Molecular Profiling of Metastatic Bladder Cancer Early-Phase Clinical Trial Participants Predicts Patient Outcomes Free

This article is featured in Highlights of This Issue, p. 359

Before 2019, patients with metastatic bladder cancer (mBC) had limited treatment options, which included cisplatin-based chemotherapy regimens, immune-checkpoint inhibitors (CPI), and single-agent chemotherapy. Up to 50% of patients with mBC are ineligible for cisplatin-based chemotherapy regimens due to medical comorbidities (1). Furthermore, in platinum-ineligible or -resistant mBC, CPIs provide low response rates of 15% to 25% despite their substantial clinical benefit (2–8). Molecular profiling (9) suggests that certain subtypes of bladder cancer have distinct prognoses and benefit differently from chemotherapy (10), immunotherapy (3), or targeted therapy (11). Erdafitinib, a pan-FGFR receptor tyrosine kinase inhibitor, was approved for patients with mBC and FGFR2 or FGFR3 alterations, which are estimated to represent in approximately 15% to 20% of patients with mBC (11). Erdafitinib had a response rate of 40%, and the median progression-free survival (PFS) is 5.5 months (11). The clinical benefit seen with erdafitinib is a beacon of hope for targeting genomic alterations in mBC, a challenging and incurable disease with an unmet need for novel therapies.

Enrolling patients with mBC in early-phase clinical trials might be challenging due to their medical comorbidities, toxicities from prior systemic therapies, and poor performance status at referral (12). However, there are potential benefits to enrolling patients with mBC in an early-phase clinical trial. Depending upon the situation, early-phase trials may provide access to promising therapies in development for mBC. Furthermore, many early-phase clinical trials have two cohorts, a dose-escalation (first-in-human: FIH) and a dose-expansion cohort (using the recommended phase II dose: RP2D). Dose-expansion cohorts are becoming more prevalent and are sometimes used for initial drug registration. In fact, a PD-L1 CPI, avelumab, was granted Food and Drug Administration (FDA) accelerated approval for mBC based upon the results of two dose-expansion early-phase trials (13). When considering all of the above factors, it can be difficult for clinicians to decide when or whether to recommend phase I trials for patients with mBC.

The objective of the present study is to evaluate the molecular and clinical characteristics and treatment outcomes of patients with mBC who enroll on early-phase clinical trials and to assess how specific and common genomic aberrations influence outcomes in these trials.

Baseline characteristics and clinical outcomes were retrospectively collected for patients with mBC who were enrolled on one or more phase I clinical trial at the University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas. Patients who received an investigational checkpoint inhibitor CPI combination during their first trial participation were labeled as having received prior CPI for their second trial participation. Given the known biological differences between bladder UC, upper tract UC (UTUC), or urethral UC, the latter two were excluded. Furthermore, the majority of patients with UTUC have borderline renal function, which limited their accrual to phase I trials. Next, we investigated if patients had tumor next-generation sequencing (NGS) performed prior to trial enrollment. Tumor NGS was either performed on tumor tissue, using one of five CLIA-certified laboratory tests with a range of 50–400 cancer-related genes assessed, or circulating tumor DNA (ctDNA), using Guardant360. This study was approved by the Institutional Review Board (IRB) of MDACC. All phase I clinical trials were also approved by the MDACC IRB, and patients provided informed written consent to prior to receiving treatment.

Endpoints of interest included response rate (RR), disease control rate (DCR), PFS, and overall survival (OS). RR was defined as complete response (CR) plus partial response (PR). DCR was defined as RR plus stable disease (SD). Best response was defined by individual trial protocol most commonly based upon the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) or immune-related RECIST (irRECIST). PFS and OS for each patient were calculated based on their individual trial participation. PFS was measured from time of trial enrollment until time of progression, death or last follow-up. OS was measured from time of trial enrollment until death or date of last follow-up. For the 12 patients with >1 trial participation, OS was calculated from the time of enrollment to the first trial, overall response rate (ORR) was based on each individual trial response evaluation, and PFS was calculated from C1D1 of each trial.

Survival curves were generated using the Kaplan–Meier approach. The median follow-up time was calculated using the reverse Kaplan–Meier method (14). Hazard ratios (HR) were calculated using the Cox proportional hazard model. A P value < 0.05 was considered statistically significant.

