Pollack Discusses Ongoing Research for Patients With Refractory mCRC and Other Hard-to-Treat GI Malignancies

Terri Pollack, DNP, APRN, FNP-C, PMHNP-BC

A 3-month improvement in overall survival (OS), though modest, may be significant for a patient with refractory metastatic colorectal cancer (mCRC) who has run out of approved treatment options, according to Terri Pollack, DNP, APRN, FNP-C, PMHNP-BC.

Pollack, a nurse practitioner with the Gastrointestinal Cancer Site Disease Group in the Department of Medical Oncology at the University of Miami Sylvester Comprehensive Cancer Center, was referring to data from the phase 3 SUNLIGHT trial (NCT04737187), which evaluated 492 patients with histologically confirmed mCRC who had already undergone treatment with fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody, and/or an anti-EGFR monoclonal antibody if they had a tumor harboring a RAS mutation.¹ In a presentation of the findings during the 2023 ASCO GI Cancers Symposium, investigators noted this was the first trial to demonstrate an improvement in OS vs an active control in the refractory mCRC setting.

In an interview with Oncology Nursing News®, Pollack discussed her interpretation of some of the data presented from the conference, and how it could apply to clinical oncology nursing. She noted that SUNLIGHT might offer hope for patients with refractory disease, who often are unable to enroll in clinical trials and therefore have few treatment options left.

Throughout the discussion, she also highlighted data presented in the biliary tract cancer space. Although some negative or inconclusive findings were read out with the use of immune checkpoints inhibitors in biliary tract cancer, Pollack noted that there still may be a useful application of the data, and that her overall experience treating patients with biliary tract cancer has been positive with this agent class.^2,3

She touched on an analysis of patients with biliary tract cancer which found no significant correlation between KRAS status and PD-L1 expression, nor a significant difference in progression-free survival (PFS) according to KRAS mutation status or PD-L1 expression, following immunotherapy. A subgroup analysis did find that patients whose disease harbored KRAS mutations and PD-L1 positivity experienced longer PFS compared with those who had a KRAS mutation but were PD-L1 negative (6.5 vs 2.6 months; P = .047).³

Lastly, Pollack discussed the safety data from the phase 3 BREAKWATER study (NCT04607421), which is assessing encorafenib (Braftovi) plus cetuximab (Erbitux) along with chemotherapy for patients with BRAF V600E–mutant mCRC. She noted that the overall findings are promising, although, in her experience, the dermatologic toxicities tend to be bothersome for patients and therefore represent a potential challenge with this treatment.⁴

Oncology Nursing News®: Please discuss your interpretation of the SUNLIGHT trial. What is the significance of these findings?¹

Pollack: The individuals [had] a diagnosis of refractory mCRC, and they received trifluridine/tipiracil (Lonsurf) plus bevacizumab (Avastin)— they were heavily pretreated. The outcome was very promising on the efficacy side. Median OS was measured and for the trifluridine/tipiracil plus bevacizumab arm it came out to 10.8 months vs 7.5 months in the trifluridine/tipiracil-only arm which is a 3.3-month improvement [HR, 0.61; 95% CI, 0.49-0.77; P < .001].

At the 12-month period, there was a 43% OS [rate] in the trifluridine/tipiracil /bevacizumab arm and a 30% [OS rate] in the trifluridine/tipiracil along arm. There were no new safety issues found either.

These individuals have been heavily pretreated. So, [there are not many other options]. A 3.3-month [improvement] in median OS can mean a lot to an individual challenged with this type of cancer.

At ASCO GI, there were some negative and nonconclusive trials in the biliary tract cancer space. For instance, the SWOG 1815 (NCT03768414) did not find a survival benefit in adding nab-paclitaxel to gemcitabine plus cisplatin compared with chemotherapy alone. What has been your experience been working with patients with biliary tract cancers? What can be expected with the current treatment options?^2,3

Biliary tract cancer is actually a very rare disease [although] in our practice, we specialize in this area.

It is true—there were some negative findings at [ASCO GI]. SWOG 1815 showed that nab-paclitaxel plus gemcitabine plus cisplatin did not improve OS.²

Additionally, there was a presentation from a team out of Seoul, South Korea, that looked at KRAS [mutation status]. KRAS is a common mutation in biliary tract cancers; [its incidence rate is around] 15%. [The investigators] looked at [tumor mutational burden] TMB in [patients with] biliary tract cancers who received immune checkpoint inhibitors as salvage treatment, [including] PD-L1 treatments, [such as] nivolumab [Opdivo] and pembrolizumab [Keytruda]. There was a total of 62 patients [treated] from 2020 to 2022, and the median age was 68 years. Forty-seven patients received pembrolizumab and 15 received nivolumab. Again, the immunotherapy was salvage therapy. They all received gemcitabine plus cisplatin in the frontline setting, and some received FOLFOX before the immune checkpoint inhibitor. The median lines of prior chemotherapy were 2.5; KRAS mutations were found in 14 of the 62 patients and 28 of the 62 were positive for PD-L1. There was no statistical correlation between the KRAS mutation and the PD-L1 expression.

