At ISGIO 2020, Michael J. Pishvaian, MD, PhD, discussed the importance of using standard-of-care chemotherapy and to test for actionable mutations in patients with pancreatic cancers, which can identify ways to individualize therapy for these patients.
Biomarker testing and precision medicine have steadily become a growing topic in different cancer settings, including pancreatic cancer. Mutations in patients with this disease are not uncommon, such as DNA damage repair (DDR) mutations, and can help direct which therapies patients should be given to lengthen their survival.
“We are making progress in the outcomes for patients with pancreatic cancer,” Michael J. Pishvaian, MD, PhD, said during the virtual 2020 International Society of Gastrointestinal Oncology (ISGIO) Conference.1 “Twenty years ago, the median overall survival [OS] was only 6 months, but in the control arms of some recently presented studies with FOLFIRINOX [folinic acid, fluorouracil, irinotecan, and oxaliplatin], the median OS was almost 15 months. So, we are going in the right direction.”
Although the median OS was better, some of the trials showing these chemotherapy regimens have improved efficacy were also negative. Pishvaian thought that “the subgroup of [patients with] pancreatic cancer that have the greatest potential for benefit in the next few years are those that have specific biomarkers. The promise of using precision medicine is to utilize predictive biomarkers to identify who will benefit from specific therapies.”
Pishvaian is an associate professor in the Department of Oncology, director of the Gastrointestinal, Developmental Therapeutics, and Clinical Research Programs at the NCR Kimmel Cancer Center at Sibley Memorial Hospital, Johns Hopkins University School of Medicine. His discussion at ISGIO covered the importance of using standard-of-care chemotherapy and to test for actionable mutations in patients with pancreatic cancers, which can identify ways to individualize therapy for these patients.
According to the data he compiled, next-generation sequencing has shown that 25% or more of patients with pancreatic cancer will have an actionable molecular biomarker, such as BRCA1/2, PALB2, STK11, and ATM. Most of these are categorized into the largest subgroup of mutations, accounting for 17% to 25% of pancreatic adenocarcinomas, which is DDR mutations.
DNA Damage Repair
One of the most common DDR mutations are germline BRCA1/2 mutations. Pishvaian highlighted that about 40% of patients who have BRCA mutations do not have a family history, and so looking at family history should not be the only screening tool used to decide if a patient should receive germline testing. Starting in 2019, germline testing is now recommended by the National Comprehensive Cancer Network (NCCN) guidelines for any patient with pancreatic cancer via comprehensive gene panels.2
Patients with pancreatic adenocarcinoma and mutations in the homologous recombination DDR pathway have shown survival benefit of over 1 year with platinum-based chemotherapy compared with patients who were DDR proficient at 2.37 years versus 1.45 years, respectively (HR, 0.44; P = .000072).3 Patients who did not receive platinum therapy at any point had no significant difference between the 2 groups (HR, 1.58; P = .154). When comparing the platinum-naïve and platinum-treated groups, the survival benefit was upwards of a year and a half, according to Pishvaian.
The other treatment that has been successful for patients with DDR mutations is PARP inhibition. Anecdotal evidence has shown consistent efficacy in BRCA1/2-mutant tumors. This includes in studies of PARP inhibitors such as olaparib (Lynparza) in 23 patients with this germline mutation and rucaparib (Rubraca) in 19 patients. For olaparib, there was a 22% overall response rate in the 23 patients, with 1 complete response and 4 partial responses.4 With rucaparib, there was a 16% response rate in the 19 patients, 1 complete response, and 2 partial responses, including in those with somatic mutations.5
Olaparib was also looked at exclusively in patients with germline BRCA1/2-mutated disease in the randomized, double-blind, phase 3 POLO trial.6 This drug was explored as a maintenance therapy versus placebo and patients demonstrated an improved progression-free survival with olaparib, with a median of 7.4 months versus 3.8 months (HR, 0.53; 95% CI, 0.35-0.82; P = .004).
For another maintenance study of a PARP inhibitor, rucaparib was used in patients with germline and somatic BRCA mutations and most of these patients had tumor shrinkage and were able to stay on this therapy for months, if not years.7
Other Actionable Mutations
Many other actionable mutations and biomarkers are found in patients with KRAS wild-type tumors and more therapies are being developed to target these biomarkers.
