Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma

This article is featured in Highlights of This Issue, p. 5541

Approximately 10% of patients with early-stage Hodgkin lymphoma and 20%–30% of patients with advanced Hodgkin lymphoma develop refractory disease after initial therapy, and patients with early relapse have poor outcomes (1). Therapeutic options for patients with relapsed or refractory Hodgkin lymphoma include salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) in patients whose disease responds to chemotherapy (2, 3). For patients whose disease is refractory to primary therapy even with aggressive approaches such as ASCT, the 5-year survival rate is around 32% (4). Patients whose disease relapses after ASCT may be candidates for allogeneic stem cell transplantation (alloSCT), which yields a 3-year relapse-free survival of around 31% (5). However, alloSCT is associated with a treatment-related mortality rate of approximately 20% (6). The approval of the targeted CD30 antibody–drug conjugate brentuximab, which leads to durable complete response (CR) in about a third of the patients, further expanded therapeutic options (7–11). Later, pembrolizumab and nivolumab, antibodies targeting the immune checkpoint programmed cell death protein 1 (PD-1), were approved for patients with refractory Hodgkin lymphoma, and cellular immunotherapy is under clinical investigation (12–15). However, there continues to be an unmet need for new therapies for relapsed Hodgkin lymphoma refractory to standard treatment.

The PI3K/protein kinase B (AKT)/mTOR signaling results in cell proliferation and resistance to apoptosis as we and others described previously (16–19). In addition, posttranslational modifications of chromatin histones are key regulators of gene expression (20). These modifications include acetylation and deacetylation of lysine residues in the tails of the core histones controlled by the balanced action of histone deacetylases (HDAC) and histone acetyltransferases, and aberrant HDAC expression is associated with diverse lymphomas (21, 22). Preclinical data suggest that mTOR and HDAC inhibitors can have synergistic activity against Hodgkin lymphoma (23). Furthermore, in an early-phase clinical trial, the combination of the mTOR inhibitor everolimus and the HDAC inhibitor panobinostat had promising activity in patients with Hodgkin lymphoma; however, 43% of the patients had to withdraw from the study due to toxicity (24). Allosteric mTOR complex 1 inhibitors such as sirolimus or everolimus have immunosuppressive and antitumor activity (25). They inhibit ribosomal protein S6 kinase beta-1 and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation, which decreases the translation of mRNAs that are critical for cell-cycle progression, such as cyclin D1, and thus leads to cell-cycle arrest and apoptosis. A paradoxical increase in p-AKT through disruption of a ribosomal protein S6 kinase beta-1−dependent negative feedback loop has been suggested as a mechanism of resistance to mTOR complex 1 inhibition. The HDAC inhibitor vorinostat targets both class I and II HDACs and has antitumor activity through diverse mechanisms, including induction of oxidative injury, upregulation of death receptors, disruption of the cell-cycle checkpoint, induction of HSP 90 acetylation (leading to increased degradation of p-AKT), and upregulation of proapoptotic proteins (26).

In a phase I trial with vorinostat and sirolimus in patients with advanced cancers, we observed a partial response (PR) lasting for 18.5 months in a patient with relapsed Hodgkin lymphoma that was refractory to nine prior therapies. Therefore, we amended the study protocol to include an expansion cohort for patients with relapsed refractory Hodgkin lymphoma at the recommended phase 2 dose (RP2D) of vorinostat and sirolimus. We also added an arm to determine MTD and/or RP2D of an alternative combination of vorinostat and mTOR inhibitor everolimus, which is a chemical derivative of sirolimus with enhanced bioavailability and shorter half-life and which also demonstrated promising activity in Hodgkin lymphoma in preclinical and early clinical studies (27–32). Here we report the safety and efficacy in patients with relapsed refractory Hodgkin lymphoma.

