Pursuing Improved Survival With KRAS, PARP Inhibitors and Metabolic Agents in Pancreatic Cancer

Although chemotherapy remains the benchmark for drug development in pancreatic cancer, signals seen with selective KRAS-targeted agents, PARP inhibitors, and metabolic agents suggest that novel approaches do have the ability to prolong survival in the advanced setting, explained Eileen O'Reilly, MD.

“It’s exciting times in pancreas cancer. We’re seeing some very interesting science being translated into the clinic,” said O’Reilly, Winthrop Rockefeller Endowed Chair in Medical Oncology at Memorial Sloan Kettering Cancer Center (MSKCC), in a virtual presentation during the 17th Annual Meeting of the International Society of Gastrointestinal Oncology^®, a program developed by Physicians’ Education Resource^® LLC.

Selective KRAS-Targeted Approaches

Enthusiasm for targeting KRAS is beginning to build, explained O’Reilly, who is also the co-director of Medical Initiatives, David M. Rubenstein Center for Pancreatic Cancer Research, section head of Hepatopancreaticobilary and Neuroendocrine Cancers, and medical oncologist at MSKCC. Although drug development in this area has been historically challenging, ongoing research suggests that certain subsets of KRAS, such as KRAS G12C, which represents 1% to 2% of pancreatic cancer, may be able to be effectively targeted.

For example, data from the phase 1/2 CodeBreak 100 trial demonstrated that the KRAS G12C inhibitor sotorasib (formally AMG 510) demonstrated anticancer activity across several advanced KRAS G12C–mutant solid tumors. Among 12 patients with pancreatic cancer, 1 patient had a partial response (PR) and at least 8 patients had stable disease (SD), said O’Reilly.¹

Another area of interest is the role KRAS mutations may play in therapies aimed in
autophagy, a cellular defense mechanism that helps promote resistance to chemotherapy.2 Investigators are pursuing autophagy inhibitors, the most well known of which is hydroxychloroquine, said O’Reilly.

In findings from a randomized phase 2 trial (NCT01506973), the addition of hydroxychloroquine to gemcitabine plus nab-paclitaxel (Abraxane) failed to improve 1-year overall survival (OS) over the chemotherapy combination alone, at 41% (95% CI, 27%-53%) versus 49% (95% CI, 35%-61%), respectively, in molecularly unselected patients with metastatic pancreatic adenocarcinoma. However, the overall response rate was 38.2% with hydroxychloroquine
(n = 55) versus 21.2% with chemotherapy alone (n = 57); all responses were PRs.²

After conducting genomic sequencing on samples from 45 participants, investigators found an imbalance between the 2 trial cohorts for KRAS mutations; all patients (n = 21; 100%) in the hydroxychloroquine arm had a mutation compared with 16 of 24 patients (66.7%) in the chemotherapyalone group. Results of an unplanned analysis showed that progression-free survival (PFS) and OS were prolonged in patients with wild-type KRAS; however, investigators
concluded the data set was too limited to draw conclusions.²

“It’s a rare subset, but an important subset, and I think we’ll be looking at ways to augment that approach with combination strategies,” said O’Reilly.

Another area of interest is autophagy inhibitors, the most well-known of which is hydroxychloroquine, said O’Reilly. In a randomized phase 2 trial, the addition of hydroxychloroquine to the combination of gemcitabine and nab-paclitaxel (Abraxane) showed a modest improvement in 1-year overall survival (OS), at 49% versus 41%, respectively. Though, response rates were higher with hydroxychloroquine.²

“We’ll have to see how this pans out with more potent inhibitors of autophagy in other contexts in pancreas cancer,” said O’Reilly.

In addition, antisense inhibition with small interfering RNA (siRNA) and Local Drug EluteR (LODER) is under evaluation as a potential way of targeting KRAS G12D. siG12D-LODER inhibitors are delivered endoscopically at the time of biopsy. Although the drugs have a slow release time of 8 to 12 weeks, the delivery device protects the small interfering RNA from degradation, said O’Reilly.