Somatic alterations were identified in tumor tissues by either hybrid capture–based targeted DNA sequencing in using FoundationOne CDx (15) or PCR-amplicon–based target capture using Oncomine (16). Somatic alterations in cell-free DNA (cfDNA) were detected by Oncomine (17) and Guardant360 (18). Lollipop figures were created using the visualize data feature by cBioPortal (19, 20), and annotation of the biological and oncogenic effects and prognostic and predictive significance of somatic molecular alterations were extracted from the OncoKB knowledge base (21). For clinical outcomes correlation, we focused on the most common mutations (>20%) in our cohort with a focus on those with available targeted therapies, i.e., FGFR3 and ERBB2.

Between June 2015 and September 2019, 43 patients with mBC were enrolled in an early-phase trial (Fig. 1). Table 1 summarizes the baseline characteristics of the patients. Consistent with the 3:1 male-dominant pattern of bladder cancer (22), 72% of patients were male, and 16% (7/43) had nonurothelial carcinoma histology (non-UC), specifically neuroendocrine carcinoma (n = 2) and urachal carcinoma (n = 5). Additionally, 13% (5/43) had UC with variant histology, specifically squamous cell (n = 3) and micropapillary (n = 2). Twenty-eight percent (12/43) of patients were enrolled in more than one trial, leading to a total of 57 trial participations (TP) who initiated therapy (Fig. 1). At time of therapy initiation, 97% (55/57) of TPs had received prior platinum therapy and 60% (34/57) had received prior CPI therapy. Sixty-five percent (37/57) of patients had a glomerular filtration rate less than 60 mL/min.

Among the 57 TPs, the median follow-up time was 17.9 months (95% CI, 16.3–NA), median PFS was 4.2 (95% CI, 2.8–9.3) months, and median OS was 9.6 (95% CI, 7.5–16.5) months (Supplementary Fig. S1A and S1B). The mechanism of action for each individual trial is detailed in Supplementary Tables S1 and S2. The ORR was 17.5% in all TPs, 12% in dose-escalation cohorts and 26% in dose-expansion cohorts at the RP2D (P = 0.11; Supplementary Fig. S1C; Supplementary Table S3). Survival was similar between both these cohorts (Supplementary Fig. S1D and S1E). Across the UC cohort (n = 48), the median PFS was 4.3 months, median OS was 10.1 months, and the ORR was 19% compared with median PFS of 3.1, median OS of 9.6 months and ORR of 11% among the non-UC cohort (n = 9).

Clinical NGS analysis was done in 95% (41/43) patients, which included cell-free DNA (cfDNA)-based NGS in 6 patients and tumor-based NGS in 35 patients (Fig. 2A). Ninety-eight percent of sequenced patients (40/41) harbored at least one somatic alteration (Fig. 2A); TP53, ERBB2, PI3KCA, FGFR3, and ARID1A alterations (alt) were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively (Fig. 2F; Supplementary Fig. S3A and S3C). Variant and non-UC histologies clustered among the TP53 alt (Fig. 2F; Supplementary Fig. S3B). Among the 12 patients harboring an ERBB2 alteration, 34% (4/12) received an ERBB2-targeting therapy with 50% (2/4) achieving PR (Fig. 2B and E). Among the 14 patients who harbored FGFR alterations, 64% (9/14) received an FGFR-targeting therapy with 1 PR, 5 SD, 2 PD, and 1 nonevaluable for response due to withdrawal of consent (Fig. 2C and D). The patients included in our analysis received a variety of investigational FGFR inhibitors other than the FDA-approved agent erdafitinib.

Patients with UC histology had 48 different TPs, which included 25 TPs in immunotherapy (IO) combinations and 21 in targeted therapy combinations (Fig. 3A). Baseline clinical risk factors were fairly balanced between patients with UC who harbored a TP53 alt and those who did not (Supplementary Table S6); nonetheless, those who with TP53 alt had a shorter median PFS of 3.2 months compared with 9.6 months in TP53 no alt patients [HR = 2.738 (1.247–6.011), P = 0.0121; Fig. 3B]. Median OS was shorter in patients with TP53 alt at 5.9 months compared with TP53 no alt at 16.5 months [HR = 1.518 (0.732–3.147), P = 0.3; Fig. 3C]. Lower ORR and disease control were noted among patients with TP53 alt in all trials (Fig. 3D). Conversely, median PFS was longer in patients harboring an FGFR alt, compared with those with no alt, 6.3 months versus 3.2 months [HR = 0.4662 (0.224–0.971), P = 0.0415; Fig. 3E]. Median OS was longer in patients with FGFR alt at 16.5 months compared with FGFR no alt at 5.3 months [HR = 0.54 (0.25–1.16), P = 0.1; Fig. 3F]. Disease control was higher among patients with FGR alt as compared with patients with FGFR no alt (Fig. 3G). Among patients with FGFR alt (n = 14), there was 20 total TPs due to 6 patients participating in more than 1 trial. PFS [HR = 0.73 (0.23–2.29), P = 0.6] and OS [HR = 0.78 (0.25–2.42), P = 0.7] were not precise enough to demonstrate a difference between TPs targeting FGFR (n = 8) and those not targeting FGFR (n = 12; Supplementary Fig. S4A and S4B; Supplementary Table S4). The median PFS was 4.2 months in patients harboring an ERBB2 alt, compared with those with ERBB2 no alt at 3 months [HR = 1.308 (0.66–2.59), P = 0.4; Fig. 3H]. No statistical difference was noted between OS of patients with an ERBB2 alt, compared with those without, 16.1, and 9.36 months, respectively (Fig. 3I).