This study was a nonrandomized, open-label, dose-escalation phase I clinical trial of vorinostat and sirolimus in patients with histologically confirmed metastatic or locally advanced cancers (NCT01087554) that included an expansion cohort for patients with relapsed/refractory Hodgkin lymphoma. Patients received RP2D of vorinostat 300 mg orally daily and sirolimus 4 mg orally daily as determined by a previously published dose-escalation part of this study (19). The trial was also amended to include a cohort of patients with advanced cancers, including patients with relapsed refractory Hodgkin lymphoma, who received an alternative combination of vorinostat 300 mg orally daily with escalating dose of everolimus 5–10 mg orally daily utilizing 3+3 design (Table 1; Supplementary File 1). Addition of vorinostat and evorolimus cohort was supported by preclinical and early clinical data (24, 27–32). Everolimus compared with siroliumus has enhanced bioavailability, shorter half-live, and has been used as an approved cancer drug. The protocol was approved by the MD Anderson's Institutional Review Board (MD Anderson IRB) and performed in accordance with its guidelines and in accordance with the Declaration of Helsinki.

Eligible patients had no available standard therapies associated with survival prolongation, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–3, and adequate organ and bone marrow function as detailed in the protocol (Supplementary File 1). Patients with previous cytotoxic chemotherapy must have been off treatment for at least 3 weeks. Patients must have had measurable or evaluable disease, and signed a written informed consent document to enroll in the trial. A full list of eligibility and treatment criteria is included in the trial protocol (Supplementary File 1). Patients continued on therapy until disease progression, unacceptable toxicity, consent withdrawal, or withdrawal for other reasons such as physician decision or noncompliance.

Adverse events (AE) were evaluated according to the NCI Common Terminology Criteria for Adverse Events version 4 at each study visit as specified in the protocol (Supplementary File 1). Therapy response [CR, PR, and stable disease (SD)] was defined and assessed according to the Revised Response Criteria for Malignant Lymphoma (Cheson criteria) and was performed at baseline and every two cycles (8 weeks; ref. 33). Progression-free survival (PFS) was calculated from day 1 of therapy until disease progression or death, whichever occurred first. Overall survival (OS) was calculated from day 1 of therapy until death.

Median PFS and OS durations were calculated using the Kaplan–Meier method. The log-rank test and Cox proportional hazards regression models were used to assess associations between patient characteristics and PFS. All tests were two-sided, and P values <0.05 were considered statistically significant. All statistical analyses were performed with the GraphPad (GraphPad Software, Inc.) or SPSS 23 (SPSS) software programs.

While the main protocol was being amended, we treated an additional 9 patients with relapsed/refractory Hodgkin lymphoma in urgent need for therapy with vorinostat and sirolimus at RP2D off-protocol. The data were analyzed under the MD Anderson IRB-approved clinical protocol DR11-0039, which allows researchers to assess treatment outcomes of patients treated off-protcol (Supplementary File 2). Efficacy data for these patients are briefly reported in this mansucript separately from the main study analysis.

Of 40 patients enrolled between July 2010 and June 2015, 22 (55%) received vorinostat and sirolimus and 18 (45%) received vorinostat and everolimus (Fig. 1). Most patients were White (55%), had nodular sclerosis Hodgkin lymphoma (84%), and stage IV disease (69%). Patients received a median of five prior therapies (range, 1–11). Prior therapies included brentuximab in 39 patients (98%), ASCT in 26 (65%), alloSCT in 12 (30%), treatment with AKT or mTOR inhibitors in 8 (20%), and treatment with HDAC inhibitors in 7 (18%). None of the patients received prior treatment with PD-1 inhibitors, which had not yet been approved at the time of enrollment. The characteristics of the 40 patients who enrolled in the study and received at least one dose are detailed in Table 2.

All 40 patients were evaluated for AEs. A detailed safety analysis for the entire dose-escalation phase of vorinostat and sirolimus in patients with diverse advanced cancers was published previously and vorinostat 300 mg orally daily and sirolimus 4 mg orally daily every 28 days was declared as RP2D (19).

In the vorinostat and everolimus arm, grade 3 transaminitis at dose level 3 (vorinostat 300 mg orally daily and everolimus 10 mg orally daily) was the only DLT (defined as treatment-related grade 4 hematologic or grade 3 or 4 nonhematologic AE within the first 28 days; Table 1). The MTD had not been reached and vorinostat 300 mg and everolimus 10 mg (both orally daily) was declared as RP2D.

