Eileen M. O’Reilly, MD
The Phase 3 POLO trial recently demonstrated the efficacy of the PARP inhibitor olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with metastatic pancreatic cancer and a germline BRCA mutation. What was the rationale for POLO, and does this trial have any immediate implications for clinical practice?
The importance of germline BRCA testing in pancreas cancer is underscored by the POLO study results.1 In individuals with pancreas cancer, about 6% to 7% of individuals will have a germline BRCA2 or BRCA1 mutation, and we know from breast and ovarian cancer that DNA repair strategies using platinum agents and PARP inhibitors have demonstrated activity and disease control. In the context of the randomized phase 3 POLO study, we now have proof of principle that PARP inhibition has value in the setting of pancreatic cancer.
The POLO study was designed to enroll patients with known germline BRCA mutations who were treated initially with platinum-based therapy, usually FOLFIRINOX. The patients had to have at least stable or responding disease at four months to be eligible for the randomization to olaparib versus placebo. This was a global study, with over 3,300 patients screened, and 250-plus patients were identified to have a germline BRCA mutation. A little under 150 went on to the randomized phase, as there was some attrition due to progressing disease, patients electing not to be randomized, and other reasons. But for those who were randomized, there was a statistically significant difference in progression-free survival, the primary endpoint of the study, as well as tumor response rate, for the PARP inhibitor over placebo. There were some very durable responses, and there were a number of patients continuing on olaparib at the time of data analysis, over two years from enrolment. We do see that some people can remain on the drug for a number of years, which is very striking, as we rarely see that in other contexts in the setting of pancreas cancer.
While overall survival data was not fully mature, there was no apparent difference in overall survival at the time of data analysis, which has been an important point of discussion in the field as to why that was the case, given there was a statistically significant improvement in progression-free survival. We don’t know for sure, but most patients went on to get platinum at the time of disease progression and speculatively the benefit may have been greater in the placebo over the olaparib arm due to overlapping mechanisms of resistance between platinum drugs and PARP inhibitors, and that might have accounted for why there wasn’t a survival difference.
The POLO trial has some direct implications for practice, and one of the most important points is that testing patients for germline BRCA mutations needs to be part of our standard practice. The NCCN guidelines were updated this year to endorse that point,2 and it is also in a recent ASCO position paper on genetic testing.3 Therefore, irrespective of age, ethnicity, gender, heritage, etc., we should be thinking about germline testing to identify this group of patients.
Another eagerly anticipated phase 3 trial was the APACT study. How would you characterize the results of this study of adjuvant nab-paclitaxel plus gemcitabine?
Adjuvant therapy is the standard for postoperative management of the patients with resected pancreas cancer. The historical precedent of single-agent gemcitabine has been displaced by gemcitabine and capecitabine, based on data from the ESPAC-4 randomized, phase 3 clinical trial,4 and more recently modified FOLFIRINOX, based on data from the PRODIGE group that demonstrated an unequivocal and relatively large advantage of this regimen over gemcitabine in disease-free survival and overall survival.
Both of those trials matured while the APACT study was underway. APACT was testing the hypothesis that gemcitabine and nab-paclitaxel, a regimen that we have in the metastatic setting, would be superior to gemcitabine in resected pancreas cancer. A very selected group of patients, with good performance status and a CA 19-9 less than 100 U/mL, were enrolled. The primary endpoint of the study was disease-free survival, as adjudicated by blinded independent central review. At the time the study was designed, the consensus was that independent central review would be very rigorous and remove the biases and subjectivity of progression event adjudication; this was well intended, but turned out to be not a good endpoint.
As presented at ASCO 2019,5 that primary endpoint was not met, with a with a median independently assessed DFS of 19.4 months for gemcitabine plus nab-paclitaxel and 18.8 months for gemcitabine (hazard ratio, 0.88; P = .1824). In a prespecified sensitivity analysis, disease-free survival as adjudicated by the investigator turned out to be significant, at a median of 16.6 months and 13.7 months for those respective arms (HR, 0.82; nominal P = .0168); that is real-world practice, such that the treating physician had access to the CA 19-9 information, access to the imaging, and of course, access to the person, and that clearly gives a more comprehensive assessment of disease status.