We observed that the response to early-phase trials in non-UC histology, which constituted 16% of our TPs, was 11% (1/9) compared with 19% (9/48) in UC histology (Supplementary Fig. S2A and S2B). The median PFS [HR = 0.55 (0.26–1.17), P = 0.1] and OS [HR = 0.71 (0.31–1.64), P = 0.4] had a positive trend among UC as compared with non-UC histology; however, no statistically significant difference was found (Supplementary Fig. S2C and S2D). Among IO trials, there were no responses among patients with non-UC histology (Supplementary Fig. S2E). Furthermore, we analyzed the effect of prior IO therapy on response to IO trials and found that RR was 28% (5/18) among IO-naïve patients as compared with 7% (1/15) among patient who had prior IO therapy, P = 0.11 (Supplementary Fig. S3A; Supplementary Table S5). Drug classes that achieved disease control in patients who had received prior IO include agents targeting CTLA4, CCR4, LXR, STAT3, and IDO1 (Supplementary Fig. S5A). Patients who had received prior IO tended to have worse PFS [HR = 1.55 (0.70–3.41), P = 0.3] and OS [HR = 1.47 (0.64–3.36), P = 0.4] on IO-based trials as compared with IO-naïve patients (Supplementary Fig. S5B and S5C).

We analyzed patients' response to early-phase trials based on their ethnicity and observed that patients with Hispanic ethnicity (N = 8) had no responses compared with 22% (10/46) among patients with non-Hispanic ethnicity (Supplementary Fig. S6A). Potential confounding factors were compared between the patients with Hispanic and non-Hispanic ethnicities (Supplementary Fig. S6B) and no significant differences were found. PFS was longer among non-Hispanic patients at 4.5 months as compared with 1.9 months in Hispanic patients (HR = 0.29, 95 CI, 0.1252–0.7073, P = 0.006; Supplementary Fig. S6C). OS had a favorable trend among patients of non-Hispanic ethnicity [HR = 0.51 (0.20–1.27), P = 0.2; Supplementary Fig. S6D).

To our knowledge, this is the first study to specifically characterize the clinical and molecular features and outcomes of mBC patients who are referred to early-phase clinical trials. We found potential benefits to enrolling in an early-phase clinical trial with an ORR of 19%, PFS of 4.2 months, and median OS of 9.6 months in heavily pretreated patients whether in a dose-escalation cohort or a dose-expansion cohort. Furthermore, we noted that the baseline genomic profile of enrolled patients drove treatment choices and was associated with DCR and survival.

According to The Cancer Genome Atlas (TCGA), 48%, 14%, and 12% of previously untreated muscle-invasive bladder cancer harbor a TP53 alt, FGFR3 alt, and ERBB2 alt, respectively (9). Of note, sequencing in our study was mostly performed on FFPE tissue from metastatic sites, which may explain the differences in alterations seen in our cohort (enriched for metastatic sites) as compared with the TCGA (enriched for primary tumor sites). Furthermore, we observed a higher rate of ERBB2 alt (29%) and FGFR3 alt (24%) as compared with TCGA, which could be explained by the referral bias of patients with potential targetable alterations to early-phase targeted therapy trials.

