A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170)

SET domain containing 2 (SETD2) is a common tumor suppressor gene that encodes for a histone H3 lysine 36 (H3K36) methyltransferase. Pathogenic loss-of-function mutations have been observed across a wide range of solid tumor malignancies including clear cell renal cell carcinoma (ccRCC; range 3%–14%, though has been reported as high as 35% in some studies; refs. 1–6). SETD2 mutations may not necessarily be biallelic. In ccRCC, the vast majority of tumors undergo chromosome 3p deletion in a region known to harbor several genes including VHL, SETD2, PBRM1, and BAP1 (4, 6). Although most ccRCC tumors are monoallelic for these 3p genes, a smaller portion of ccRCC tumors acquire a second loss of function SETD2 mutation in the remaining allele rendering the loss biallelic with complete loss of H3K36 methyltransferase.

SETD2 has a canonical function as a key methyltransferase responsible for trimethylation of histone H3K36 (H3K36me3), a mark which plays a role in transcription, splicing, DNA damage repair, and maintenance of genomic integrity and stability (7). SETD2 also has methyltransferase activity toward alternative targets such as α-tubulin and interacts with several other proteins including TP53 (3, 8, 9). Haploinsufficiency for SETD2 causes a subset of the genomic instability seen with biallelic loss (10). Clinically in ccRCC, biallelic SETD2 alterations have been associated with adverse cancer-specific outcomes such as higher tumor stage, increased likelihood for recurrence or metastatic disease, and worse cancer-specific survival (11, 12). There have also been reports of worse outcomes for other SETD2-deficient tumors including breast (3, 13) The widespread loss of SETD2 in various malignancies and association with poor prognosis warrants therapeutic development of agents targeting this alteration.

WEE1 is an inhibitory tyrosine kinase, interacting with CDK1 and CDK2 at various points in the cell cycle including the S-phase and G2/M-phase transition, resulting in S-phase and G2/M-phase transition delays and the suppression of early mitotic events and mitotic catastrophe (14). Inhibition of WEE1 was previously found to promote unscheduled mitotic entry through CDK1 activation, leading to loss of genome integrity (15). Additionally, preclinical studies of WEE1 inhibition with adavosertib (also known as AZD1775) have demonstrated a synthetic lethal effect in SETD2-deficient cancers in cell lines (16). SETD2 deficiency results in reduced trimethylation of histone H3K36 (H3K35me3), leading to reduced expression of ribonucleotide reductase regulatory subunit M2 (RRM2), which leads to further reduction in dNTP subunits. Therefore, resulting in effects on transcription, splicing, DNA damage repair, and maintenance of genomic integrity and stability (16) With the addition of WEE1 inhibition, preclinical studies showed the abolishment of DNA replication in SETD2-deficient cells through further depletion of dNTP pools (monomeric units of DNA) via further reduced expression of RRM2 (16). Adavosertib monotherapy demonstrated both synthetic lethal effects and resulted in significant tumor regression in SETD2-deficient renal cell carcinoma xenograft models (16).

Adavosertib (AZD1775) is a potent and selective WEE1 inhibitor that was previously evaluated in a phase I trial investigating doses ranging from 200 to 400 mg once daily (days 1–5 and 8–12 of each 21-day cycle) in 42 patients with advanced solid tumors (17). There were two dose-limiting toxicities observed at the 400 mg daily dosing level (grade 4 pancytopenia), thereby establishing 300 mg once daily (days 1–5 and 8–12 of each 21-day cycle) as the RP2D with similar plasma exposures to those from twice-daily dosing, with partial responses in 6/42 (14%) of patients (17). Thus, this RP2D was also used for this subsequent phase 2 study.

The purpose of this phase II study (NCT03284385) was to evaluate the efficacy and safety of adavosertib monotherapy in patients with SETD2-altered ccRCC and other locally advanced or metastatic solid tumor malignancies.