Overall survival data are still maturing, but median investigator-assessed overall survival were nevertheless significantly longer in the gemcitabine/nab-paclitaxel arm at the time of the analysis presented as ASCO. Thus, the current standards in the adjuvant setting, in my opinion, remain modified FOLFIRINOX for a fit, healthy group of patients, gemcitabine and capecitabine as an alternative, and perhaps gemcitabine on its own for the less vigorous or older patient. I think right now, we cannot say that there’s a clear role for gemcitabine and nab-paclitaxel in the adjuvant setting, although it’s possible that the survival data over time could inform whether that perspective changes.
Moving back to the metastatic setting, there was recently an updated report that nanoliposomal irinotecan had promising activity as a frontline treatment. Could you describe the results and current status of these investigations?
The combination of a nanoliposomal formulation of irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) has been a standard option for patients with metastatic pancreatic cancer who have previously been exposed to gemcitabine. That is based in part on results of the randomized, phase 3 NAPOLI-1 trial, which demonstrated that the combination of nal-IRI plus 5-FU/LV significantly prolonged overall survival versus 5-FU/LV alone.6
More recently, the combination of nal-IRI, 5-FU/LV, and oxaliplatin (NAPOX) has been evaluated as a first-line treatment of patients with metastatic pancreatic cancer in a phase 1/2, open-label trial. The NAPOX regimen is designed to build on what we know about FOLFIRINOX and to position nanoliposomal irinotecan in the frontline, untreated pancreas cancer setting. The pharmacokinetics behind the nanoparticle-bound formulation of irinotecan are interesting, in that there is more active drug specifically at the tumor site, so at least theoretically, there could be less toxicity. We do know that nanoparticle formulations in general have a value in pancreas cancer, the other example being nab-paclitaxel, which is FDA approved with gemcitabine and is a nanoparticle formulation of a taxane.
Updated data on first-line NAPOX, just recently presented at the ESMO GI meeting in the summer of 2019, demonstrate that this regimen appears to have had manageable toxicity and promising anti-tumor activity among the 56 patients enrolled and treated in the phase 1/2 study.7 The disease control rate was 72% at 16 weeks, which gives us a sense of how many patients were able to stay on therapy and that the overall cancer control was at a landmark timepoint. The major toxicities were, as you might expect with this combination, mainly GI considerations, and also hematologic, in terms of myelosuppression and neutropenia. According to investigators, those results warrant further clinical assessment. A decision has recently been made that a phase 3 trial evaluating this regimen will now proceed.
Some recent reports have suggested that a PEGPH20 may represent a new approach for treating pancreatic tumors. What’s different about this approach, and how it might work in the pancreatic cancer setting?
PEGPH20 is a PEGylated form of a recombinant human hyaluronidase. Many people may be aware that hyaluronic acid injection has been used for a long period of time to treat joint conditions. The rationale for using PEGPH20 in pancreas cancer is that this tumor has a complex stromal microenvironment that is composed of a lot of hyaluronan, among a lot of other components. PEGylated hyaluronidase has been shown to modulate the physiology of the microenvironment, altering the vasculature and the vascular dynamics and to facilitate blood flow into the tumor, deplete hyaluronan and enhance drug delivery to the tumor. These observations have been shown preclinically in a number of very elegant experiments that supported testing this approach clinically.
Namely, a randomized phase 2 study called HALO-202 was conducted to evaluate PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) versus AG in patients with untreated, metastatic pancreatic ductal adenocarcinoma. Results of HALO-202, presented at a previous ASCO meeting and recently published, showed that the PAG regimen improved progression-free survival overall, as well as in “HA-high” patients, or those with high levels of hyaluronan expression. Initially, increased thromboembolic events had been observed in the PAG arm, but the study protocol was amended to include screening for baseline thromboembolic events and enoxaparin thromboprophylaxis, and investigators reported that these modifications decreased thromboembolic events.8
Those data supported the recently completed, phase 3 trial known as HALO-301,9 which enrolled approximately 500 patients with stage IV, previously untreated pancreatic ductal adenocarcinoma, all of whom were HA-high. It’s nice to see another biomarker-selected population—as we previously discussed, the POLO study provides proof-of-principle of a biomarker-directed strategy, and HALO-301 could be a second example, if it ultimately reads out to be positive. So HALO-301 will be an important study, and we’re hoping to see data on this before the end of 2019.