In our study, we included 7 patients with rare histology variants, i.e., neuroendocrine and urachal adenocarcinoma that did not have urothelial carcinoma in their tumor. Furthermore, the genomic/survival analyses were restricted to urothelial histology to avoid the heterogeneity of including other histologies. The first pivotal report to show that TP53 protein change (surrogate for TP53 alt) was predictive of worse outcome in patients with localized UC undergoing cystectomy was published by Esrig and colleagues in 1994 (23). A meta-analysis performed 10 years later was inconclusive due to the lack of sufficient evidence (24). Our results support the association between TP53 alt and worse outcomes in metastatic UC (mUC). Conversely, FGFR alt (FGFR3 alt, in particular) has been correlated with a better survival in patients with invasive UC (25) and this is supported by our analysis in mUC. The improved PFS among FGFR alt patients could be due to distinct disease biology (10) versus the availability of agents to target this alteration. Of note, a majority of patients with mUC and FGFR alt (n = 14) have received an FGFR-targeting agent in an early-phase trial (n = 9). On the other hand, only a minority of patients harboring an ERBB2 alt received an ERBB2-targeting agent (34%), perhaps explaining the lack of improved PFS among this cohort as compared with those with ERBB2 no alt.

Patients with mBC frequently present with multiple comorbidities including obstructive renal insufficiency (12), and this frequently results in their exclusion from early-phase trials. We observed that 38% (26/69) of consented patients with mBC were not able to proceed with treatment due to a variety of reasons (Fig. 1), which highlights the challenges in enrolling patients with mBC in early-phase trials. The American Society of Clinical Oncology (ASCO) has recently recommended the ASCO-Friends eligibility criteria in clinical trials (26), which could enable nearly twice as many patients to participate in a trial (27). ASCO-Friends criteria could be considered for patients with mBC participating in early-phase trials.

Next, we report patients' clinical response to early-phase trials in rare non-UC histology that do not currently have an approved agent by the FDA after progression on first-line platinum-based chemotherapy. Our analysis showed that variant histologies enrich for TP53 alt, which could explain the trend toward worse outcomes in this cohort. Nonetheless, agents targeting ERK, CCR4, and PARP achieved disease control in few patients.

We observed that patients with prior IO exposure had low responses to IO-based trials compared with patients who were IO naïve. However, we noted, in a small sample, that agents targeting CTLA4, CCR4, LXR, STAT3, and IDO1 showed some early signs of clinical activity in the post-IO setting.

Additionally, we observed that patients of Hispanic ethnicity had lower response rates and shorter PFS with a trend toward shorter OS. The clinical significance of this disparity finding is unclear given the small sample size and will need to be validated using larger cohorts.

Our study is limited by the small sample size, which reflects difficulties in referring patients with mBC to early-phase trials. Furthermore, our patients were treated with agents utilizing diverse mechanisms of action, i.e., immunotherapy versus targeted therapy; therefore, our findings need to be validated in a more expanded cohort of patients. In addition, among patients with FGFR alt, treatment agents targeting FGFR had different molecular structure and spectrum of FGFR1–4 inhibition making the evaluated group heterogeneous. Nonetheless, the evaluated FGFR-targeting agents were consistently effective in providing disease control.

Our study specifically characterized the outcomes of patients with mBC treated on early-phase trials. We observed promising clinical activity with several novel immunotherapeutic and targeted therapy strategies. In particular, the responses noted with agents inhibiting FGFR and ERBB2 support the value of targeting these pathways in mBC. Furthermore, we observed that harboring a somatic TP53 alt after receiving standard-of-care platinum-based therapy is associated with low response and survival in early-phase trials and remains an area of need for novel therapy strategies.