Following preclinical demonstration of efficacy, siG12D-LODER was tested in a phase 1/2a trial (NCT01188785) in combination with chemotherapy as first-line treatment for patients with inoperable locally advanced pancreatic cancer. Among 15 patients who received the therapy, 2 PRs and 10 cases of SD were reported.³

“We saw a number of partial responses and stable disease, and encouraging safety and survival signals, suggesting that this is worthy of further development,” said O’Reilly.

The drug will undergo further evaluation in a single-arm, phase 2 trial and is expected to advance to a randomized phase 3 trial, said O’Reilly.

Overall, KRAS mutations were identified in 95% of 324 pancreatic cancer tumor samples, making these alterations the most frequently observed mutations in the malignancy, according to a
molecular profiling study that O’Reilly and colleagues conducted.⁴ Of the 18 samples (5.4%) that were KRAS wild type, a number of alternative oncogenic drivers were identified as potentially targetable. These include NRG1, NTRK, ROS1, ALK, and FGFR fusions, as well as BRAF and HER2 alterations, said O’Reilly.

Providing an anecdotal example of the potential for such targeted strategies, O’Reilly shared a case of a patient with an NRG1 fusion who, after receiving standard therapy, received the heregulin pathway inhibitor zenocutuzumab (MCLA-128) and achieved a sustained response and marked reduction in CA 19-9 level.

O'Reilly noted that afatinib (Gilotrif), a pan-HER inhibitor, and other HER2/3 inhibitors are being evaluated in pancreas cancer.

PARP Inhibition

Germline testing is recommended for all patients with pancreatic cancer, and tumor and somatic testing is recommended for all patients with locally advanced or metastatic disease who are candidates for anticancer therapy, said O’Reilly.

Overall, approximately 26% of patients with pancreatic cancer have mutations for which therapies have been identified.⁵ Although the rate of actionable mutations in practice represents the minority of patients, taking the time to test these patients can lead to drastically improved survival. In a retrospective analysis, investigators found that patients who were matched with targeted therapy for their genomic alteration (n = 46) experienced a doubling in OS versus those who went unmatched, at 2.58 years versus 1.51 years, respectively (HR, 0.42; P = .0004).⁴

Moreover, data from the phase 3 POLO trial have reinforced the importance of tumor testing in practice, explained O’Reilly. In the trial, researchers evaluated the efficacy of olaparib (Lynparza) as maintenance therapy in 154 patients who had a germline BRCA1/2 mutation and metastatic pancreatic cancer, which had not progressed during first-line platinum-based chemotherapy.

Patients were randomized 3:2 to receive oral olaparib tablets at 300 mg twice daily as maintenance therapy (n = 92) versus placebo, also twice daily (n = 62).

The median progression-free survival (PFS) was 7.4 months with olaparib versus 3.8 months with placebo (HR, 0.53; 95% CI, 0.35-0.82; P = .004). After 1 year, 33.7% of patients receiving olaparib showed no signs of disease progression compared with 14.5% of those who received placebo.⁵

An interim analysis of OS at data maturity of 46% demonstrated no difference between arms, with a median OS of 18.9 months with olaparib versus 18.1 months with placebo (HR, 0.91; 95% CI, 0.56-1.46; P = .68). A final event-driven OS analysis is expected to occur in 2020 once 106 deaths have occurred out of 154 patients.

In December 2019, the FDA approved olaparib for the maintenance treatment of patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen, based on the POLO findings.⁶

A number of studies are underway, building on the proof-of-principle from the POLO study, explained O’Reilly, evaluating whether the addition of a checkpoint inhibitor to a PARP inhibitor can lead to improved outcomes following platinum-based therapy.