This was a Simon two-stage, phase II, parallel cohort study that evaluated adavosertib monotherapy in biologically male and female patients at least age 18 years and older, with histologically confirmed locally advanced or metastatic solid tumor malignancies in two cohorts: (A) Solid tumor malignancies other than ccRCC and (B) ccRCC. Patients were not randomized and were not blinded in this phase 2 study. Cohort A (N = 9) included patients with solid tumor malignancies other than ccRCC with disease progression on at least one prior systemic therapy. Cohort B (N = 9) included patients with ccRCC with disease progression on at least one prior systemic therapy including prior tyrosine kinase inhibitor or immune checkpoint inhibitor. All patients were required to have evidence of a pathogenic SETD2 mutation in archival tumor tissue by a local or central Clinical Laboratory Improvement Amendments–approved assay. Molecular profiling platforms included the following: Caris Comprehensive Molecular Profiling (2/18 patients; ref. 18), FoundationOne CDx (8/18 patients; ref. 19), Tempus Xt (4/18 patients; ref. 20), the Massachusetts General Brigham Dana–Farber Cancer Institute OncoPanel (3/18 patients; ref. 21), and the MD Anderson Solid Tumor Genomic Assay Tumor DNA Panel (1/18 patients; ref. 22). Additional eligibility criteria included measurable disease by RECIST 1.1 criteria, an Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate hematologic, renal, and hepatic function. A full list of exclusion criteria is provided in Supplementary Protocol S1, which provides the study protocol.

The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. All patients provided written informed consent. This study (NCT03284385) was conducted at 11 different cancer centers in the United States through the National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network under an NCI-sponsored investigational new drug application.

Patients received adavosertib at a starting dose of 300 mg once daily by mouth on days 1 to 5 and 8 to 12 of each 21-day cycle. Dose modifications were allowed based on established criteria without the need for weight-based dosing (see Supplementary Protocol S1). Intra-patient dose re-escalation was not permitted. Treatment with adavosertib continued until disease progression by RECIST 1.1 criteria, unacceptable adverse events, clinical progression, and general or specific changes in the condition of the patient that rendered the patient unacceptable for further treatment as judged by the investigator.

Safety assessments were performed at regular intervals per the protocol. These included routine vital signs, physical exams, safety labs (complete blood count with differential; complete metabolic panel, LDH), and adverse event evaluations on Cycle (C) 1 Day (D) 1, C1D8, C1D15, C2D1, C2D8, and subsequently at the beginning of each cycle from C3D1 onward. ECGs were obtained at baseline and at the beginning of each cycle from C1D1 onward. Radiologic evaluation with tumor measurements was obtained at baseline and every 9 weeks ± 1 week.

For correlative analysis, formalin-fixed, paraffin-embedded tissue was obtained from archival tumor specimens during the screening process for enrolled patients when available. IHC was performed on formalin-fixed, paraffin-embedded tissue sections in the UCSF Cancer Center Tissue Core using a rabbit polyclonal antibody against H3K36me3 (Cell Signaling Technology, #9763). All immunostains were scored by a board-certified anatomic pathologist (GK). Negative H3K36me3 expression was defined as no nuclear staining in the tumor cells. Positive H3K36me3 expression was quantitated as a percentage of tumor cell nuclei stained per total tumor cell nuclei and scored as weak (1+), moderate (2+), or strong (3+) intensity. Background stromal and inflammatory cells were used as internal controls (positive nuclear staining). External controls included tumors confirmed to harbor inactivating SETD2 mutations (H3K36me3-negative), tumors confirmed to lack SETD2 mutations (H3K36me3-positive), and nonneoplastic normal liver tissue.

The primary endpoint was the investigator-assessed objective response rate (ORR) by RECIST 1.1. Patients who received study treatment and at least one imaging assessment on study after C1D1 were considered evaluable for the primary endpoint. Secondary endpoints include progression-free survival (PFS), duration of response, and frequency and severity of adverse events. PFS was defined as the duration from the start of treatment to the date of progression by RECIST criteria. Safety analyses were obtained for all patients who received at least one dose of adavosertib, by patient summary as graded by the NCI Common Terminology Criteria for Adverse Events Version 5.0. Exploratory analyses included evaluation of the loss of trimethylation H3K36me3 mark by IHC from archival tumor tissue along with specific types of SETD2 alteration and their association with clinical outcomes.

The study employed a Simon two-stage design for each cohort. Nine patients were accrued in the first stage of the study in each of the two cohorts. In either cohort, if one or more confirmed objective responses were observed, an additional 21 patients were planned to be accrued during stage 2 in that particular patient cohort. If more than four confirmed objective responses were observed in total, the null hypothesis was rejected. The target total sample size achieved 90% power to detect a difference in objective response of 20% [25% vs. 5% historical control from prior phase 1 studies (18, 19)] with a one-sided type I error rate of 5%. The cutoff date for efficacy analysis was November 4, 2023 (one patient in Cohort B remained on treatment at that time). All 18 evaluable patients who received at least one dose of adavosertib were included in the safety population.

