Nihilism Remains a Barrier to Effective Treatment Delivery in Pancreatic Cancer

Jonathan Mizrahi, MD

The standard of care for pancreatic cancer has not changed drastically in recent years, although more is known about optimal treatment sequencing. However, the nihilism associated with the disease has prevented some patients from seeking treatment that could prolong survival and improve quality of life, according to Jonathan Mizrahi, MD.

“Combating nihilism in pancreatic cancer [is a vital issue]. For patients who are diagnosed with pancreatic cancer, have them evaluated by someone who knows how to treat pancreatic cancer and understands what benefits [each] therapy can offer them, particularly in the stage IV setting,” Mizrahi said in an interview with OncLive® following a State of the Science Summit™ on gastrointestinal (GI) malignancies.

In the interview, Mizrahi, the chair of the meeting and a medical oncologist at Ochsner Cancer Institute, discussed updates from the meeting in pancreatic cancer and hepatocellular carcinoma (HCC), the growing role of immunotherapy in GI cancer, and the ‘watch and wait’ protocol seen in rectal cancer.

OncLive^®: How can nihilism associated with pancreatic cancer be addressed to ensure patients receive potentially beneficial treatment?

Mizrahi: Nihilism is an important concept to combat in pancreatic cancer. A lot of it starts with patient education and provider education. It matters what provider a patient sees first, and this is documented by retrospective database studies. If a patient sees a medical oncologist first, they’re more likely to receive systemic therapy that can be life-prolonging. [However], if a patient sees a surgeon first, they’re less likely to get chemotherapy, [although] most of them will. Moreover, some patients don’t make it to a surgeon or a medical oncologist, and those are the patients who we are missing out [on treating].

In the primary care community, perhaps in the lay community, people talk to friends and family, and they hear pancreatic cancer [and say], ‘Well, there’s nothing we can do about it.’ That nihilism is something [clinicians] should be aware of so that we can do a better job of promoting that we have treatments that can not only prolong [a patient’s] life but make them feel better. The first indication for chemotherapy for pancreatic cancer was that it made a patient’s quality of life better and reduced symptoms. Not only can we prolong patients’ lives, but we can potentially reduce their symptoms [as well]. We have some tools that can achieve that, so [addressing nihilism] is an incredibly important point.

Could you expand on the implications of the phase 3 NAPOLI-1 trial (NCT01494506) in metastatic pancreatic cancer?

The NAPOLI-1 study is the only second-line study we have in terms of [large] phase 3 studies looking at pretreated patients with pancreatic cancer. This trial took patients who had prior first-line gemcitabine-based chemotherapy and randomized them to 1 of 3 arms. Ultimately, what was observed is 5-fluorouracil [5-FU] plus nanoliposomal irinotecan was superior to 5-FU alone and to nanoliposomal irinotecan alone. That [combination] has become the de facto standard of care for patients in need of second-line chemotherapy [because it led to] prolongation of overall survival [OS] and progression-free survival in that population.

If you have a patient who starts on gemcitabine and nab-paclitaxel [Abraxane], which is a reasonable and appropriate option for a lot of patients, then an appropriate second-line treatment, [per the] National Comprehensive Cancer Network guidelines’ category 1 recommendation based on the NAPOLI-1 study, would be 5-FU and nanoliposomal irinotecan.

What molecular alterations should be tested for and why?

The special populations in pancreatic cancer are ones that need to be searched for. [These patients] are special because we don’t see them very often, but when we do, we do have agents that can be helpful for them. In about 1% or less of patients, we see microsatellite instability–high [MSI-H] or mismatch repair–deficient [dMMR] proteins. For those patients, pembrolizumab [Keytruda] is effective.

[Another special population] is patients who have a TRK fusion. These patients can benefit from NTRK inhibitors, and this fusion is found in about 1% of patients.

[Among] recent studies that we’ve seen, 1 that came out at the 2022 Gastrointestinal Cancers Symposium [ASCO GI] and an ASCO plenary session [involved] patients with certain KRAS mutations. KRAS is a mutation that is found in virtually all patients with pancreatic cancer, and a subset have a KRAS G12C mutation. Some of these KRAS G12C inhibitors can be effective in this population. We’ve seen data on adagrasib and sotorasib [Lumakras]. Both agents seem to have some efficacy in this population [as single agents].

The problem is how infrequently we see these mutations. About 1% of all KRAS mutations seen in the pancreatic cancer population [are KRAS G12C mutations]. However, if we don’t look, we’re not going to find them. If we’re sequencing patients and finding out they have a KRAS mutation, which most of them will, [we must find out] what their [specific] mutation is and possibly enroll them on a clinical trial, or try to get an off-label treatment with KRAS inhibitors. This is an important option for patients who don’t have many good options after standard chemotherapy.

What ongoing clinical trials are exploring immunotherapy in pancreatic cancer?

