Ongoing Research in Pancreatic Cancer Focusing on Molecular Targets

Eileen M. O’Reilly, MD

Explorative therapeutic strategies for patients with pancreatic cancer continue to move through the clinical trial pipeline, comprising targeted therapy, stromal modulation, and metabolic agents, with the niche for immunotherapy still being debated, explained Eileen M. O’Reilly, MD.

A way to move these strategies further along is through the use of genomic testing, as well as enrolling patients on innovative studies, she added.

“A key point is to think about germline testing for all patients, think about somatic profiling, and identify the infrequent groups of individuals with mutations for which there are targeted agents in trials, or are potentially accessible,” said O’Reilly, the associate director for Clinical Research in the David M. Rubenstein Center for Pancreatic Cancer Research and the Winthrop Rockefeller chair of Medical Oncology at Memorial Sloan Kettering Cancer Center. “Clinical trials are a key theme and we always want to emphasize that approach. That is how we learn, and how we also learn if something doesn't work sooner rather than later.”

For example, in patients with germline BRCA-positive metastatic pancreatic cancer, results from the phase III POLO trial showed that maintenance therapy with olaparib (Lynparza) led to a median progression-free survival (PFS) of 7.4 months compared with 3.8 months for placebo (HR, 0.53; 95% CI, 0.35-0.82; P = .0038).¹ At an interim analysis, there was not a statistically significant difference in overall survival (OS) between arms at 18.9 months versus 18.1 months for olaparib and placebo, respectively.

Health-related quality of life (HRQoL) data of the POLO trial, which were presented during the 2019 ESMO Congress, showed that HRQoL was preserved with maintenance olaparib and was not found to have meaningful differences compared with placebo, supporting the clinical benefit with the PARP inhibitor in this patient population.² An additional POLO analysis showed that patients on the olaparib arm were on treatment significantly longer than with placebo (7.2 vs 3.8 months, respectively), and that initiation of subsequent therapy was delayed longer in patients on the olaparib arm than on placebo (8.6 months vs 5.7 months, respectively).³

In an interview with OncLive during the 2019 ESMO Congress, O’Reilly discussed emerging strategies in pancreatic cancer.

OncLive: What is the current state of locally advanced pancreatic cancer treatment?

O’Reilly: The two commonly used neoadjuvant regimens are modified FOLFIRINOX or gemcitabine/nab-paclitaxel (Abraxane). Both have been studied in the locally advanced setting. The NEOLAP study, was a randomized study in about 33 centers in Germany that looked at 2 cycles of initial gemcitabine/nab-paclitaxel. Patients were randomized to either continue gemcitabine/nab-paclitaxel or switch to modified FOLFIRINOX. The study looked at a variety of outcomes, including the number of patients who went to surgery, survival outcomes, safety, and toxicity. Both of these regimens were active—no question. The patients who underwent surgery had the best outcomes. You have to be careful with the comparisons, but the modified FOLFIRINOX probably had the edge in terms of survival outcomes.

What novel therapeutic strategies are emerging?

There are a lot of things in development in advanced pancreas cancer. The big themes would be DNA repair, stromal modulation, metabolism, and immunotherapy, where it fits. We have examples of positive studies in the DNA repair setting [of patients with] germline BRCA mutations.

As part of the POLO study, there was the option to be randomized to either olaparib or placebo. That was a positive trial in terms of its primary endpoint of PFS; there were also higher response rates on the olaparib arm with some very durable responses. That establishes the precedent that selected genomic targeting in pancreas cancer can work. For a subset, we now need to amplify that signal and extend it to a broader population.

With regard to stromal modulation, a number of drugs have been developed. The current big one is PEGPH20, which has been looked with chemotherapy in advanced pancreas cancer. We will hopefully have data in the very near future to comment on that strategy.

Metabolism is an emerging theme. We don't have late-stage study results yet, but a couple of examples would be asparaginase, which has been developed primarily in Europe; it's a compound that's covered in red blood cells and delivered in combination with chemotherapy. Randomized phase II [data] presented at the 2018 ESMO Congress was positive, and that is now in phase III development.