Thank you very much for your comments. One final question as we close: are there any new developments of note with regard to immunotherapy in pancreatic cancer?
There has been huge interest in seeing how immunotherapies may be applied to pancreas cancer. Some older data looking at single-agent immune checkpoint inhibitors have shown a very small number of responses in a tiny subset of patients, including in the 1% to 2% of individuals with pancreas cancer and mismatch repair deficiency. There are a number of combination checkpoint inhibitor studies, including a phase 2 randomized clinical trial that we were involved in, recently published in JAMA Oncology,10 looking at durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma; the treatment was well tolerated, but the threshold for efficacy was not met with very low response responses and short progression-free survival.
So it’s become pretty clear that for pancreas cancer in general, neither one nor two checkpoint inhibitors is sufficient for the vast majority of patients. The field has moved beyond that to see what are other ways that we can integrate immune therapy in pancreas cancer. A strategy that I think is showing some preliminary promise is combining immunotherapy with chemotherapy, and an example of this was a phase 1b study, presented at the most recent AACR 2019 meeting, demonstrating that a CD40 agonistic monoclonal antibody, APX005M together with gemcitabine and nab-paclitaxel, with or without nivolumab, had a manageable safety profile and promising antitumor activity in patients with previously untreated metastatic ductal pancreatic adenocarcinoma.11
We are waiting for these latter data to mature to see whether that approach can be positioned in a frontline space. Meanwhile, a number of other platform studies evaluating immunotherapy combinations or chemoimmunotherapy in a second-line setting. I anticipate that over the next 6 to 12 months, we’re going to see some early reports that will be very helpful to provide a benchmark reference for how these approaches measure up.
- Kindler HL, Hammel P, Reni M, et al. Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial. J Clin Oncol. 2019;37(18_suppl):LBA4-LBA4. doi:10.1200/JCO.2019.37.18_suppl.LBA4
- NCCN Clinical Practice Guidelines in Oncology. Pancreatic Adenocarcinoma. Version 2.2019. April 2019. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed July 3, 2019.
- Stoffel EM, McKernin SE, Brand R, et al. Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol Off J Am Soc Clin Oncol. 2019;37(2):153-164. doi:10.1200/JCO.18.01489
- Neoptolemos JP, Palmer DH, Ghaneh P, 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. The Lancet. 2017;389(10073):1011-1024. doi:10.1016/S0140-6736(16)32409-6
- Tempero MA, Reni M, Riess H, et al. APACT: phase III, multicenter, international, open-label, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma. J Clin Oncol. 2019;37(15_suppl):4000-4000. doi:10.1200/JCO.2019.37.15_suppl.4000
- Wang-Gillam A, Li C-P, Bodoky 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 Lond Engl. 2016;387(10018):545-557. doi:10.1016/S0140-6736(15)00986-1
- Wainberg Z, Boland P, Lieu C, et al. A phase 1/2, open-label, dose-expansion study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2019;30(Supplement_4). doi:10.1093/annonc/mdz157.004
- Hingorani SR, Bullock AJ, Seery TE, et al. Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA). J Clin Oncol. 2017;35(15_suppl):4008-4008. doi:10.1200/JCO.2017.35.15_suppl.4008
- A Study of PEGylated Recombinant Human Hyaluronidase in Combination With Nab-Paclitaxel Plus Gemcitabine Compared With Placebo Plus Nab-Paclitaxel and Gemcitabine in Participants With Hyaluronan-High Stage IV Previously Untreated Pancreatic Ductal Adenocarcinoma. https://clinicaltrials.gov/ct2/show/NCT02715804. Accessed August 21, 2019.
- O’Reilly EM, Oh D-Y, Dhani N, et al. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. July 2019. doi:10.1001/jamaoncol.2019.1588
- O’Hara MH, O’Reilly EM, Rosemarie M, et al. A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients. Cancer Res. 2019;79(13 Supplement):CT004-CT004. doi:10.1158/1538-7445.SABCS18-CT004
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