Detailing the Impact on SOC in GI Cancer After ASCO GI

Jun Gong, MD, and Daneng Li, MD, discussed the most impactful trials coming from 2024 ASCO GI.

Following the 2024 Gastrointestinal Cancers Symposium hosted by the American Society of Clinical Oncology, Jun Gong, MD, and Daneng Li, MD, participated in a live X (formerly known as Twitter) Spaces event to discuss the most breaking presentations to come out of the conference.

Gong, medical director for Colorectal Cancer Medicine and an associate professor at Cedars Sinai, and Li, associate professor in the Department of Medical Oncology and Therapeutics Research and codirector of the Neuroendocrine Tumor Program at City of Hope, broke down numerous trials and what their results mean for patients and clinicians.

Liver Cancer and Neuroendocrine Tumors

Phase 3 NETTER-2 Trial

To kick off the discussion, Li mentioned the phase 3 NETTER-2 trial (NCT03972488) assessing lutetium (Lu) 177 dotatate (177Lu-Dotatate; Lutathera) plus octreotide vs octreotide alone in patients with advanced grade 2/3 well-differentiated gastroenteropancreatic neuroendocrine tumors.¹

“We can essentially move from further lines of therapy in the advanced setting now to earlier settings, particularly for those patients who have more aggressive disease, for those with higher grade 2 tumors or even well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors. This set the stage for the NETTER-2 trial,” said Li.

Of the 226 patients enrolled, patients were randomly assigned 2:1 to receive either 117Lu-Dotatate at 4 × 7.4 GBq plus 30 mg of octreotide long-acting repeatable (LAR) every 8 weeks or high-dose octreotide LAR at 60 mg every 4 weeks. Additionally, patients were stratified by grade 2 or 3 or tumor origin.

The median progression-free survival (PFS) was 22.8 months (95% CI, 19.4-not evaluable [NE]) vs 8.5 months (95% CI, 7.7-13.8) with high-dose octreotide (stratified HR, 0.276; 95% CI, 0.182-0.418; P < .0001).

The overall response rate (ORR) was 43.0% (95% CI, 35.0%-51.3%) in the 177Lu-Dotatate arm and 9.3% (95% CI, 3.8%-18.3%) in the high-dose octreotide arm (stratified OR, 7.81; 95% CI, 3.32-18.40; P < .0001). Between both arms, the complete response was 5.3% vs 0%, partial response was 37.7% vs 9.3%, and stable disease was 47.7% vs 56.0%, respectively. The median duration of response was 23.3 months (95% CI, 18.4- NE) vs NE (95% CI, 2.3-NE) in both arms, respectively.

Regarding all-grade adverse effects (AEs), they occurred in 93% and 95% of treated patients in the 177Lu-Dotatate and high-dose octreotide arms, and all-grade treatment-related AEs (TRAEs) occurred in 69% and 59% of patients, respectively. Between the 177Lu-Dotatate and high-dose octreotide arms, grade 3 or higher AEs occurred in 35% and 27% of treated patients and grade 3 or higher TRAEs occurred in 16% and 4% of patients, respectively.

“This [trial] speaks to how this would ultimately impact our sequence of treatment. From my perspective, you can consider this, especially for patients where you’re looking for significant tumor shrinkage, because the authors were able to show a very high ORR of over 40% with this population. We use this in terms of all-comers. Especially, with some of the grade 2 neuroendocrine tumors even with higher Ki-67, I don’t think that’s yet to be determined, and it’s somewhat of a selective process,” concluded Li.

Phase 3 EMERALD-1 Trial

Next, Li discussed the results from the phase 3 EMERALD-1 trial (NCT03778957) investigating transarterial chemoembolization (TACE) plus durvalumab (Imfinzi) with or without bevacizumab (Avastin) for patients with unresectable hepatocellular carcinoma.²

Regarding treatment selection, Li noted, “This is potentially taking the idea that now that we have better systemic therapies in the advanced setting, how can we move this to an intermediate-stage setting?”

A total of 616 patients were randomly assigned 1:1:1 and divided into arm A of durvalumab given at 1500 mg every 4 weeks with or without TACE, arm B of durvalumab at 1500 mg every 4 weeks plus TACE, and arm C of placebo every 4 weeks plus TACE.

After TACE was completed, patients in arm A went on to receive durvalumab at 1120 mg every 3 weeks plus placebo, arm B was given durvalumab at 1120 mg every 3 weeks plus bevacizumab at 15 mg/kg every 3 weeks, and arm C was given placebo.

The median PFS for durvalumab/bevacizumab plus TACE was 15.0 months (95% CI, 11.1-18.9) vs 8.2 months (95% CI, 6.9-11.1) in the placebo plus TACE arm (HR, 0.77; 95% CI, 0.61-0.98; P = .032). At 12 months the PFS rate in the combination arm was 55.5% vs 39.8% in the placebo arm, and at 18 months it was 43.1% vs 28.3%.

The median PFS for patients receiving durvalumab plus TACE was 10.0 months (95% CI, 9.0-12.7) vs 8.2 (95% CI, 6.9-11.1) in the placebo plus TACE arm (HR, 0.94; 95% CI, 0.75-1.19; P = .638).

The ORR was 41.0% for the durvalumab plus TACE arm, 43.6% for the combination plus TACE arm, and 29.6% for the placebo arm. A confirmed response occurred in 41.0%, 43.6%, and 29.6%; a complete response occurred in 1.5%, 3.0%, and 2.5%; and a partial response occurred in 39.5%, 40.6%, and 27.1% among the 3 treatment arms, respectively.