Among the 22 patients with Hodgkin lymphoma who received vorinostat and sirolimus, the most frequent treatment-related AEs were thrombocytopenia (82%), neutropenia (55%), anemia (45%), transaminitis (45%), and mucositis (41%), and the most frequent grade 3 or 4 treatment-related AEs were thrombocytopenia (55%), neutropenia (27%), and anemia (23%; Table 3).

Among the 18 patients who received vorinostat and everolimus, the most frequent treatment-related AEs were thrombocytopenia (94%), anemia (50%), mucositis (33%), and neutropenia (28%), and the most frequent grade 3 or 4 toxicities were thrombocytopenia (67%), neutropenia (22%), and anemia (17%; Table 3).

Dose interruptions and/or reductions, mostly because of thrombocytopenia, were required for 15 of the 22 patients (68%) receiving vorinostat and sirolimus, and 12 of the 18 patients (67%) receiving vorinostat and everolimus. Details are listed in Supplementary Table S1 and Supplementary Fig. S1 for vorinostat with sirolimus and in Supplementary Table S2 and Supplementary Fig. S2 for vorinostat with everolimus.

Of the 40 patients, 4 had clinical disease progression (vorinostat and sirolimus, n = 1; vorinostat and everolimus, n = 3) and 1 withdrew consent (vorinostat and everolimus) before the first restaging scan.

In the vorinostat and sirolimus arm, 6 (27%) patients attained a CR and 6 (27%) patients attained PR with a combined objective response rate (ORR) of 55% (Table 4). In addition, 8 (36%) patients had SD, which in 7 (32%) of them was associated with >20% tumor shrinkage (Fig. 2A; Supplementary Fig. S3). Of the patients with a CR or PR, 3 (1 with a CR and 2 with a PR) received prior treatment with the AKT inhibitor MK-2206, and 1 with a CR received prior treatment with the HDAC inhibitor panobinostat. We also analyzed associations between ORR and clinical factors such as ECOG PS (0 vs. ≥1), serum LDH (normal vs. high), serum albumin (normal vs. low), number of metastatic sites involved (≤2 vs. >2), and stage (IV vs. <IV), and found a trend toward higher ORR in patients with ECOG 0 compared with ≥1 (6/7, 86% vs. 6/15, 40%; P = 0.07).

In the vorinostat and everolimus arm, 2 (11%) patients attained CR and 4 (22%) patients attained PR with a combined ORR rate of 33% (Table 4) and responses were observed across all three dose levels. In addition, 8 (44%) patients had SD, which in 6 (33%) of them was associated with >20% tumor shrinkage (Fig. 2B). We also analyzed associations between ORR and clinical factors such as ECOG PS, LDH, albumin, number of metastatic sites involved, and stage, and found higher ORR in patients with ≤2 metastatic sites compared to >2 (4/5, 80% vs. 2/13, 15%; P = 0.022) and in patients stage <IV compared with IV (5/7, 71% vs. 1/11, 9%; P = 0.013). There was no difference in ORR between vorinostat and sirolimus compared with vorinostat and everolimus (12/22, 55% vs. 6/18, 33%; P = 0.22).

While our protocol was being amended we treated an additional 9 patients with heavily pretreated Hodgkin lymphoma (all had prior brentuximab, 3 had prior AKT/mTOR inhibitors, and 1 prior HDAC inhibitor), who had no alternative treatment options and were in urgent need of therapy, with vorinostat and sirolimus at RP2D off-label. Of these 9 patients, 4 (44%) attained CR and 3 (33%) attained PR (ORR rate of 78%). These patients are not included in the study analysis.