Immunotherapy has been a tough nut to crack with pancreatic cancer. Single-agent PD-1/PD-L1 and CTLA-4 checkpoint inhibitors have not been effective in pancreatic cancer. Combinations of checkpoint inhibitors with chemotherapy have been the next avenue of research. [However], these have not proven to be successful in improving survival in the first-line setting. We saw an example of this at ASGO GI with sintilimab in combination with chemotherapy. Although response rates were improved with the combination of this PD-1 inhibitor and FOLFIRINOX [folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin], the survival was not improved. As a first-line combination, this did not seem to be effective.

As single agents or in combination, we’ve seen data with PD-1 and CTLA-4 [inhibitors] in unselected patients with pancreatic cancer, and that strategy doesn’t seem to be effective either.

The reasons [why immunotherapy has been ineffective in pancreatic cancer] are complicated, but a lot of it has to do with the fact that the immune microenvironment for pancreatic cancer is very immune suppressive. It has a large amount of dense fibrotic stroma and a number of immune cells that are creating an environment that is not conducive to CD8 or CD4 cells infiltrating the tumors to provide that immune [activity]. That is one of the reasons that we don’t see immunotherapy working that well in pancreatic cancer.

[Immunotherapy] will still be studied in combination with other drugs and other checkpoints. Combining immunotherapy with other targeted agents in the immune microenvironment continues to be an ongoing area of research. But it’s been a challenge in the pancreatic cancer field and hopefully one that we’ll soon learn how to overcome.

What are some of the areas that need to be addressed in terms of future clinical trials in pancreatic cancer?

There are a few different areas that are going to be the short-term focus of advancing [treatment for] pancreatic cancer. One is getting answers from the phase 3 NAPOLI-3 study [NCT04083235], as to what the optimal first-line chemotherapy regimen is for patients with metastatic pancreatic cancer. That study is looking at gemcitabine and nab-paclitaxel, an approved standard first-line chemotherapy option vs NALIRIFOX, or liposomal irinotecan plus 5-FU/leucovorin, and oxaliplatin. This is like a modified FOLFIRINOX regimen but using nanoliposomal irinotecan instead of irinotecan. [NAPOLI-3] might give us an answer as to which of these regimens is superior in the first-line setting.

Another cooperative group study that’s being done is [the phase 3 ALLIANCE A021806 trial (NCT04340141)] evaluating the optimal sequence of treatment in patients with resectable pancreatic cancer. A more [frequently] used approach is putting patients on neoadjuvant chemotherapy, moving them to surgery, and finishing up chemotherapy, rather than doing up-front resection followed by 6 months of chemotherapy. But that’s never been tested in any prospective phase 3 studies, and that’s something that’s being done the ALLIANCE study: looking at FOLFIRINOX and its optimal sequencing.

Beyond that, expanding our repertoire of targeted therapies [is important]. More patients are getting sequenced, and the recognition that these patients should be genomically and molecularly sequenced [has increased]. We will be seeing more targets and hopefully more drugs will come out. We’ll see more research and excitement around other targets to hit. That could be KRAS G12D, which is a target that’s been elusive. If we made breakthroughs in that arena, we would see an important benefit for these patients who need more treatments.

Nathan Bolton, MD, of Ochsner Cancer Institute, discussed the optimal management of localized pancreatic cancer. How does resectability affect treatment decisions for these patients?

Whether a patient’s cancer is resectable needs to be determined in a multidisciplinary manner. A patient will have their pancreatic protocol CT scan, which will evaluate the vascular anatomy well and its relationship to the tumor. Sometimes an endoscopic ultrasound can also be helpful in looking at the vasculature and its relationship to the tumor. Then, a conversation should occur between radiology, surgery, medical oncology, and perhaps radiation oncology, to determine a sequence of therapy.

We have different criteria to determine whether a patient’s tumor is resectable, borderline resectable, or locally advanced, and we should be utilizing that multidisciplinary discussion to determine the optimal therapeutic sequence.

The role of radiation is a controversial one in resectable and borderline resectable pancreatic cancer, but we know that those patients need chemotherapy regardless. The ALLIANCE A021806 study will help us figure out the optimal sequence of chemotherapy. Is better to do it up front, followed by surgery and more chemotherapy? Or should we do surgery followed by chemotherapy? A lot of institutions are moving toward doing neoadjuvant chemotherapy for a variety of reasons. Whether that truly improves OS is a question that we’ll hopefully have the answer to soon.

Suma Reddy-Satti, MD, of Ochsner Cancer Institute, discussed HCC. How has the treatment landscape within this disease evolved in recent years?

The treatment landscape in HCC has evolved dramatically. Four or 5 years ago, there was 1 agent on the market for first-line treatment of HCC: sorafenib [Nexavar]. Now, you are hard pressed to find many people who use sorafenib in the first-line setting.