AEs occurred in 92.7%, 98.1%, and 93.0%; serious AEs occurred in 36.2%, 48.1%, and 31.0%; and AEs leading to discontinuation occurred in 12.1%, 24.7%, and 7.0% of patients in the durvalumab plus TACE arm, combination arm, and placebo arm, respectively.

Gong asked Li whether TACE is preferred over transarterial radioembolization (TARE). Li responded, “We use both. It depends on the patient presentation—we are trending more, and we tend to use more TARE or Y90 [radioembolization]. This is because of some of the potential effects on the patients. A lot of times patients can recover much quicker from [TARE], and [you can] get maybe a little bit better control of the disease.”

Li added that the use of TACE can incorporate a multidisciplinary team to help bring more encompassed care to the patients.

Colorectal Cancer and ctDNA

Phase 3 CheckMate-8HW Trial

Next, Gong spoke about results from the phase 3 CheckMate-8HW trial (NCT04008030) looking at first-line nivolumab (Opdivo) plus ipilimumab (Yervoy) vs chemotherapy for patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient metastatic colorectal cancer (CRC).³

“I thought this was one of the more exciting studies. This was a comparator in a way to the phase 3 KEYNOTE-177 trial [NCT02563002], which led to pembrolizumab [Keytruda] being established as the first-line standard for MSI-[H] metastatic CRC,” noted Gong.

A total of 303 patients were enrolled and randomly assigned 2:2:1 and were given ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks; nivolumab at 240 mg every 2 weeks for 6 doses, followed by nivolumab at 480 mg every 4 weeks; or chemotherapy with or without targeted therapies.

A clinically meaningful PFS was observed at a median follow-up of 24.3 months. In the combination arm, the PFS was not reached (95% CI, 38.4 months-NE) compared with 5.9 months (95% CI, 4.4-7.8) in the chemotherapy arm (HR, 0.21; 95% CI, 0.13-0.34; P < .0001).

When safety was evaluated, it was determined to be consistent with previously reported data.

“The takeaway from this is that it’s exciting. This solidifies that we shouldn’t be using chemotherapy as a first-line standard [for] MSI-[H] metastatic CRC,” said Gong.

BESPOKE Study

To conclude this section, Gong discussed the BESPOKE study (NCT04264702), which investigated how disease recurrence for patients receiving adjuvant chemotherapy was influenced by minimal residual disease (MRD) and detected by circulating tumor DNA (ctDNA) for patients with stage II and III CRC.⁴

“BESPOKE was a multicenter [study], but it was localized to the United States and investigated a stage II to III population postoperatively,” said Gong.

Of the 295 patients enrolled, 130 had stage II and 165 had stage III CRC. Overall, there was a significant association between MRD positivity and worse disease-free survival (DFS; HR, 20.8; 95% CI, 10.0-43.4; P < .0001). This was also noted for those with stage II (HR, 25.7; 95% CI, 6.8-96.7) and stage III disease (HR, 18.1; 95% CI, 7.3-45.1). Of note, patients who had received surgery and were MRD negative had a DFS that was not reached vs those who were MRD positive with a DFS of 15.98 months.

At 12 weeks, ctDNA clearance was observed in 39.1% of patients who were MRD positive. The DFS was 24.2 months for those with ctDNA clearance and 13.8 months for those with MRD positivity (HR, 0.4; 95% CI, 0.1-1.0; P = .045). Of note, worse DFS was observed in those who were ctDNA negative at 4 and 12 weeks (HR, 22.5; 95% CI, 6.8-75.0; P < .0001).

A total of 44.4% of patients with ctDNA clearance had disease recurrence, and they were ctDNA positive prior to relapse.

Audience Insights/Commentary

After Gong and Li finished discussing their top trials from the conference, they turned to answering questions from the audience. One audience member wanted to know how they had been able to use the recently approved fruquintinib (Fruzaqla) in clinical practice and how tolerable they thought it was.⁵

“We have used it on several patients already. It’s tolerable. It’s still quite early on for these patients; it was only [recently] approved. The first interval assessment scans have yet to be played out. This is something that we’re rapidly using in the clinic,” said Gong.

Li agreed that it is tolerable but has used it in only a few patients so far. He does want to see additional real-world data and experience as it is so newly approved.

As the subject was only briefly touched upon, users wanted to know the cohosts’ thoughts on ctDNA use in gastrointestinal cancer. Li noted that it is beginning to expand to other fields for testing and treatment but said he doesn’t know whether they can yet use it across different disease states.

Gong mentioned a few studies coming out in gastric and pancreatic cancer focusing on ctDNA use. However, as with Li, he agreed it was a bit early to determine whether they can use it in these settings and is awaiting the results.

References

1. Singh S, Halperin DM, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: primary analysis of the phase 3 randomized NETTER-2 study. J Clin Oncol. 2024;42(suppl 3):LBA588. doi:10.1200/JCO.2024.42.3_suppl.LBA588
2. Lencioni R, Kudo M, Erinjeri J, et al. EMERALD-1: a phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. J Clin Oncol. 2024;42(suppl 3):LBA432. doi.10.1200/JCO.2024.42.3_suppl.LBA432
3. Andre T, Elez E, Van Cutsem E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): first results of the CheckMate 8HW study. J Clin Oncol. 2024;42(suppl 3):LBA768. doi.10.1200/JCO.2024.42.3_suppl.LBA768
4. Kasi PM, Aushev VN, Ensor J, et al. Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): interim analysis of BESPOKE CRC study. J Clin Oncol. 2024;42(suppl3). doi:10.1200/JCO.2024.42.3_suppl.9
5. FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. November 8, 2023. Accessed February 7, 2024. https://shorturl.at/isJW2