The median follow-up for 22 patients treated with vorinostat and sirolimus was 43.3 months. At the time of analysis, 13 patients discontinued therapy because of disease progression, 1 patient withdrew consent due to grade 3 neuropathy, 3 patients withdrew consent and continued on therapy outside of the study due to logistical reasons (inability to travel), 1 patient was removed from study for noncompliance, and 2 patients (1 with a CR and 1 with a PR) were removed from study because of referral for alloSCT. In addition, 2 patients with CR continued on therapy for 43.3 and 46.3 months, respectively. The median PFS duration was 5.8 months [95% confidence interval (CI), 3.7–7.9; Fig. 3A] and patients with CR or PR had a longer median PFS than patients without (18 months, 95% CI, 3.1–32.9 vs. 3.2 months, 95% CI, 1.0–5.4; P = 0.019; Fig. 3B). We also analyzed associations between PFS and clinical factors such as ECOG PS (0 vs. ≥1), serum LDH (normal vs. high), serum albumin (normal vs. low), number of metastatic sites involved (≤2 vs. >2), and stage (IV vs. <IV), and found a trend toward a longer median PFS in patients with ECOG 0 compared with ≥1 (not reached vs. 4.6 months, 95% CI, 1.5–7.7; P = 0.06; Supplementary Fig. S4). At the time of analysis, 9 (41%) patients had died and a median OS had not been reached.

The median follow-up for 18 patients treated with vorinostat and everolimus was 21 months. At the time of analysis, 14 patients discontinued therapy because of disease progression, 1 patient withdrew consent due to grade 3 thrombocytopenia, 1 patient was removed from study for noncompliance, 1 patient with a CR was removed from study because of referral for donor lymphocyte infusion, and 1 patient was removed from the study due to physician decision. The median PFS duration was 4.8 months (95% CI, 3.0–6.6; Fig. 3A) and there was no difference in median PFS between patients with CR or PR and patients without (5.7 months, 95% CI, 4.0–7.4 vs. 4.8 months, 95% CI, 2.7–6.9; P = 0.9; Fig. 3C). We also analyzed associations between PFS and clinical factors such as ECOG PS, LDH, albumin, number of metastatic sites involved, and stage, and found a longer median PFS in patients with normal LDH compared with high (5.8 months, 95% CI, 4.4–7.2 vs. 1.6 months, 95% CI, 1.3–1.9; P < 0.001; Supplementary Fig. S5) and in patients with normal albumin compared with low (5.8 months, 95% CI, 4.4–7.2 vs. 1.6 months, 95% CI, 1.3–1.9; P < 0.001; Supplementary Fig. S6). There was no difference in a median PFS between vorinostat and sirolimus compared with vorinostat and everolimus (5.8 months vs. 4.8 months; P = 0.13; Fig. 3A). At the time of analysis, 5 patients (28%) had died and a median OS had not been reached.

Our study demonstrated that the combined inhibition of HDAC and mTOR can be effective in patients with relapsed/refractory Hodgkin lymphoma. Responses appeared to be more frequent in patients who received vorinostat and sirolimus; however, small numbers and absence of randomization precludes definitive conclusions. Of note, responses were seen even in patients who received prior treatment with AKT or HDAC inhibitors.

Both combinations had similar, manageable safety profiles, which were comparable to safety results of our phase I dose-escalation part of this study of vorinostat and sirolimus, which enrolled patients with advanced cancers (19). The most frequent AEs were hematologic AEs such as thrombocytopenia (grade 4 in 11%–36% of patients), and 67% to 68% of patients required dose interruptions and/or reductions.

Historically, vorinostat demonstrated modest single-agent activity in a phase II SWOG S0517 study of 25 patients with relapsed/refractory Hodgkin lymphoma (median of three prior therapies) with only 1 (4%) PR and median PFS of 4.8 months (34). Similarly, single-agent administration of another HDAC inhibitor entinostat in a phase II study in 49 patients with relapsed/refractory Hodgkin lymphoma demonstrated an ORR of 12% with median PFS of 5.5 months (35). Other HDAC inhibitors such as mocetinostat and panobinostat reported higher ORR of 21% to 35% and 27%, respectively (36, 37).

