Kundranda Covers Key Trials Generating Excitement in Pancreatic Cancer Paradigm

Although the pancreatic cancer treatment paradigm has suffered from a period of stagnation, several ongoing research efforts are being made to improve outcomes for patients, according to Madappa Kundranda, MD, PhD, who added that trials like NAPOLI-3 and AVENGER 500 are generating excitement in the space.

“When I reflect on the pancreatic cancer treatment landscape, it has been a bit disappointing, but we have worked through these disappointments, ever since 1997 when we didn't have a standard of care,” said Kundranda. “That was when we [only] had gemcitabine, a single agent. Since then, through many trials, we've slowly but surely, improved survival and the quality of life for our patients.”

Updated data from the phase 1/2 NAPOLI-3 trial of liposomal irinotecan plus 5-florouracil (5-FU)/leucovorin plus oxaliplatin (NALIRIFOX) presented during the 2020 ESMO World Congress on Gastrointestinal Cancer demonstrated a tolerable safety profile with promising antitumor activity when used as a first-line treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.

Additionally, other notable research being done in the space is in the multicenter, open-label, phase 3 AVENGER 500 trial, in which investigators areevaluating the efficacy and safety of devimistat (CPI-613) in combination with modified FOLFIRINOX as a first-line treatment for patients with metastatic adenocarcinoma of the pancreas, according to Kundranda. “This is certainly one of those studies that will be eagerly awaited,” he said.

In an interview with OncLive during the virtual 2020 International Perspectives in Cancer on Gastrointestinal Cancer, Kundranda, thedirector of the Gastrointestinal Oncology Program and the deputy chief of the Division of Medical Oncology at Banner Health MD Anderson Cancer Center in Gilbert, Arizona, discussed the significance of the NAPOLI-1 and NAPOLI-3 trials in pancreatic cancer, other exciting research efforts that are ongoing, and key challenges still faced in the space.

OncLive: Could you shed light on the pivotal NAPOLI-1 trial and the ongoing NAPOLI-3 trial?

Kundranda: Liposomal irinotecan is an interesting compound. The first time we evaluated this agent was in the refractory space with patients who had been exposed toa gemcitabine-based regimen. In this global phase 3 NAPOLI-1 study, there were 3 arms. Two arms were initially initiated and 1 was comparing [the agent] to the [standard in the] refractory setting which, way back then, was single-agent 5-FU or nanoliposomal irinotecan. Midway through the study we realized that it made sense to add a third treatment arm examining the combination of 5-FU/LV and liposomal irinotecan.

Clearly, when we looked at the responses between the single agents, whether it’s 5-FU or liposomal irinotecan, they were very comparable. However, when we looked at the responses between the combination versus the single agent, mainly the 5-FU, we saw an improvement in both overall survival (OS) and disease-free survival. The OS landed about 6.1 months with the combination of 5-FU/leucovorin and liposomal irinotecan.

The next obvious question was whether we could move this to the up-front space of substituting the irinotecan in the FOLFIRINOX regimen, which is a regimen from the PRODIGE study, with liposomal irinotecan to see whether that would improve survival. Results from the phase 1/2 study, which was recently presented at ESMO World Congress on Gastrointestinal Cancer, clearly demonstrated [antitumor activity and a manageable toxicity profile]. It was a small study, where the primary end point was to determine the safety and efficacy [of NALIRIFOX] compared with nab-paclitaxel (Abraxane) plus gemcitabine, which is still one of the standards of care based on MPACT study. The secondary end points [of the trial] included survival and response rates.

[The regimen] didn’t [result in] the grade 3 toxicities that we [usually see with the FOLFIRINOX] combination. Neither did the regimen lead to a higher degree of fatigue or peripheral neuropathy. The grade 3 toxicities that we did see, which were reported in approximately two-thirds of patients, [were in line with what] we commonly see: hematological, electrolyte, and gastrointestinal toxicities. When we examined survival, interestingly, the median OS was about 12.6 months [with the regimen]. We don’t like to make cross-trial comparisons, but when we look at the PRODIGE trial with modified FOLFIRINOX, [this number] falls in that same realm [of efficacy]. However, as we know with phase 1 and phase 2 [trials], the survival rates could be a lot higher [in these earlier phases of research], but then when we run a randomized phase 3 trial, they [could drop].

[That being said], 12.6 months is certainly a promising a number to work with. [We saw] a median progression-free survival of about 9.2 months, as well. That's what led to the FDA’s decision to grant a fast track designation to NALIRIFOX for the frontline treatment of patients with metastatic pancreatic adenocarcinoma. This trial, NAPOLI-3, is ongoing.

Another phase 3 study (NCT03504423) is evaluating devimistat (CPI-613)plus modified FOLFIRINOX compared to standard FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma. Could you speak to this trial?

Devimistat isa very interesting agent because it targets the TCA cycle and the entry of the carbon molecules. One of the things that we realized with metastatic pancreatic cancer and other cancers is that, targeting the mitochondria is certainly a good way to achieve better disease control and eventually improved survival.

The AVENGER 500 study, which is based on an initial phase 1/2 study, demonstrated promise with regard to this [approach]. In the study, [patients were] randomized to receive either modified FOLFIRINOX or modified FOLFIRINOX with devimistat.

Although eagerly awaited, the concern with this trial is that the standard arm certainly can have more toxicities that we've seen within the US patient population. It’s certainly something to look forward to with regard to dose reductions, which might skew the data one way or another.

What are the key challenges faced in this space?

With regard to pancreatic cancer, we’ve had a whole slew of over 30 negative phase 3 trials that had been done in the metastatic setting, which certainly is disappointing for many of us. However, what's truly encouraging is the fact that this space has looked at [so many approaches]. Whether you're looking at it from an immunotherapy standpoint, a chemotherapy standpoint, whether you're looking at the microbiome or you're looking at epigenetic changes, [one thing is clear]. We are in a situation of weakness to a certain extent because this is not one of those tumors that are easily targetable other than the tumors that harbor mutations like BRCA, which are only account for approximately 5% of the overall patient population.

Nevertheless, it provides us with an opportunity to push the bar to [achieve that success seen in] breast cancer, or [with] immuno-oncology in lung cancer, which has seen that tremendous change, or even in melanoma. Looking at all these aspects makes a huge difference and this is where I believe the ground is fertile for additional research.

Where should future research efforts be focused?

With regard to clinical trials, I truly believe that patients, whether they’re being treated in the first-, second-, or the third-line setting, with all tumor types, but specifically pancreatic ductal adenocarcinomas, the standard of care just isn't enough. As such, any patient should be offered a clinical trial in any of these settings, especially those who have a good performance status.

Several trials are ongoing. In addition to the NAPOLI and AVENGER trials, but also we saw data presented during the 2020 ASCO Virtual Scientific Program which looked at FOLFIRINOX versus gemcitabine plus nab-paclitaxel as neoadjuvant treatment in patients who are resectable and borderline resectable. [Those results] suggested that a triplet regimen might not be better than a doublet. At this point, in selective patients, we certainly need to look at options wherein this might be more effective. One trial is looking at gemcitabine and nab-paclitaxel on a bi-weekly schedule in the elderly patient population. In these patients, even the standard regimen has been poorly tolerated. Certainly, these are things we need to look at. We need to continue to look at the genomic sequencing in all of these patients to try to find targetable mutations that we can address.