Tanios S. Bekaii-Saab, MD.
Frontline chemotherapy selection in metastatic pancreatic cancer and the integration of targeted agents into the first-line treatment of metastatic colorectal cancer (mCRC) have prompted the evolution of more personalized approaches, according to Tanios Bekaii-Saab, MD.
In the second part of an interview with OncLive®, Bekaii-Saab reviewed the implications of the phase 3 NAPOLI-3 trial (NCT04083235) and the interation of liposomal irinotecan (Onivyde), leucovorin, fluorouracil, and oxaliplatin (NALIRIFOX) into the frontline treatment paradigm alongside other chemotherapy regimens, including gemcitabine plus nab-paclitaxel (Abraxane) and FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin). He compared the efficacy, tolerability, and real-world adoption of NALIRIFOX with FOLFIRINOX and gemcitabine/nab-paclitaxel, and addressed factors influencing regimen selection in both community and academic settings.
He also discussed emerging sequencing strategies in mCRC, citing pivotal data from the phase 3 BREAKWATER trial (NCT04607421) of encorafenib (Braftovi) plus cetuximab (Erbitux) with chemotherapy in patients with BRAF V600E–mutated disease, and highlighting other studies that could help bring targeted therapies to the up-front setting.
Bekaii-Saab is a professor of medicine at Mayo Clinic College of Medicine and Science and a consultant in the Division of Hematology and Oncology at Mayo Clinic in Phoenix, Arizona.
In the first part of the interview, Bekaii-Saab outlined considerations in the treatment of patients with advanced biliary tract cancer.
OncLive: How do you currently approach frontline chemotherapy selection for patients with metastatic pancreatic cancer, particularly in light of the FDA approval of NALIRIFOX?
Bekaii-Saab: With [pancreatic] cancer, we remain limited in terms of [treatment] outcomes. [In February 2024], there was an approval by the FDA [for NALIRIFOX], which showed superiority vs the doublet [of gemcitabine and nab-paclitaxel] in the NAPOLI-3 trial. What gets confusing is that FOLFIRINOX was never shown to be superior to gemcitabine plus nab-paclitaxel [in a prospective trial]. They have never been compared head-to-head, so we don’t know [comparative efficacy directly], but indirectly, at least, we can draw from the different studies.
How do tolerability and community practice considerations influence the use of NALIRIFOX in pancreatic cancer?
[NALIRIFOX] is more toxic, although weekly gemcitabine and nab-paclitaxel tends to be very toxic. Most practice in the United States has moved to biweekly gemcitabine and nab-paclitaxel, which makes it much easier to tolerate and is perhaps preferable outside of a clinical trial. Even some clinical trials now are trying to build on that experience with biweekly gemcitabine and nab-paclitaxel to combine [the regimen] with [novel agents], which is great news for our patients because I think that’s a much more tolerable regimen.
As far as I can tell from the community, the uptake and move to NALIRIFOX has been very slow, and a lot of folks have been reluctant. We’ve had a lot of experience with NALIRIFOX, and I can tell you, it is tough [to tolerate]. It’s a bit tougher than FOLFIRINOX, in my experience, but when [appropriate], one may consider NALIRIFOX.
A lot of our patients get treated in the neoadjuvant setting with FOLFIRINOX. There are no [large-scale] data for NALIRIFOX [in the neoadjuvant setting]; there’s one smaller study that suggested it may have a benefit. Overall, if you look at the landscape today, gemcitabine and nab-paclitaxel remains the dominant treatment option for patients in both the community and academic settings. Primarily, [FOLFIRINOX is used] in academic settings, and a lot of it has to do with patients being better selected, as those who end up in academic settings are often younger with better performance status.
NALIRIFOX is a consideration for many patients, and [clinicians] have to have experience with it. Most folks in the United States have not worked with NALIRIFOX except on clinical trials, so more folks have not been accustomed to using NALIRIFOX.
It would be ideal to have a study comparing NALIRIFOX to FOLFIRINOX. Unfortunately, that study will never happen. At this point in time, [chemotherapy selection is based on] patient preference [and] physician preference, and it’s a point of discussion with the patients about which 1 of the 3 [regimens] to use, with a preference remaining primarily for clinical trial [enrollment] for these patients since the outcomes with chemotherapy overall have not been optimized.
How are you currently approaching sequencing decisions in mCRC?
CRC has become very target-rich, with a number of agents that have been approved in the first-line [setting] now [in combination] with biologics. We just saw data from the [phase 3] BREAKWATER trial [NCT04607421], bringing encorafenib [Braftovi] plus cetuximab [Erbitux] to the first line with chemotherapy [following a December 2024 FDA accelerated approval]. We had the data with mFOLFOX6; we’re still waiting on the data with FOLFIRI [from BREAKWATER], which I’m pretty excited about seeing because I do think [irinotecan] synergizes much better with [this class] of agents.
Although the benefit seems to be primarily with mFOLFOX6, it will be very interesting to see the FOLFIRI data when they come out. [That portion of the study] was completed a little bit later with FOLFIRI, but [BREAKWATER] has already transformed how we treat patients with BRAF V600E mutations, which is certainly one of the worst drivers for CRC.
We know that for [patients with] microsatellite instability–high [MSI-H] disease, we have the option of pembrolizumab [Keytruda], and now we have the added option of ipilimumab [Yervoy] plus nivolumab [Opdivo] based on [the phase 3] CheckMate 8HW trial [NCT04008030].
[For patients who harbor] HER2 amplifications, tucatinib [Tukysa] plus trastuzumab [Herceptin] has been approved by the FDA, based on the [phase 2] MOUNTAINEER study [NCT03043313] that John Strickler, MD, [of Duke Cancer Institute], and I led. [The efficacy and safety of that regimen] is now being confirmed in [the phase 3] MOUNTAINEER-3 trial [NCT05253651] in the first line. Hopefully, this will move HER2-targeted therapy to the first line if MOUNTAINEER-3 is positive.
The same applies for [patients with] KRAS G12C mutations. We’ve seen some very interesting results with adagrasib [(Krazati) plus cetuximab] and with sotorasib [Lumakras] plus panitumumab [Vectibix] in later lines, leading to FDA approvals. These combinations are again being evaluated in the first line.
With more targeted agents potentially moving from later-line to first-line therapy in CRC, how are you approaching sequencing decisions across molecular subgroups, and where do you see the greatest remaining unmet needs?
In terms of sequencing, a lot of these agents approved in later lines of therapy are moving to first line—they are either already approved or on their way through clinical trials. CRC is becoming very exciting. It’s not a question anymore of bevacizumab [Avastin] vs cetuximab or panitumumab; it’s more a question of how to place all these different subgroups of patients. Where do you start with the biologic plus chemotherapy first vs [targeted therapy]? Hopefully, more studies will cover the first-line landscape.
Unfortunately for most patients, we still have no [molecular] targets, especially for those with RAS wild-type [disease], those without BRAF alterations, or those without MSI-H tumors. For the KRAS-mutated tumors, we have a number of these pan-RAS inhibitors and KRAS G12D inhibitors, in addition to KRAS G12C inhibitors, that are also making their way and helping us at least cover that area. For the RAS wild-type population, we’re limited primarily to EGFR inhibitors, unless there’s a BRAF mutation or it is an MSI-H tumor.
More work needs to be done there, and a lot of it is being done with combination strategies or new antibodies that are coming through. It’s an exciting time for CRC, based on a lot of the recent discoveries and ongoing trials aiming to move biologics into the first line.