Commentary
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Author(s):
Katrina S. Pedersen, MD, MS, details how the treatment of patients with gastrointestinal malignancies is evolving and notes notable trials as well as approvals.
The treatment of patients with gastrointestinal malignancies such as metastatic colorectal cancer (mCRC) and pancreatic cancer has evolved throughout 2023 with the addition of FDA-approved treatment regimens into the paradigm, including fruquintinib (Fruzaqla) in mCRC and irinotecan liposome (Onivyde) with oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (NALIRIFOX) in the frontline treatment of metastatic pancreatic adenocarcinoma.1,2 Excitement continues to stir in the oncology community as pivotal trials read out and ongoing ones hold potential, according to Katrina S. Pedersen, MD, MS.
"There is a lot of anticipation right now with the ongoing phase 3 BREAKWATER trial [NCT04607421] which is looking at encorafenib [Braftovi] and cetuximab [Erbitux] both alone and in combination with standard doublet chemotherapy vs standard chemotherapy alone in frontline BRAF V600E–mutated CRC,” Pedersen said in an interview with OncLive®. “We have the approval for encorafenib plus cetuximab in the second-line and later and it certainly has been a big advancement for this highly aggressive molecular subset of CRC. We’re very interested to see if there is any enhanced survival benefit by earlier targeting of this [mutation].”
In addition to encorafenib, all eyes have been on fruquintinib and trifluridine/tipiracil (TAS-102; Lonsurf) in combination with bevacizumab (Avastin) following the practice-changing data from the phase 3 FRESCO-2 (NCT04322539) and SUNLIGHT (NCT04737187) trials that led to approvals of these agents, respectively. In the FRESCO-2 trial, fruquintinib plus best supportive care demonstrated a median overall survival (OS) of 7.4 months (95% CI, 6.7-8.2) compared with 4.8 months (95% CI, 4.0-5.8) in the placebo arm (HR, 0.662; 95% CI, 0.549-0.800; P < .001).3 Further, in SUNLIGHT the addition of bevacizumab to trifluridine/tipiracil resulted in a median OS of 10.8 months (95% CI, 9.4-11.8) vs 7.5 months (95% CI, 6.3-8.6) with trifluridine/tipiracil alone, translating to a 39% reduction in the risk of death (HR, 0.61; 95% CI, 0.49-0.77; 1-sided P < .001).4
In the interview following an OncLive State of the Science Summit™ which she chaired, Pedersen, an associate professor in the Division of Oncology in the John T. Milliken Department of Medicine at the Washington University School of Medicine in St. Louis, Missouri, shared updates on these advancements along with others in CRC, hepatocellular carcinoma (HCC), and pancreatic cancer.
Pedersen: One advancement was in refractory mCRC [for] patients who have already gotten fluoropyrimidine-, oxaliplatin-, [and] irinotecan-[based chemotherapy], a VEGF inhibitor– as long as it’s not contraindicated– and an EGFR inhibitor if it’s appropriate. [This is] usually in the third-line and later [setting] and there were 2 big advances that were approved [for these patients] last year.
An advancement came following data from the SUNLIGHT trial, which showed that trifluridine and tipiracil with bevacizumab is superior to trifluridine and tipiracil alone in improving progression-free survival PFS and OS for these patients. There is additional clinical benefit that I’m already seeing in my practice compared with trifluridine and tipiracil alone. At the end of the year, fruquintinib was approved by the FDA for use in the same population. We also have additional data from the FRESCO-2 trial that showed that fruquintinib even in patients who had previously received treatment with trifluridine and tipiracil or regorafenib [Stivarga], [resulted in] a PFS and OS benefit—[and this is] a more refractory population than seen in SUNLIGHT and proceeding trials.
These are 2 big therapeutic [agents that are] options that can be broadly applied not just in biomarker-selected populations.
Another [theme in 2023] advancement was in molecularly targeted subsets of patients. The FDA approval of the HER2 inhibitor tucatinib [Tukysa] with trastuzumab [Herceptin] for patients who have progressed on standard frontline and second-line chemotherapy is the first anti-HER2 therapy that has been FDA-approved to date in mCRC.
We saw a lot of data on the emergence of adagrasib [Krazati] too. What’s interesting is that in these trials of CRC, we saw more durable and meaningful benefits with the addition of an estrogen receptor inhibitor such as panitumumab [Vectibix]. I find that experience mirrors what we’ve seen with other MAP kinase–targeted interventions like BRAF inhibitors, [although] we don’t have FDA approvals on those quite yet. However, they are under review and accelerated review, so I wouldn’t be surprised if we start having more accessibility to those agents in the future.
In addition, I’m also excited about the phase 2 SEAMARK trial [NCT05217446] which is looking at patients with BRAF V600E mutations and CRC who also have concurrent microsatellite instability or DNA mismatch repair deficiency. This is to understand if combinations of BRAF-targeted therapy such as encorafenib with immunotherapy may be more beneficial for that selected population.
I fully agree with the big topic he highlighted in that there have been enough advancements to warrant germline and somatic genomic testing for patients with metastatic pancreatic cancer [in the] up-front [setting]; there are certain therapies you might gravitate toward even with standard chemotherapy based on the molecular profile.
Beyond that, one big advancement that came out this past year was the NALIRIFOX regimen, which was just recently FDA-approved. We saw the data from the frontline phase 3 NAPOLI 3 trial [NCT04083235] comparing NALIRIFOX vs gemcitabine with nab-paclitaxel [Abraxane]. This is the first time in a trial that we’ve seen a head-to-head comparison of the triplet vs the doublet approach in pancreatic cancer.
Although this is approved, and certainly an advance, I call it more of a lateral advancement because the survival outcomes pretty much recapitulated what we saw with the original FOLFIRINOX and gemcitabine with nab-paclitaxel data from approximately a decade ago. However, it’s always helpful to define which patients should receive what approach by having data like this to turn to.
The introduction of immunotherapy into the HCC treatment paradigm has been incredibly important and has shifted the degree of clinical benefit that patients with unresectable HCC can achieve. There have been 2 cornerstone trials at this point that have come out, one with the atezolizumab [Tecentriq] and bevacizumab combination for systemic treatment-naive HCC. The other is the phase 3 HIMALAYA trial [NCT03298451] which uses the STRIDE [Single Tremelimumab Regular Interval Durvalumab] regimen or durvalumab [Imfinzi] with a priming dose of tremelimumab [Imjudo] followed by ongoing durvalumab maintenance.
What we’re noticing is although maybe not always to the same degree of benefit as was reported in the trial, at least here in our North American patients, we have seen a shift with the tolerability of the regimens and with the PFS and OS of many of our patients with HCC since these options have come around. They have not been studied head-to-head to know whether an immunotherapy combination vs immunotherapy plus a VEGF-targeting agent with bevacizumab is better.
We tend to use more patient-based and more clinical factors to choose who should get what agents, but I’m certainly seeing real-life benefit with both [investigational regimens from these trials] and that’s very exciting. As we are now moving into next-generation combinations with other targeted drugs with immunotherapy for HCC, we are crossing modalities not just with other medications, but also in combining immunotherapy with more liver-directed therapies such as transarterial chemoembolization, other ablations, external beam radiation, and in some cases resection.