The data generated in this study are not publicly available because of patient privacy requirements but are available upon reasonable request from the corresponding author. Other data generated in this study are available within the article and its supplementary data files.

Between May 2019 and October 2021, 18 patients were enrolled in the intention-to-treat population. Baseline characteristics are shown in Table 1. The median age at study entry was 60 years (range 45–74), Eastern Cooperative Oncology Group PS 0 in 8/18 patients (44.4%). In Cohort A (other solid tumors), 44.4% received prior immunotherapy, 44.4% received prior tyrosine kinase inhibitors, and 77.8% received “other” chemotherapy. In Cohort B (ccRCC), 88.9% of patients received prior immunotherapy, 66.7% received prior tyrosine kinase inhibitors, and 11.1% received “other” chemotherapy. In both cohorts, the median number of prior systemic therapies was 2.

Patient disposition is shown in Fig. 1.

The median follow-up for the study population was 20.87 months. Seventeen patients discontinued treatment because of disease progression (n = 10), adverse event (n = 4), patient withdrawal (n = 2), or death (n = 1). The median duration of treatment was 1.28 months (range 0.04–21+ months; Fig. 2).

No objective responses were observed in either Cohort A (Other Solid Tumor) or Cohort B (ccRCC) per RECIST 1.1, and thus, study accrual was halted after stage 1 in both cohorts. Minor tumor regressions of any magnitude were observed in 4/18 (22.2%) patients, including one patient with nonclear cell (papillary) RCC, and three patients with ccRCC (Fig. 3).

In Cohort A (other solid tumors), the investigator-assessed median PFS was 1.43 months (Fig. 4). The median duration of treatment was 1.43 months (range 0.03–2.63) as shown in Fig. 2.

In Cohort B (ccRCC), the investigator-assessed median PFS was 3.77 months (Fig. 4). The median duration of treatment was 3.76 months (range 0.03–20.86) as shown in Fig. 2. SD > 4 months was observed in 3/9 (33.3%) patients with ccRCC, including one patient who remains on treatment after >20 months at the cutoff date.

The reasons for discontinuation of the study drug were because of progressive disease (59%), adverse event (23%), patient withdrawal (12%), or death unrelated to the study drug (6%).

Across both cohorts, 3/18 patients (17%) discontinued the study drug because of an adverse event. Of these, one patient (6%) had grade 2 nausea and vomiting that was possibly related to the study drug. Two patients (11%) discontinued for adverse events determined to be unrelated to the study treatment (n = 1 venous thromboembolism; n = 1 grade 3 paresthesias). Table 2 outlines the most common treatment-emergent adverse events involving ≥25% of patients, which included nausea, anemia, diarrhea, and neutropenia.

Of 18 patients accrued, only 8/18 (44.4%) had archival tissue submitted to evaluate the loss of H3K36me3 by IHC as an exploratory biomarker correlative analysis (five patients from Cohort A; three patients from Cohort B; Supplementary Figs. S2 and S3). The small number of patients where such tissue was available further limits any signals or conclusions from this exploratory analysis.

In cohort A, 3/5 (60%) evaluable patients demonstrated loss of H3K36me3 by IHC, whereas 2/5 (40%) evaluable patients did not demonstrate this loss. In cohort B, 3/3 (100%) evaluable patients demonstrated loss of H3K36me3 by IHC. Although the sample size was limited, there did not seem to be an association between the loss of trimethylation mark with either tumor regression or duration of treatment on study.

Frameshift, nonsense, missense, and splice site mutations in SETD2 were identified in nine (50%), seven (39%), one (6%), and one (6%) of the patients, respectively. Although the small sample size precluded statistical evaluation, there seemed to be a higher probability of clinical benefit with respect to the duration of treatment among those patients with frameshift mutations in SETD2.