For example, at the 2020 American Society of Oncology (ASCO) Virtual Scientific Program, different predictive markers for immunotherapy were presented, such as LRP1B pathogenic genomic alterations.8 Among 101 patients with this alteration treated with immune checkpoint inhibitors, a retrospective analysis showed that the overall response rate was 57%, and went down to only 56% when excluding patients who had microsatellite instability–high or tumor mutational burden–high tumors.
Although these alterations are rare, they occasionally occur in pancreatic cancer, according to Pishvaian. There were similar study results for POLE mutations presented during the ASCO meeting.
Another target in pancreatic cancer is BRAF mutations. Specifically, one patient with a BRAF V600E mutation has shown a sustained partial response with dabrafenib (Tafinlar) plus trametinib (Mekinist).9 A phase 2 trial for patients with pancreatic cancer and BRAF V600E mutations will be launching shortly, looking at the use of encorafenib (Braftovi) and binimetinib (Mektovi).
“The subgroups of patients with predictive biomarkers is exciting, is growing, and there are definitely some promising results; some cases specific to pancreatic cancer and in many cases, not specific to pancreatic cancer,” Pishvaian said. “It is a call to action that we need to be sure that we're testing these patients because most of the time these gene mutations don't necessarily present themselves. There's nothing clinically about the patient that would suggest that they have an underlying mutation. We need to systematically incorporate biomarker testing for these patients.”
Incorporating Biomarker Testing
Pishvaian recognized that most of the time, patients cannot wait weeks for test results to come back. Instead he suggested using the standard-of-care chemotherapy while waiting for the results of the molecular testing that may reveal the patient is part of the 25% who would benefit from a targeted therapy.
The NCCN guidelines recommend tumor or somatic gene profiling for patients with locally advanced or metastatic disease who are potential candidates for anti-cancer treatments, which is almost 80% of that population.2
Pishvaian and his colleagues looked at the OS benefit for patients with actionable mutations in a retrospective study and found that of 677 with outcome information, 189 had actionable findings upon molecular profiling.10 Of the 189, 46 received molecularly matched therapy. These patients had a year longer median OS compared with those who did not have a matched therapy (HR, 0.42; P = .000388). Furthermore, patients with no actionable marker had a 1.3-year worse OS than those who received a matched therapy (HR, 0.34; P = .00000229).
“It emphasizes the idea that it's important to go looking for it, and if you find something, to find a way to get those patients the appropriately matched therapy either on-label, off-label, or in the context of a clinical trial,” he concluded.
1. Pishvaian MJ. Individualizing therapy for patients with pancreas cancer:
highlighting data from ASCO and ESMO 2020. Slides presented at: 2020 International Society of Gastrointestinal Oncology (ISGIO) Conference; October 2-3, 2020; Virtual.
2. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2020. Accessed October 6, 2020. https://bit.ly/2GDl7qW
3. Pishvaian MJ, Blais EM, Brody JR, et al. Outcomes in patients with pancreatic adenocarcinoma with genetic mutations in dna damage response pathways: results from the know your tumor program. JCO Precis Oncol. Published online October 23, 2019. doi:10.1200/PO.19.00115
4. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;20;33(3):244-250. doi:10.1200/JCO.2014.56.2728
5. Shroff RT, Hendifar A, McWilliams RR, et al. Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precis Oncol. Published online May 16, 2018. doi:10.1200/PO.17.00316
6. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;25;381(4):317-327. doi:10.1056/NEJMoa1903387
7. Binder KAR, Mick R, O’Hara M, et al. A Phase II, single arm study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic mutation in BRCA1, BRCA2 or PALB2. Cancer Res. 2019;79(suppl 13):CT234. doi:10.1158/1538-7445.AM2019-CT234
8. Brown LC, Sedhom R, Schwartz EB, et al. Association of LRP1B pathogenic genomic alterations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types. J Clin Oncol. 2020;38(suppl 15):3007. doi:10.1200/JCO.2020.38.15_suppl.3007
9. Guan M, Bender RJ, Pishvaian MJ, et al. Molecular and clinical characterization of BRAF mutations in pancreatic ductal adenocarcinomas (PDACs). J Clin Oncol. 2018;36(suppl 4):214. doi:10.1200/JCO.2018.36.4_suppl.214
10. Pishvaian MJ, Blais EM, Brody JR, 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):508-518. doi:10.1016/S1470-2045(20)30074-7