Lenvatinib [Lenvima] was shown to be noninferior to sorafenib a few years ago. More recently, we saw data from the phase 3 IMbrave150 trial [NCT03434379] with the combination of immunotherapy and VEGF inhibition with bevacizumab [Avastin] and atezolizumab [Tecentriq]. That [combination] proved to be a game changer in terms of OS advantage compared with sorafenib.

Most recently, we have data from the phase 3 HIMALAYA trial [NCT03298451], looking at tremelimumab plus regular interval durvalumab [Imfinzi; the STRIDE regimen]. That regimen is a combination of a PD-L1 inhibitor and a CTLA-4 inhibitor. That would be a VEGF inhibitor–free combination, purely immunotherapy. It offers another potential first-line treatment that we did not have just a few years ago. Not only do we have more options, but these options seem to be better than what we had just 4 or 5 years ago.

Lingling Du, MD, of Ochsner Cancer Institute, discussed the role of immunotherapy in gastroesophageal cancer. What have nivolumab (Opdivo)-based combinations demonstrated in these patients?

It’s been exciting to see immunotherapy make its way into gastroesophageal cancers. We have seen that with both pembrolizumab and nivolumab. [For example], we saw in the phase 3 CheckMate649 trial [NCT02872116] that the addition of nivolumab to chemotherapy improved patient survival vs chemotherapy alone. That was in all-comers, but we also saw that in patients who had a higher PD-L1 combined positive score [CPS], in particular a PD-L1 CPS greater than 5. High PD-L1 CPS conferred better benefit than lower PD-L1 scores. There is some controversy around whether patients should get [nivolumab plus chemotherapy] regardless of whether they have PD-L1–positive tumors or whether they should only receive it in the case of having a PD-L1–positive tumor. But nivolumab has proved to be a significant game changer for these patients.

This is also the case in the adjuvant setting. In the adjuvant setting for patients with esophageal cancer who had their chemoradiation according to the CROSS regimen [carboplatin and paclitaxel with concurrent radiotherapy], followed by surgery if they have residual disease, we know that according to the phase 3 Checkmate-577 trial [NCT02743494], the addition of nivolumab in the adjuvant setting for up to 1 year improved patients’ disease-free survival from 11 months to 22 months. Whether all patients or just patients who are PD-L1 positive are benefiting from that regimen is still up for discussion, but it looked like there was a signal in the PD-L1–negative group.

Nivolumab, pembrolizumab, and all checkpoint inhibition has been a game changer in what we’re able to offer patients with gastroesophageal cancers.

William Forrest Johnston, MD, of Ochsner Cancer Institute, discussed the ‘watch and wait’ protocol for rectal cancer. What does this protocol entail?

The paradigm of rectal cancer has evolved quite a bit. The sequencing of chemotherapy, radiation, and surgery has gone through all different permutations, and a lot of institutions, including Ochsner Cancer Institute, have moved toward the concept of total neoadjuvant therapy. That is where we are giving chemotherapy and radiation up front for localized rectal cancer, potentially followed by surgery. Surgery is the last step in that process.

When you [discuss the sequence of] radiation vs chemotherapy, people can have disagreements. At our institution, we’re primarily doing radiation first, whether that’s short-course radiation or traditional long-course chemoradiation over 5 weeks, and this depends on some patient variables. But for patients who have their full total neoadjuvant therapy, we then check the response to that treatment.

There is a subset of patients, anywhere from one-quarter to one-third or even higher, who can have a complete clinical response, meaning on their imaging, endoscopically, or on a digital rectal exam, we’re not seeing, feeling, or detecting any evidence of residual cancer. Based on database studies that have looked at patients who have gone through this watch and wait program, some of those patients can avoid surgery altogether and have just as good of an outcome.

That doesn’t mean we don’t do surgery [and stop managing the patient’s disease]. There’s a very close management surveillance protocol for these patients, which involves intensive imaging and endoscopic surveillance to ensure there’s no recurrence. For most patients, if they do recur, they recur locally and you can then proceed with surgery. The minority of patients, if they recur, will recur distantly, and one could argue that they would recur distantly regardless of whether they received the surgery.

There are patients who we think can be cured from this cancer without having to undergo surgery. For a lot of patients, that’s a good, viable option for them. Obviously, the long-term outcomes on this are still being gathered, but this seems to be a promising option for a number of patients and one that we’re already utilizing.

How would you evaluate the current state of the treatment of GI cancers?

The management of GI cancers has gotten very complex in a good way. Our options are not only changing but improving. We’re seeing the upper GI space move with the addition of immunotherapy. In pancreatic cancer, although our therapies have not changed dramatically, how we sequence them has. I can’t understate the value of having an experienced surgeon and someone who does a high volume of pancreatic surgeries [treat these patients].

As far as colorectal and liver cancer, multidisciplinary care is important, experience is important, and going to high volume centers that see a lot of these cancers and can offer the best management is crucial. Things have gotten complex in a good way, and having the experience in multidisciplinary care is invaluable.