The median OS and PFS of patients were 5.2 and 3.5 months, respectively. There was no statistically significant difference in PFS, according to the KRAS mutation status, whether it be mutant or wild-type, and the PD-L1 expression, whether it was positive or negative.

There was a subgroup analysis and patients with KRAS mutation and PD-L1 positive [status] had longer PFS compared to patients with KRAS mutations and PD-L1 negative [status].

Conclusively, PD-L1 expression might be a novel biomarker for individuals with biliary tract cancers with KRAS mutation, but not in those with the wild-type KRAS. For me, the takeaway for this is: we have further opened the opportunities for immune checkpoint inhibitors in this in this space.

In my personal experience, we have treated individuals with biliary tract cancer with ipilimumab [Yervoy] and nivolumab and we have seen some very nice results. I do not have any data to share, but the results nonetheless have proven to be median OS very similar to these.

I think about milestones. So, let's say we started [an individual on treatment] today, and their grandchild or their child, or niece or nephew, is getting married in June. This is the end of February, June is 4 months away. They might have a pretty decent performance status at that mark for that June wedding, or the 3-month mark for that May graduation. Now, might we lose them by August? Yes. But [maybe] we can hit some milestones. And that for me is where OS and PFS come in to play.

What do the data from BREAKWATER study tell us and what are the limitations of these data?⁴

There are no first-line treatment options indicated specifically for individuals with BRAF V600E mCRC. There was another study, BEACON CRC [NCT04607421], which looked at BRAF inhibitor encorafenib plus EGFR inhibitor cetuximab [EC]. This [combination] was approved for previously treated patients with BRAF V600E–mutant metastatic colorectal cancer.⁵ What BREAKWATER did was they went a little further. It was an open-label, global, multicenter study. This is a randomized phase 3 study looking at efficacy and safety and it evaluated first-line EC with or without chemotherapy. The patients had to have a BRAF V600E mutation as well as mCRC.

Patients were previously treated with BRAF [inhibitors], EGFR inhibitors, oxaliplatin, and/or irinotecan were excluded. So interesting. If you received oxaliplatin or irinotecan, which would mean most probably FOLFOX or FOLFIRI and/or a BRAF/EGFR inhibitor, you were excluded. Patients received encorafenib at 300 mg daily plus cetuximab at 500 mg/m2 every 2 weeks or FOLFIRI [once every 2 weeks] or modified FOLFOX6 [once every 2 weeks]. These were all 28-day cycles. The primary end point was frequency of dose-limiting toxicities.

I would consider the limitations being acneiform dermatitis, because what we find in practice is that a lot of patients do not want that acneiform rash on their face. They will ask to stop treatment, even though they know it’s potentially life-extending treatment because of that acneiform rash.

Nausea is something we can manage. The grade 3 or higher incidence of nausea came up as 0. So, this [regimen likely] would not cause a provider to suspend treatment because of nausea.

So [overall] these were favorable results.

References

1. Tabernero J, Prager GW, Fakih M, et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: the phase 3 randomized SUNLIGHT study. J Clin Oncol. 2023;41(suppl 4):4. doi:10.1200/JCO.2023.41.4_suppl.4
2. Shroff RT, Guthrie KA, Scott AJ, et al. SWOG 1815: a phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers. J Clin Oncol. 2023;41(suppl 4):LBA490. doi:10.1200/JCO.2023.41.4_suppl.LBA490
3. Jeong SY, Kim ST, Jang JY. The efficacy of immune checkpoint inhibitors in biliary tract cancer with KRAS mutation. J Clin Oncol. 2023;41(suppl 4):598. doi:10.1200/JCO.2023.41.4_suppl.598
4. Kopetz S, Yoshino T, Kim T, et al. BREAKWATER safety lead-in (SLI): encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC). J Clin Oncol. 2023;41(suppl 4):119. doi:10.1200/JCO.2023.41.4_suppl.119
5. FDA approves encorafenib in combination with cetuximab for metastatic colorectal cancer with a BRAF V600E mutation. FDA. Updated April 9, 2020. Accessed February 23, 2023. bit.ly/3KysLlt