Prior preclinical studies demonstrated a significant synthetic lethal effect with single-agent WEE1 inhibition in SETD2-deficient cancer models including ccRCC (16). Although therapeutic development of adavosertib has been in combination with other therapies (DNA damage repair targets such as PARP inhibitors and cytotoxic chemotherapy), we sought to evaluate single-agent activity in SETD2-altered solid tumor malignancies with a particular emphasis on ccRCC, given the significant and durable tumor regressions observed in preclinical studies, with the potential to have less adverse events and improved toxicity profiles compared with its use in combination with other cancer-directed therapies. Despite the compelling scientific rationale and preclinical data, we did not observe strong evidence of synthetic lethal effect clinically, as there were no objective responses observed despite pathogenic mutations in the SETD2 gene. There was, intriguingly, a subset of patients who experienced clinical benefits with durable stable disease on treatment lasting for more than 4 months, including one patient with ongoing stable disease for more than 2 years.

The limited clinical activity observed with single-agent adavosertib in the current study is consistent with the prior results of this agent and other single-agent WEE1 inhibitors in genomically unselected patient populations. A phase Ib study of adavosertib in 80 patients with ovarian cancer, triple-negative breast cancer, or small-cell lung cancer demonstrated ORRs between 0% and 6.3% (23). Another phase Ib study of adavosertib monotherapy in 62 patients with various malignancies noted an ORR of 3.4% (2/58 evaluable patients) with only partial responses observed (24). These are lower response rates compared with another phase II study of adavosertib monotherapy in 34 evaluable patients with uterine serous carcinoma (USC) demonstrated an ORR of 29.4%, with one complete response and nine partial responses, although this is possibly because of the increased replicative stress of USC and subsequent increased susceptibility to WEE1 inhibition (25). In another phase II study of adavosertib monotherapy in patients with RAS/TP53-mutant metastatic colorectal cancer demonstrated improved PFS but only one patient with a partial response was noted. In a previously published abstract, azenosertib (formerly known as ZN-c3), another WEE1 inhibitor, was evaluated in a phase I study of 39 patients with advanced or metastatic solid tumors refractory to standard therapy. Of 16 evaluable patients, five had stable disease and two had partial responses (ORR = 12.5%), suggesting clinical activity (26). In another previously published abstract of ZN-c3 in patients with advanced/recurrent USC, the phase I study demonstrated an ORR of 12.5%, with partial responses observed in 3/12 evaluable patients (27).

Overall, the safety and tolerability profile were similar to that reported in various phase I/II studies of adavosertib monotherapy. There were similar frequencies of fatigue, nausea, vomiting, diarrhea, and anemia when compared with other phase II studies of adavosertib monotherapy in genomically unselected and TP53-mutant cancers (25, 28, 29).

We chose to utilize an intermittent dosing schedule of adavosertib, based on the safety profile observed in prior studies, with the goal of limiting treatment breaks that were required to lessen the degree of hematologic toxicity with continuous dosing (17). Takebe and colleagues previously showed that once-daily adavosertib maximum tolerated dose (MTD) at 300 mg QDAY exhibited a dose-proportional pharmacokinetic profile similar to the twice-daily MTD (225 mg BID), with plasma concentrations being higher on day 5 compared with day 1 (17). With an approximately 11-hour half-life for this agent, the MTD for once-daily adavosertib yielded comparable plasma exposures to the MTD for the twice-daily regimen (17). From a pharmacodynamic standpoint, an intermittent dosing schedule may potentially limit antitumor activity because of partial recovery of WEE1 enzymatic activity after the dosing interval, with a possible target rebound effect during the dosing break, which has also been observed in other kinase inhibitors as noted by Takebe and colleagues (17). Additional investigation is needed to determine any relationship between target recovery and antitumor activity.

Interestingly, all four patients who had modest tumor regression had pathogenic frameshift mutations in SETD2, compared with nonsense, missense, or splice site mutations, along with a trend toward longer treatment duration with frameshift mutations. In the entire study population, one patient with rectal cancer and one patient with ccRCC had a co-mutated TP53 pathogenic alteration, although none of them had tumor regression. The functional impact of different classes of genomic alterations in the SETD2 gene warrants further investigation.

