Trends in pancreatic cancer clinical trials in the United States
Main Article Content
Abstract
Trends in clinical trials for pancreatic cancer between 2011-2020 were tracked in the Pancreatic Cancer Action Network database originally designed to assist in identifying open trials for eligible patients. More than 125 trials specific for pancreatic cancer or including no more than one additional cancer type have been open each year, the majority for patients with a diagnosis of pancreatic adenocarcinoma (PAC). The trends indicate an active and progressive pancreatic cancer research community and include an increasing number of trials for previously treated patients, the emergence of trials for post-adjuvant or maintenance therapy, an increasing number of research-intensive phase 0 trials, increasing seamless phase I/II and II/III trials to improve efficiency, and an increasing number of phase III trials despite historical failures. Trials were analyzed by treatment type and included trials to optimize standard chemotherapy or radiation therapy, trials targeting tumor pathways, the stroma, or the immune system, biomarker-specified trials, and a miscellaneous category of trials testing tumor metabolism, complementary medicine approaches, or alternate energy sources. There was a dramatic increase in immunotherapy trials over this time. Several biomarker-specified trials were initiated, and FDA approval was obtained for biomarker-specified targeted agents, many in a tissue-agnostic setting, indicating an increase in a precision medicine approach to pancreatic cancer treatment. An increasing number of trials tested non-standard approaches, many which progressed to phase III. The trends suggest an encouraging trajectory of pancreatic cancer clinical research.
Keywords:
kidney, AKI, oxygen, ischemia, reperfusion, oxidative damage, organ injury, normoxia, hyperoxia, hypoxia, FIO2, murine
Article Details
How to Cite
MATRISIAN, Lynn M et al.
Trends in pancreatic cancer clinical trials in the United States.
Medical Research Archives, [S.l.], v. 9, n. 11, nov. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2578>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v9i11.2578.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. 10.3322/caac.21660
2. Ferlay J, Partensky C, Bray F. More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol. 2016;55(9-10):1158-60. 10.1080/0284186X.2016.1197419
3. Rahib L, Wehner M.R., Matrisian, L.M., Nead, K.T. Projection of cancer incidence and death to 2040 in the U.S.: impact of cancer screening and a changing demographic. submitted. 2021.
4. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. 10.3322/caac.21654
5. Ansari D, Gustafsson A, Andersson R. Update on the management of pancreatic cancer: surgery is not enough. World J Gastroenterol. 2015;21(11):3157-65. 10.3748/wjg.v21.i11.3157
6. Tempero MA, Malafa MP, Chiorean EG, Czito B, Scaife C, Narang AK, et al. Pancreatic Adenocarcinoma, Version 1.2019. J Natl Compr Canc Netw. 2019;17(3):202-10. 10.6004/jnccn.2019.0014
7. Hoos WA, James PM, Rahib L, Talley AW, Fleshman JM, Matrisian LM. Pancreatic cancer clinical trials and accrual in the United States. J Clin Oncol. 2013;31(27):3432-8. 10.1200/JCO.2013.49.4823
8. Matrisian LM, Berlin JD. The Past, Present, and Future of Pancreatic Cancer Clinical Trials. Am Soc Clin Oncol Educ Book. 2016;35:e205-15. 10.14694/EDBK_159117
10.1200/EDBK_159117
9. cancer.gov. [Available from: https://www.cancer.gov/research/infrastructure/clinical-trials/nctn.
10. Rahib L, Fleshman JM, Matrisian LM, Berlin JD. Evaluation of Pancreatic Cancer Clinical Trials and Benchmarks for Clinically Meaningful Future Trials: A Systematic Review. JAMA Oncol. 2016;2(9):1209-16. 10.1001/jamaoncol.2016.0585
11. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10. 10.1200/JCO.19.02105
12. Bear AS, Vonderheide RH, O'Hara MH. Challenges and Opportunities for Pancreatic Cancer Immunotherapy. Cancer Cell. 2020;38(6):788-802. 10.1016/j.ccell.2020.08.004
13. Waters AM, Der CJ. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 2018;8(9). 10.1101/cshperspect.a031435
14. Flaherty KT, Gray R, Chen A, Li S, Patton D, Hamilton SR, et al. The Molecular Analysis for Therapy Choice (NCI-MATCH) Trial: Lessons for Genomic Trial Design. J Natl Cancer Inst. 2020;112(10):1021-9. 10.1093/jnci/djz245
15. Mangat PK, Halabi S, Bruinooge SS, Garrett-Mayer E, Alva A, Janeway KA, et al. Rationale and Design of the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. JCO Precis Oncol. 2018;2018. 10.1200/PO.18.00122
16. Ahn ER, editor Olaparib (O) in patients (pts) with pancreatic cancer with BRCA1/2 inactivating mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study2020; ASCO Virtual Scientific Program: American Society of Clinical Oncology.
17. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418-29. 10.1016/j.ccr.2012.01.007
18. Hingorani SR, Zheng L, Bullock AJ, Seery TE, Harris WP, Sigal DS, et al. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. J Clin Oncol. 2018;36(4):359-66. 10.1200/JCO.2017.74.9564
19. Ramanathan RK, McDonough SL, Philip PA, Hingorani SR, Lacy J, Kortmansky JS, et al. Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313. J Clin Oncol. 2019;37(13):1062-9. 10.1200/JCO.18.01295
20. Van Cutsem E, Tempero MA, Sigal D, Oh DY, Fazio N, Macarulla T, et al. Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma. J Clin Oncol. 2020;38(27):3185-94. 10.1200/JCO.20.00590
21. Abrams RA, Winter KA, Safran H, Goodman KA, Regine WF, Berger AC, et al. Results of the NRG Oncology/RTOG 0848 Adjuvant Chemotherapy Question-Erlotinib+Gemcitabine for Resected Cancer of the Pancreatic Head: A Phase II Randomized Clinical Trial. Am J Clin Oncol. 2020;43(3):173-9. 10.1097/COC.0000000000000633
22. Shinde A, Verma V, Li R, Glaser S, Raoof M, Warner SG, et al. The role of sequential radiation following adjuvant chemotherapy in resected pancreatic cancer. J Gastrointest Oncol. 2019;10(3):462-73. 10.21037/jgo.2019.01.19
23. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-57. 10.1016/S0140-6736(15)00986-1
24. Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011-24. 10.1016/S0140-6736(16)32409-6
25. Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018;379(25):2395-406. 10.1056/NEJMoa1809775
26. Motoi F, Kosuge T, Ueno H, Yamaue H, Satoi S, Sho M, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49(2):190-4. 10.1093/jjco/hyy190
27. Jang JY, Han Y, Lee H, Kim SW, Kwon W, Lee KH, et al. Oncological Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer: A Prospective, Randomized, Open-label, Multicenter Phase 2/3 Trial. Ann Surg. 2018;268(2):215-22. 10.1097/SLA.0000000000002705
28. Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020;38(16):1763-73. 10.1200/JCO.19.02274
29. Burris HA, 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-13. 10.1200/JCO.1997.15.6.2403
30. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231-7. 10.1200/JCO.2008.20.0238
31. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-25. 10.1056/NEJMoa1011923
32. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-13. 10.1126/science.aan6733
33. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-9. 10.1056/NEJMoa1714448
34. Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-82. 10.1016/S1470-2045(19)30691-6
35. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019;381(4):317-27. 10.1056/NEJMoa1903387
36. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-65. 10.1016/S1470-2045(20)30445-9
37. Forsythe A, Zhang W, Phillip Strauss U, Fellous M, Korei M, Keating K. A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors. Ther Adv Med Oncol. 2020;12:1758835920975613. 10.1177/1758835920975613
38. Hu ZI, Shia J, Stadler ZK, Varghese AM, Capanu M, Salo-Mullen E, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res. 2018;24(6):1326-36. 10.1158/1078-0432.CCR-17-3099
39. Lai E, Ziranu P, Spanu D, Dubois M, Pretta A, Tolu S, et al. BRCA-mutant pancreatic ductal adenocarcinoma. Br J Cancer. 2021. 10.1038/s41416-021-01469-9
40. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495-501. 10.1038/nature14169
41. Lowery MA, Jordan EJ, Basturk O, Ptashkin RN, Zehir A, Berger MF, et al. Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype. Clin Cancer Res. 2017;23(20):6094-100. 10.1158/1078-0432.CCR-17-0899
42. Cancer Genome Atlas Research Network. Electronic address aadhe, Cancer Genome Atlas Research N. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017;32(2):185-203 e13. 10.1016/j.ccell.2017.07.007
43. Pishvaian MJ, Bender RJ, Halverson D, Rahib L, Hendifar AE, Mikhail S, et al. Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative. Clin Cancer Res. 2018;24(20):5018-27. 10.1158/1078-0432.CCR-18-0531
44. Pishvaian MJ, Blais EM, Brody JR, Lyons E, DeArbeloa P, Hendifar A, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020;21(4):508-18. 10.1016/S1470-2045(20)30074-7
45. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-703. 10.1056/NEJMoa1304369
46. Tempero M, Oh DY, Tabernero J, Reni M, Van Cutsem E, Hendifar A, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021. 10.1016/j.annonc.2021.01.070
47. Tan AC, Ashley DM, Khasraw M. Adapting to a Pandemic - Conducting Oncology Trials during the SARS-CoV-2 Pandemic. Clin Cancer Res. 2020;26(13):3100-3. 10.1158/1078-0432.CCR-20-1364
2. Ferlay J, Partensky C, Bray F. More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol. 2016;55(9-10):1158-60. 10.1080/0284186X.2016.1197419
3. Rahib L, Wehner M.R., Matrisian, L.M., Nead, K.T. Projection of cancer incidence and death to 2040 in the U.S.: impact of cancer screening and a changing demographic. submitted. 2021.
4. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. 10.3322/caac.21654
5. Ansari D, Gustafsson A, Andersson R. Update on the management of pancreatic cancer: surgery is not enough. World J Gastroenterol. 2015;21(11):3157-65. 10.3748/wjg.v21.i11.3157
6. Tempero MA, Malafa MP, Chiorean EG, Czito B, Scaife C, Narang AK, et al. Pancreatic Adenocarcinoma, Version 1.2019. J Natl Compr Canc Netw. 2019;17(3):202-10. 10.6004/jnccn.2019.0014
7. Hoos WA, James PM, Rahib L, Talley AW, Fleshman JM, Matrisian LM. Pancreatic cancer clinical trials and accrual in the United States. J Clin Oncol. 2013;31(27):3432-8. 10.1200/JCO.2013.49.4823
8. Matrisian LM, Berlin JD. The Past, Present, and Future of Pancreatic Cancer Clinical Trials. Am Soc Clin Oncol Educ Book. 2016;35:e205-15. 10.14694/EDBK_159117
10.1200/EDBK_159117
9. cancer.gov. [Available from: https://www.cancer.gov/research/infrastructure/clinical-trials/nctn.
10. Rahib L, Fleshman JM, Matrisian LM, Berlin JD. Evaluation of Pancreatic Cancer Clinical Trials and Benchmarks for Clinically Meaningful Future Trials: A Systematic Review. JAMA Oncol. 2016;2(9):1209-16. 10.1001/jamaoncol.2016.0585
11. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10. 10.1200/JCO.19.02105
12. Bear AS, Vonderheide RH, O'Hara MH. Challenges and Opportunities for Pancreatic Cancer Immunotherapy. Cancer Cell. 2020;38(6):788-802. 10.1016/j.ccell.2020.08.004
13. Waters AM, Der CJ. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 2018;8(9). 10.1101/cshperspect.a031435
14. Flaherty KT, Gray R, Chen A, Li S, Patton D, Hamilton SR, et al. The Molecular Analysis for Therapy Choice (NCI-MATCH) Trial: Lessons for Genomic Trial Design. J Natl Cancer Inst. 2020;112(10):1021-9. 10.1093/jnci/djz245
15. Mangat PK, Halabi S, Bruinooge SS, Garrett-Mayer E, Alva A, Janeway KA, et al. Rationale and Design of the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. JCO Precis Oncol. 2018;2018. 10.1200/PO.18.00122
16. Ahn ER, editor Olaparib (O) in patients (pts) with pancreatic cancer with BRCA1/2 inactivating mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study2020; ASCO Virtual Scientific Program: American Society of Clinical Oncology.
17. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418-29. 10.1016/j.ccr.2012.01.007
18. Hingorani SR, Zheng L, Bullock AJ, Seery TE, Harris WP, Sigal DS, et al. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. J Clin Oncol. 2018;36(4):359-66. 10.1200/JCO.2017.74.9564
19. Ramanathan RK, McDonough SL, Philip PA, Hingorani SR, Lacy J, Kortmansky JS, et al. Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313. J Clin Oncol. 2019;37(13):1062-9. 10.1200/JCO.18.01295
20. Van Cutsem E, Tempero MA, Sigal D, Oh DY, Fazio N, Macarulla T, et al. Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma. J Clin Oncol. 2020;38(27):3185-94. 10.1200/JCO.20.00590
21. Abrams RA, Winter KA, Safran H, Goodman KA, Regine WF, Berger AC, et al. Results of the NRG Oncology/RTOG 0848 Adjuvant Chemotherapy Question-Erlotinib+Gemcitabine for Resected Cancer of the Pancreatic Head: A Phase II Randomized Clinical Trial. Am J Clin Oncol. 2020;43(3):173-9. 10.1097/COC.0000000000000633
22. Shinde A, Verma V, Li R, Glaser S, Raoof M, Warner SG, et al. The role of sequential radiation following adjuvant chemotherapy in resected pancreatic cancer. J Gastrointest Oncol. 2019;10(3):462-73. 10.21037/jgo.2019.01.19
23. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-57. 10.1016/S0140-6736(15)00986-1
24. Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011-24. 10.1016/S0140-6736(16)32409-6
25. Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018;379(25):2395-406. 10.1056/NEJMoa1809775
26. Motoi F, Kosuge T, Ueno H, Yamaue H, Satoi S, Sho M, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49(2):190-4. 10.1093/jjco/hyy190
27. Jang JY, Han Y, Lee H, Kim SW, Kwon W, Lee KH, et al. Oncological Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer: A Prospective, Randomized, Open-label, Multicenter Phase 2/3 Trial. Ann Surg. 2018;268(2):215-22. 10.1097/SLA.0000000000002705
28. Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020;38(16):1763-73. 10.1200/JCO.19.02274
29. Burris HA, 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-13. 10.1200/JCO.1997.15.6.2403
30. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231-7. 10.1200/JCO.2008.20.0238
31. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-25. 10.1056/NEJMoa1011923
32. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-13. 10.1126/science.aan6733
33. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-9. 10.1056/NEJMoa1714448
34. Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-82. 10.1016/S1470-2045(19)30691-6
35. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019;381(4):317-27. 10.1056/NEJMoa1903387
36. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-65. 10.1016/S1470-2045(20)30445-9
37. Forsythe A, Zhang W, Phillip Strauss U, Fellous M, Korei M, Keating K. A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors. Ther Adv Med Oncol. 2020;12:1758835920975613. 10.1177/1758835920975613
38. Hu ZI, Shia J, Stadler ZK, Varghese AM, Capanu M, Salo-Mullen E, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res. 2018;24(6):1326-36. 10.1158/1078-0432.CCR-17-3099
39. Lai E, Ziranu P, Spanu D, Dubois M, Pretta A, Tolu S, et al. BRCA-mutant pancreatic ductal adenocarcinoma. Br J Cancer. 2021. 10.1038/s41416-021-01469-9
40. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495-501. 10.1038/nature14169
41. Lowery MA, Jordan EJ, Basturk O, Ptashkin RN, Zehir A, Berger MF, et al. Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype. Clin Cancer Res. 2017;23(20):6094-100. 10.1158/1078-0432.CCR-17-0899
42. Cancer Genome Atlas Research Network. Electronic address aadhe, Cancer Genome Atlas Research N. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017;32(2):185-203 e13. 10.1016/j.ccell.2017.07.007
43. Pishvaian MJ, Bender RJ, Halverson D, Rahib L, Hendifar AE, Mikhail S, et al. Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative. Clin Cancer Res. 2018;24(20):5018-27. 10.1158/1078-0432.CCR-18-0531
44. Pishvaian MJ, Blais EM, Brody JR, Lyons E, DeArbeloa P, Hendifar A, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020;21(4):508-18. 10.1016/S1470-2045(20)30074-7
45. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-703. 10.1056/NEJMoa1304369
46. Tempero M, Oh DY, Tabernero J, Reni M, Van Cutsem E, Hendifar A, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021. 10.1016/j.annonc.2021.01.070
47. Tan AC, Ashley DM, Khasraw M. Adapting to a Pandemic - Conducting Oncology Trials during the SARS-CoV-2 Pandemic. Clin Cancer Res. 2020;26(13):3100-3. 10.1158/1078-0432.CCR-20-1364