Single-agent mTOR inhibitors such as everolimus demonstrated ORRs of 46% to 47% in phase II settings with relatively low CR rates of 5% to 9% despite patients were less pretreated with brentuximab vedotin (up to 26%) compared with our study (98%; refs. 31, 32). In addition, our results compare favorably with the phase I study of panobinostat and everolimus, in which patients with Hodgkin lymphoma demonstrated an ORR of 43%, CR rate of 15%, and median PFS duration of 4 months (24). Compared with patients in our study, those in the panobinostat and everolimus study had a lower median number of prior therapies (3 vs. 5) and a lower rate of prior ASCT (40% vs. 65%); however, 80% of the patients receiving panobinostat plus everolimus required dose interruptions, and 59% of the patients treated with the recommended dose for expansion had grade 4 thrombocytopenia. Compared with vorinostat and sirolimus, both panobinostat with everolimus and vorinostat with everolimus attained fewer CRs; however, small patient numbers and absence of randomization precludes any conclusion about whether everolimus is indeed inferior to sirolimus as a partner for combinations with HDAC inhibitors in the treatment of Hodgkin lymphoma.

Patients were enrolled to our study before the PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab received approval for the treatment of relapsed/refractory Hodgkin lymphoma. That approval was based on early clinical studies showing ORR rate of 87% and 74%, CR rates of 17% and 22%, and PFS rates of 86% at 24 weeks and 63.4% at 9 months for nivolumab and pembrolizumab, respectively (13, 14). Compared with patients in those early studies, patients in our study had higher rates of prior treatment with brentuximab (98% vs. 78% and 83%), ASCT (65% vs. 61% and 65%), and alloSCT (30% vs. 0%). In a large phase II study with 243 patients with relapsed/refractory Hodgkin lymphoma after ASCT failure (74% received prior brentuximab), nivolumab demonstrated an ORR of 69% with a CR rate of 16% and a median PFS of 14.7 months (15). PD-1 inhibitors compared to combinations of HDAC and mTOR inhibitors have mostly nonoverlapping AEs, and their combined use could plausbly increase efficacy against Hodgkin lymphoma, given that both HDAC and mTOR inhibitors have been suggested to increase anticancer immune response (23, 26, 38, 39).

Our study had several limitations. First, it enrolled a relatively small number of patients all in an early-phase setting. Second, none of the patients received prior PD-1 inhibitors, and it is unclear if the same salutary activity can be achieved in a post−PD-1 inhibitor setting. Third, while patients treated with vorinostat and sirolimus received RP2D, patients treated on the dose-escalation study with vorinostat and everolimus were treated with everolimus doses from 5 mg to 10 mg daily, which could have impacted efficacy. Fourth, the most promising combination of vorinostat and sirolimus comprised older drugs that are now off-patent, potentially complicating the drug development trajectory beyond early-phase trials.

In summary, combined HDAC and mTOR inhibition has encouraging activity in patients with relapsed and/or refractory Hodgkin lymphoma and warrants further investigation.