This study allowed any patient with a pathogenic SETD2 alteration, without a variant allele frequency cutoff; thus, we were unable to verify the presence of biallelic loss of SETD2. Although only one patient in our study population had a missense mutation, and another one patient with a splice-site mutation, it is unclear the impact on the response that a biallelic loss of function of SETD2 could have made. In patients with ccRCC demonstrating a sequenced alteration of SETD2 (i.e., frameshift), it can be presumed that the pathogenic SETD2 loss is biallelic due to the ubiquitous 3p loss in this tumor type. Monoallelic loss of SETD2 is not sufficient to disrupt H3K36 methylation, which may account for the preserved trimethylation mark in 2/8 evaluable archival tissue samples confirmed to harbor a SETD2 mutation. Loss of trimethylation mark of H3K36me3 was observed in the majority of evaluable tumors but did not seem to be associated with clinical outcomes. However, the sample size of evaluable tumors was small to fully appreciate any potential signal or derive any conclusions. The lack of available tissue for the exploratory biomarker is a limitation of this study. In addition, this study did not obtain ontreatment biopsies for documentation of the loss of RRM2, which may have been required for synthetic lethal effects (compared with what was seen in the preclinical models). Further investigation is needed to determine if other genomic or proteomic biomarkers could identify a subset of patients who could derive benefit from WEE1 inhibition given as monotherapy.

With the small size of the study population, we are also not able to fully evaluate and explore the impact of concurrent pathogenic alterations with SETD2 that may impact the efficacy of adavosertib monotherapy. For example, only 3/18 (16.7%%) of patients had each of the following concurrent pathogenic mutations: TP53 mutations and CDKN2A/B loss. Two patients (11.1%) did have a KRAS mutation. Moreover, 1/18 (5.6%) of patients had each of the following concurrent pathogenic mutations: ATM, MYC amplification. There were no CCNE1 amplification or MYT1 mutations. Prior studies have reported possible increased response to adavosertib in TP53-mutant or CCNE1-amplified solid tumor malignancies, and possible resistance to adavosertib via MYT1 overexpression (17, 29–31). Adavosertib in combination with carboplatin has demonstrated clinical benefit with an ORR of 41% in patients with TP53-mutant, platinum-resistant ovarian cancer (29). Thus, additional identifying potential biomarkers to help better select patients who may respond to WEE1 inhibition, including the possibility of using PTEN as a biomarker for efficient WEE1 cancer therapy (32)

Lastly, the sample size of this study was small but lacked racial/ethnic diversity, further limiting the generalizability of these data. This warrants subsequent systems improvement to enhance underrepresented minority patient recruitment into clinical trials.

Overall, therapeutic targets for patients with SETD2-mutated cancers are still an unmet clinical need warranting further investigation. There are several ongoing clinical trials of WEE1 inhibitors in combination with other agents including cytotoxic chemotherapy and/or radiation (NCT03028766, NCT03012477, NCT06015659, NCT01164995, NCT02194829, NCT02101775, NCT02906059, NCT02037230, NCT04460937, NCT05815160, NCT03345784, NCT05765812, and NCT02341456). There could be some potential for investigating WEE1 inhibitors in combination with other DNA damage repair targeting agents (e.g., ATR inhibitors and CHK inhibitors). In addition, further investigation of predictive biomarkers is needed for the selection of patients with SETD2 alterations who may derive a response to WEE1 inhibitors alone or in combination with other cancer-directed therapies.