CPI-613, another metabolic agent, is being evaluated in combination with modified FOLFIRINOX in patients with untreated advanced pancreas cancer. We're still looking to see if immunotherapy [is effective in pancreas cancer].

What other specific studies would you like to highlight?

There was a follow-up on the POLO data with regard to post-treatment therapies, and how that might have impacted the neutral survival signal. Some quality-of-life data (QoL) from the same study were also presented.

There was some additional follow-up on the APACT trial, which compared gemcitabine/nab-paclitaxel with gemcitabine alone in the adjuvant setting. This was negative in terms of the primary endpoint of blinded independent central review disease-free survival, but it trended in terms of survival for the combination. We'll see how that pans out.

[There is also some research] in pancreas cancer looking at where the field is going in terms of genomic-based treatments. It's exciting to think that we might be able to begin selecting treatments for a broader group of people

Could you expand on the QoL data from the POLO study?

The QoL data from POLO showed that both arms were well tolerated. One has to keep in mind that the QoL levels for people entering the study was high in both arms, which is quite good. The PARP inhibitor was overall relatively well tolerated with some anemia, fatigue, and gastrointestinal toxicity. After a certain point, there was not an adequate number of patients to be able to evaluate sequential data. It's a little hard to interpret, but it resonates with what we see.

When pancreas cancer is well controlled, as it was on both arms entering the randomization phase, the acute symptoms of the disease are much improved for most patients; that QoL is relatively good. It's a little bit of a surprise that there wasn't [more of a] difference between [olaparib and] placebo; these are relatively small numbers. We have to keep an open mind.

[The follow-up data] are not that much longer because the initial data were presented this summer. However, it showed some additional analyses on the adjuvant setting, just underscoring that the primary endpoint was negative, but that there may be a signal in terms of overall survival. We will probably have a final data cut on this sometime in the near future, which will significantly update the analysis that was presented at the 2019 ASCO Annual Meeting.

What other targets are being investigated in this space?

[There is progress with] stromal modulation DNA repair and extending that [practice] to broader groups of people, meaning people with other homologous repair gene mutation. Does the signal with olaparib apply if you have PALB2, somatic BRCA, ATM, mcm5-bob1, or NBN mutations? A lot of these are very rare.

Can we combine a PARP inhibitor with other agents? We saw some very nice data in ovarian cancer of bevacizumab (Avastin) combined with a PARP inhibitor that was pretty interesting. We have our eyes on that in terms of thinking how that could apply to the pancreas world. We need to keep in mind that VEGF-targeted strategies have not, for the most part, shown value in pancreas cancer. It's an angiogenic-driven tumor, to a degree. We have to see, but it will certainly be worth thinking about developing a number of trials in this area.

Immunotherapy did not have new data [at the 2019 ESMO Congress], but that is a topical theme in pancreas cancer. We know that single agent checkpoint inhibitors aren't sufficient in this disease; neither do combination checkpoint inhibitors. We are waiting to see whether combinations of chemotherapy and immunotherapy, which are being evaluated in the frontline and second-line settings, should mature out over the next year. Other immune-modulating agents, such as CD40-directed agents, is an interesting drug that modulates the microenvironment and may make it more immune responsive. If that strategy works, that will be very important in pancreas cancer.

References

1. 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, abstr LBA4). doi: 10.1200/JCO.2019.37.18_suppl.LBA4.
2. Hammel P, Kindler HL, Reni M, et al. Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib. Ann Oncol. 2019;30 (suppl_5):v253-v324. doi: 10.1093/annonc/mdz247.
3. Van Cutsem E, Golan T, Hammel P, et al. POLO: Time to treatment discontinuation and subsequent therapies following maintenance olaparib for patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC). Ann Oncol. 2019;30(suppl_5): mdz247.020. doi: 10.1093/annonc/mdz247.020.