P. Msaouel reports personal fees from Mirati Therapeutics, Bristol-Myers Squibb, Exelixis, Pfizer, Exelixis, and Axiom Healthcare Strategies and grants from Mirati Therapeutics, Bristol-Myers Squibb, and Takeda Pharmaceutical Company outside the submitted work. F. Meric-Bernstam reports personal fees from Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, The Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks, Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, Chugai Biopharmaceuticals, Mayo Clinic, and Rutgers Cancer Institute of New Jersey, grants from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals, Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co., and other from Beth Israel Deaconess Medical Center outside the submitted work. A. Naing reports grants from National Cancer Institute, EMD Serono, MedImmune, Karyopharm Therapeutics, Incyte, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology, grants and non-financial support from ARMO BioSciences, grants and personal fees from Novartis, CytomX Therapeutics and Kymab, personal fees from Genome and Company, OncoSec KEYNOTE-695, and STCube Pharmaceuticals outside the submitted work. S. Piha-Paul reports other from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol-Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Daiichi Sankyo, Inc., Eli Lilly, ENB Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, and NCI/NIH P30CA016672–Core Grant (CCSG Shared Resources) outside the submitted work. J. Filip reports grants from Novartis, Genetech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Piqur, Symphogen, Bristol-Myers Squibb, Asana, Synthorx, FujiFilm Pharmaceuticals, and Proximagen, grants and personal fees from Deciphera, Ideaya Biosciences, and Sotio, personal fees from Guardant Health, Illumina, IFM Therapeutics, Synlogic, Puretech Health, and Immunomet, personal fees and other from Cardiff Oncology outside the submitted work. T.A. Yap reports grants from Artios, Constellation, Cyteir, Eli Lilly, Forbius, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Novartis, Ribon Therapeutics, Regeneron, Sanofi, Scholar Rock, Tesaro, and Vertex Pharmaceuticals, grants and personal fees from AstraZeneca, Bayer, Clovis, EMD Serono, F-Star, Merck, Pfizer, Repare, and Seattle Genetics, personal fees from Almac, Aduro, Atrin, Axiom, Bristol-Myers Squibb, Calithera, Cybrexa, Guidepoint, Ignyta, I-Mab, Jansen, Roche, Rubius, Schrodinger, Varian, and Zai Labs outside the submitted work. D.S. Hong reports grants, personal fees, and other from Bayer, grants from AbbVie, Aldi-Norte, Astra-Zeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Erasca, Fate Therapeutics, Ignyta, Kite, Kyowa, Lilly, Merck, Medimmune, Mirati, Molecular Templates, Mologen, Navier, NCI-CTEP, Novartis, Numab, Turning Point, Verstatem, and VM Oncology, grants and other from miRNA, Genmab, and LOXO, grants and personal fees from Adaptimmune, Genentech, Pfizer, Seattle Genetics, Takeda, Amgen, and Infinity, other from AACR, ASCO, and SITC, personal fees from Alpha Insights, Acuta, Axiom, Baxter, Boxer Capital, COG, Ecor1, GLG, Group H, Guidepoint, HCW Precision, Janssen, Merrimack, Medscape, Numab, Prime Oncology, ST Cube, Tavistock, Trieza Therapeutics, WebMD, Molecular Match, OncoResponse, and Presagia outside the submitted work. E. Campbell reports personal fees from Eisai, Seattle Genetics and Genentech, grants, personal fees, and other from Pfizer, grants and personal fees from EMD Serono, Exelixis, ApricityHealth, Bristol-Myers Squibb, and other from Roche outside the submitted work. A.O. Siefker-Radtke reports grants and personal fees from Janssen and Basilea Pharmaceuticals during the conduct of the study; personal fees from AstraZeneca, Genentech, and Seattle Genetics, grants and personal fees from Merck, Mirati, Nektar Therapeutics, grants from Bristol-Myers Squibb, and Millennium outside the submitted work. V. Subbiah reports grants from Incyte during the conduct of the study; and Vivek Subbiah, Research funding/grant support for clinical trials: FUJIFILM Pharmaceuticals U.S.A., Inc., Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Pharmamar, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, LOXO Oncology, Medimmune, Altum, Dragonfly therapeutics, Takeda and Roche/Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center. Travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte, US-FDA, Consultancy/Advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, Medimmune, Novartis. No disclosures were reported by the other authors.

O. Alhalabi: Conceptualization, data curation, software, formal analysis, investigation, visualization, writing–original draft, writing–review and editing. A.W. Hahn: Conceptualization, validation, investigation, methodology, writing–original draft, writing–review and editing. P. Msaouel: Supervision, methodology, and project administration. A.Y. Andreev-Drakhlin: Writing–review and editing. F. Meric-Bernstam: Writing–review and editing. A. Naing: Writing–review and editing. S. Piha-Paul: Writing–review and editing. J. Filip: Writing–review and editing. S. Pant: Writing–review and editing. T.A. Yap: Writing–review and editing. D.S. Hong: Writing–review and editing. S. Fu: Writing–review and editing. D. Karp: Writing–review and editing. E. Campbell: Data curation and software. H. Le: Data curation and software. M.T. Campbell: Data curation and software. A.Y. Shah: Writing–review and editing. N.M. Tannir: Writing–review and editing. A.O. Siefker-Radtke: Writing–review and editing. J. Gao: Writing–review and editing. J. Roszik: Formal analysis, supervision, and methodology. V. Subbiah: Conceptualization, resources, supervision, funding acquisition, visualization, writing–original draft, writing–review and editing.

This work was supported in part by The Cancer Prevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (1U01CA180964), the Center for Clinical and Translational Sciences (NCATS) (1UL1TR000371 and 1UL1TR003167), the NCI of the NIH (R01CA242845-01A1), and The MD Anderson Cancer Center Support Grant (P30 CA016672). The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. O. Alhalabi is supported through a young investigator award from the Conquer Cancer foundation of the ASCO.