117 625 per QALY in comparison to pembrolizumab + axitinib followed by cabozantinib. In patients with intermediate/poor risk, nivolumab + ipilimumab followed by cabozantinib added $2252 in costs and yielded 0.60 QALYs compared to cabozantinib followed by nivolumab, yielding an ICER of $4184. Limitations include differences in median follow-up duration between treatments. CONCLUSIONS: Pembrolizumab + lenvatinib followed by cabozantinib, and pembrolizumab + axitinib followed by cabozantinib were cost-effective treatment sequences for patients with favorable-risk mRCC. Nivolumab +ipilimumab followed by cabozantinib was the most cost-effective treatment sequence for patients with intermediate-/poor-risk mRCC, dominating all preferred treatments. PATIENT SUMMARY: Because new treatments for kidney cancer have not been compared head to head, comparison of their cost and efficacy can help in making decisions about the best treatments to use first. Our model showed that patients with a favorable risk profile are most likely to benefit from pembrolizumab and lenvatinib or axitinib followed by cabozantinib, while patients with an intermediate or poor risk profile will probably benefit most from nivolumab and ipilimumab followed by cabozantinib.