W.K. Rathmell reports other support from AstraZeneca during the conduct of the study, as well as other support from Caribou, Sitryx, and Merck outside the submitted work. G.I. Shapiro reports grants from the National Cancer Institute during the conduct of the study, as well as grants and personal fees from Merck KGaA/EMD Serono; grants from Tango, Bristol Myers Squibb, Merck & Co., Pfizer, and Eli Lilly and personal fees from Bicycle Therapeutics, ImmunoMet, Concarlo Therapeutics, Kymera Therapeutics, Janssen, Xinthera, and Circle Pharma outside the submitted work, and a patent to dosage regimen for sapacitabine and seliciclib issued and a patent to compositions and methods for predicting response and resistance to CDK4/6 inhibition issued. D. Mahalingam reports personal fees from BMS, Exelixis, Qurient, and Eisai, grants from Oncolytics and Merck; personal fees from Actuate; and grants from Rafael Pharma outside the submitted work. A.R. Kaleblasty reports grants from NCI during the conduct of the study; grants and personal fees from Pfizer, AstraZeneca, BMS, EMD Serono, Exelixis, Genentech, Gilead Sciences, Immunomedics, Novartis, Seattle Genetics, Astellas, and Amgen; personal fees from Aveo; grants and personal fees from Eisai, Janssen, and Merck; personal fees from Myovant Science; grants from Sanofi; grants and personal fees from Bayer; grants from Arvinas, Mirati therapeutics, and POINT Biopharma outside the submitted work; and stock and other ownership interests in ECOM Medical. M. Parikh reports personal fees from Pfizer and personal fees from Bristol Myers Squibb; other support from Karyopharm; nonfinancial support from Gilead; personal fees from Sanofi Aventis, Natera, and Exelixis; and nonfinancial support from Bayer outside the submitted work. S.A. Boerner reports grants from Yale Cancer Center during the conduct of the study. G. Krings reports other support from Roche outside the submitted work. T.F. Burns reports grants from Novartis; other support from Advarra; personal fees from Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals Inc., Amgen, AstraZeneca, Eli Lilly and Company, and Takeda Pharmaceuticals USA, Inc., outside the submitted work. P.N. Munster reports grants from AZ during the conduct of the study; grants from AMG, InventisBio, BlissBio, Arvinias, Revolution Medicine, JSI, Seagen, Merck, DragonFly, Relay, Scorpion, GSK, Bluepring, and Nurix; and personal fees from JNJ outside the submitted work. A. Ashworth reports personal fees and other support from Kytarro, Ovibio, Cytomx, and Cambridge Science Corporation; personal fees from Genentech and Novartis; personal fees and other support from Gladiator, Circle Pharma, Bluestar/Clearnote, Ambagon, Phoenix Molecular Designs, Yingli/280bio, NextRNA, ProLynx, Trial Library, Oric, Hap10, Tango, and Azkarra outside the submitted work; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca from which he has benefited financially (and may do so in the future). P. LoRusso reports grants from the National Cancer Institute during the conduct of the study, as well as other support from AbbVie, Roche-Genentech, Takeda, SOTIO, Agenus, IQVIA, Pfizer, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Kyowa Kirin Pharmaceutical Development, Kineta, Zentalis Pharmaceuticals, Molecular Templates, ABL Bio, STCube Pharmaceuticals, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanistic, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant Sciences, NeuroTrials, Actuate Therapeutics, Atreca Development, Amgen CodeBreak 202, Cullinan, DrenBio, Quanta Therapeutics, Schrodinger, and Boehringer Ingelheim outside the submitted work. R.R. Aggarwal reports grants and personal fees from Amgen; grants from Johnson and Johnson; grants and personal fees from Merck; personal fees from Novartis, Pfizer, and Dendreon; grants from Zenith Epigenetics; personal fees from EcoR1 Capital, Boxer Capital, Flare Therapeutics, Harpoon Therapeutics, and Prostate Cancer Clinical Trials Consortium outside the submitted work. No disclosures were reported by the other authors.

E. Maldonado: Data curation, software, formal analysis, investigation, visualization, methodology, writing-original draft, writing-review and editing. W. K. Rathmell: Data curation, formal analysis, investigation, writing-review and editing. G. I. Shapiro: Data curation, formal analysis, investigation, writing-review and editing. N. Takebe: Conceptualization, data curation, formal analysis, investigation, project administration, writing-review and editing. J. Rodon: Data curation, formal analysis, investigation, writing-review and editing. D. Mahalingam: Data curation, formal analysis, investigation, writing-review and editing. N. A. Trikalinos: Data curation, formal analysis, investigation, writing-review and editing. A. R. Kalebasty: Data curation, formal analysis, investigation, writing-review and editing. M. Parikh: Data curation, formal analysis, investigation, writing-review and editing. S. A. Boerner: Data curation, formal analysis, investigation, project administration, writing-review and editing. C. Balido: Data curation, project administration, writing-review and editing. G. Krings: Conceptualization, resources, data curation, formal analysis, validation, investigation, methodology, project administration, writing-review and editing. T. F. Burns: Data curation, project administration, writing-review and editing. E. K. Bergsland: Conceptualization, resources, data curation, formal analysis, supervision, investigation, methodology, writing-review and editing. P. N. Munster: Conceptualization, resources, data curation, formal analysis, supervision, investigation, writing-review and editing. A. Ashworth: Conceptualization, resources, data curation, formal analysis, supervision, investigation, writing-review and editing. P. LoRusso: Conceptualization, resources, supervision, funding acquisition, investigation, writing-review and editing. R. R. Aggarwal: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing-original draft, project administration, writing-review and editing.

We would like to thank the patients and their families/caregivers for their participation. This study was sponsored by the National Cancer Institute, UM1 grant# 1UM1CA186689 (P. LoRusso) and UM1CA186709 (G.I. Shapiro). This study was partly funded by AstraZeneca (AZ) but was not sponsored by AZ.