Metabolic Agents

Another area of exploration in pancreatic cancer involves the development of agents that target metabolic processes. Devimistat (CPI-613) is currently under investigation in the phase 3 AVENGER trial as frontline therapy for patients with metastatic pancreatic adenocarcinoma. Patients are being randomized to 500 mg/m² of devimistat plus modified FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) or standard FOLFIRINOX. The experimental drug will
be administered on days 1 and 3 of each cycle (14 days), and chemotherapy will be given to participants in both arms from day 1 to 3 of each cycle.

“The trial has completed enrollment based on an interesting signal in a phase 1b trial. [Devimistat] interferes with the tricarboxylic acid cycle and has direct antimitochondrial effect. It’s also building on FOLFIRINOX and is one of the few studies that does so with regard to novel therapeutics in pancreas cancer,” said O’Reilly.

Eryaspase is another agent that falls under the umbrella of investigational metabolic agents in pancreatic cancer, explained O’Reilly. The agentis an asparaginase inhibitor that demonstrated improvements in OS (HR, 0.60) and PFS (HR, 0.56) as second-line therapy in combination with gemcitabine or FOLFOX6.⁷

“The drug is encapsulated in red blood cells and given as an infusion,” said O’Reilly.

The therapy demonstrated statistically significant improvements in OS and PFS in combination with chemotherapy as second-line treatment of patients with advanced pancreatic adenocarcinoma in a phase 2b trial (NCT02195180). Patients were randomized 2:1 to receive either eryaspase in combination with gemcitabine or modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) or to gemcitabine or modified FOLFOX6 alone.

The experimental combination resulted in median OS of 6.0 months (95% CI, 4.8-6.6) versus 4.4 months (95% CI, 3.0-5.0), which translated into a 40% reduction in the risk of progression or death (HR, 0.60; 95% CI, 0.41-0.87; P = .008) The median PFS was 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.6 months (95% CI, 1.4-1.8) in the chemotherapy-alone group (HR, 0.56; 95% CI, 0.37-0.84; P = .005).7

In April 2020, the FDA granted a fast track designation to eryaspase for the treatment of patients with metastatic pancreatic cancer in the second-line setting. The designation is based on the ongoing phase 3 TRYBECA-1 trial (NCT03665441), which is evaluating the agent in combination with chemotherapy versus chemotherapy alone in the second-line setting.⁸

With regard to immunotherapy, pancreatic cancer is the prototypic disease for a highly immunosuppressed environment, said O’Reilly. Single-agent checkpoint inhibitors have no role to play in pancreatic cancer, apart from perhaps in patients with microsatellite instability–high or mismatch repair deficient tumors, and even combination strategies with or without chemotherapy have been unable to show a robust benefit in survival.

“We know we can reproducibly alter the microenvironment, but it remains to be seen whether that can be converted into a clinically meaningful signal,” concluded O’Reilly.

References

1. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207-1217. doi:10.1056/NEJMoa1917239
2. Karasic TB, O’Hara MH, Loaiza-Bonilla A, et al. Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5(7):993-998. doi:10.1001/jamaoncol.2019.0684
3. Golan T, Khvalevsky EZ, Hubert A, et al. RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget. 2015;6(27):24560-24570. doi:10.18632/oncotarget.4183
4. Lowery MA, Jordan EJ, Basturk O, et al. Real-time genomic profiling of pancreatic ductal adenocarcinoma: potential actionability and correlation with clinical phenotype. Clin Cancer Res. 2017;23(20):6094-6100. doi:10.1158/1078-0432.CCR-17-0899
5. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched targeted 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
6. FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma. FDA. December 30, 2019. Accessed October 27, 2020.https://bit.ly/2HFiTbs
7. Hammel P, Fabienne P, Mineur L, et al. Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: an open-label, randomized phase IIb trial. Eur J Cancer. 2020;124:91-101. doi:10.1016/j.ejca.2019.10.020
8. ERYTECH granted U.S. FDA fast track designation for eryaspase in second-line pancreatic cancer. ERYTECH. News release. April 28, 2020. Accessed October 2, 2020. https://yhoo.it/3cQ4jJp.