F. Janku reports grants from Novartis, Genentech, BioMed, Valley Discoveries, Astellas, Agios, Plexxikon, Piqur, Symphogen, Bristol-Myers Squibb, Asana, and Proximagen (research); grants and other from Deciphera (research, advisory board); other from Guardant Health, IFM Therapeutics, and Synlogic (advisory board); personal fees and other from Trovagene (consultant, ownership interests); and personal fees from Immunomet (consultant) during the conduct of the study. H. Park serves as site PI for clinical trials funded by the following entities (all fees paid to the institution): Ambrx, Amgen, Aprea Therapeutics AB, Array BioPharma, Bayer BeiGene, BJ Bioscience, Bristol-Myers Squibb, Daiichi Pharmaceutical, Eli Lilly, EMD Serono, Five Prime Therapeutics, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, ImmuneOncia Therapeutics, Immunomedics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Medimmune, Medivation, Merck, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, Seattle Genetics, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Vertex Pharmaceuticals, and Xencor Inc. S.G. Call reports grants from Non-Standard of Care Clinical Charge Program at MD Anderson, Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy at MD Anderson, National Center for Advancing Translational Sciences, and NIH through MD Anderson Cancer Center Support Grant during the conduct of the study. Y. Oki reports other from Genentech (current employment) outside the submitted work. V. Subbiah reports grants from Novartis (clinical trials research support) outside the submitted work; research funding/grant support for clinical trials from Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals; travel support from Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; consultancy/advisory board at Helsinn, Loxo Oncology/Eli Lilly, R-Pharma US, Incyte, QED Pharma, Medimmune, Novartis, Signant Health; and other from Medscape. D.S. Hong reports research/grant funding from AbbVie, Adaptimune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo, Merck, Medimmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; travel, accommodations, expenses from Bayer, Loxo, miRNA, Genmab, AACR, ASCO, and SITC; consulting or advisory roles with Alpha Insights, Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, COG, Ecorl, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD; and other ownership interests in Molecular Match (advisory); OncoResponse (founder); Presagia Inc (advisor). A. Naing reports grants from NCI, EMD Serono, Medimmune, Karyopharm Therapeutics, Incyte, Neon Therapeutics, Calithera Biosciences, Top Alliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, and NeoImmuneTech; grants and nonfinancial support from ARMO BioSciences (travel and accommodation expense); grants and personal fees from Novartis (advisory board), Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics (advisory board); and personal fees from Genome & Company (advisory board) outside the submitted work. G.S. Falchook reports royalties from Wolters Kluwer (self, 2014–present); advisory roles with Fujifilm (to institution, 2018) and EMD Serono (self, 2010, 2011); travel (self, for work or research related to institution) from Bristol Myers Squibb (2015), EMD Serono (2011–2013), Fujifilm (2018), Millennium (2013), and Sara Cannon Research Institute; speakers honorarium for CME from Total Health Conferencing (2019) and Rocky Mountain Oncology (2020); and research funding to institution from 3-V Biosciences, Abbisko, Abbvie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, NIH, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, Regeneron, Rgenix, Ribon, Sapience, Strategia, Syndax, Synthorx, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, and Xencor. D.D. Karp reports grants from MD Anderson Cancer Center (Cancer Center support grant and NIH Clinical Translational Science Award grant) during the conduct of the study; other from Wolters Kluwer Publishers (royalties for Handbook of Targeted Cancer Therapy & Immunotherapy); personal fees from Black Beret Life Sciences (consulting); and grants from Phosplatin Therapeutics (principal investigator) outside the submitted work. S.A. 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 Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Icyte Corp., Jacobio Pharmaceuticals Co., Medimmune, LLC, Medivation, Inc., Merck Sharp & 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. (clinical trial research support received through the institution), and NCI/CIH Core grant (CCSG shared resources) No. P30CA016672 (clinical trial research support received through the institution) outside the submitted work. I. Garrido-Laguna reports other from Pfizer, BMS, Tolero, Incyte, Tizona, Array, Novartis, GSK, OncoMed, Genetech, Halozyme, Lilly, Glenmark, Redhill, Bayer, Taiho, Medimmune, Amgen, Rafael, and Seattle Genetics (payment to institution for role as study PI) outside the submitted work; and ad-hoc advisory boards for Pfizer, Array, and Eisai. E.J. Shpall reports personal fees from Novartis (consulting fees, honorarium), Magenta (consulting fees, honorarium), Adaptimmune (consulting fees), Cellgene (consulting fees), Partner Therapeutics (consulting fees, honorarium), Mesoblast (consulting fees), and Axio (consulting fees) outside the submitted work, and is listed as a coinventor on a provisional patent application that is owned by MD Anderson and licensed to Takeda. S.S. Neelapu reports grants and personal fees from Kite/Gilead, Bristol-Myers Squibb, Allogene, Unum Therapeutics, Precision Biosciences, and Merck; grants from Cellectis; personal fees from Pfizer, Poseida, Karus, Acerta, Celgene, Novartis, Cell Medica/Kuur, Incyte, Legend Biotech, Adicet Bio, Calibr; and other from Takeda Pharmaceuticals (royalty income) outside the submitted work. F. Meric-Bernstam reports personal fees from Arduro BioTech (consulting), Alkermes (consulting), F. Hoffman-LaRoche Ltd. (consulting), IBM Watson (consulting), Jackson Laboratory (consulting), Kolon Life Science (consulting), OrigiMed (consulting), PACT Pharma (consulting), Paraxel International (consulting), Pfizer Inc. (consulting), Samsung Bioepis (consulting), Seattle Genetics (consulting, advisory board), Tyra Biosciences (consulting), Xencor (consulting), Zymeworks (consulting), Immunomedics (advisory board), Inflection Biosciences (advisory board), and Mersana Therapeutics (advisory board); grants and personal fees from DebioPharm (consulting, sponsored research), eFFECTOR Therapeutics (consulting, sponsored research), Genentech Inc. (consulting, sponsored research), Puma Biotechnology (advisory board, sponsored research), Silverback Therapeutics (advisory board), Spectrum Pharmaceuticals (advisory board), Zentalis (advisory board); grants from Aileron Therapeutics (sponsored research), AstraZeneca (sponsored research), Bayer Healthcare Pharmaceutical (sponsored research), Calithera Biosciences (sponsored research), Curis Inc. (sponsored research), CytomX Therapeutics Inc (sponsored research), Daiichi Sankyo Co. Ltd. (sponsored research), Guardant Health (sponsored research), Millennium Pharmaceuticals (sponsored research), Novartis (sponsored research), Taiho Pharmaceutical Co. (sponsored research); and other from Chugai Biopharmaceuticals (honoraria - speaking engagement), Mayo Clinic (honoraria - speaking engagement), Rutgers Cancer Institute of New Jersey (honoraria - speaking engagement), and Beth Israel Deaconess Medical Center (travel related) outside the submitted work. R. Kurzrock receives research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant; consultant and/or speaker fees and/or advisory board for X-Biotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, and TD2/Volastra; has an equity interest in IDbyDNA and CureMatch Inc; serves on the Board of CureMatch and CureMetrix; and is a cofounder of CureMatch. M.A. Fanale reports other from Seattle Genetics (employment and stocks) outside the submitted work. No potential conflicts of interest were disclosed by the other authors.

F. Janku: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, methodology, writing-original draft, writing-review and editing. H. Park: Data curation, writing-review and editing. S.G. Call: Data curation, formal analysis, writing-original draft, writing-review and editing. K. Madwani: Data curation, writing-review and editing. Y. Oki: Data curation, writing-review and editing, provision of patients. V. Subbiah: Data curation, writing-review and editing, provision of patients. D.S. Hong: Data curation, writing-review and editing, provision of patients. A. Naing: Data curation, writing-review and editing, provision of patients. V.M. Velez-Bravo: Data curation, project administration, writing-review and editing. T.G. Barnes: Data curation, writing-review and editing. F.B. Hagemeister: Data curation, writing-review and editing, provision of patients. G.S. Falchook: Data curation, writing-review and editing, provision of patients. D.D. Karp: Data curation, writing-review and editing, provision of patients. J.J. Wheler: Data curation, writing-review and editing, provision of patients. S.A. Piha-Paul: Data curation, writing-review and editing, provision of patients. I. Garrido-Laguna: Conceptualization, methodology, writing-review and editing. E.J. Shpall: Data curation, writing-review and editing, provision of patients. L.E. Fayad: Data curation, writing-review and editing, provision of patients. S.S. Neelapu: Data curation, writing-review and editing, provision of patients. F. Meric-Bernstam: Supervision, writing-review and editing. R. Kurzrock: Conceptualization, resources, supervision, funding acquisition, writing-review and editing. M.A. Fanale: Conceptualization, data curation, writing-review and editing, provision of patients.

This study was supported by the Non-Standard of Care Clinical Charge Program at MD Anderson (to F. Janku), the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy at MD Anderson (to F. Janku), the National Center for Advancing Translational Sciences (grant no. UL1 TR000371, to F. Janku, V. Subbiah, D.S. Hong, A. Naing, D.D. Karp, S.A. Piha-Paul, and F. Meric-Bernstam), and the NIH through MD Anderson's Cancer Center Support Grant (P30 CA016672, all authors).

Authors would also like to acknowledge Mr. Joseph Munch from the Department of Scientific Publications, the University of Texas MD Anderson Cancer Center for his editorial and grammar assistance.

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