New and Updated Data in GI Cancer Trials Show Continued Benefit With Targeted and Immunotherapy Agents

In the field of gastrointestinal (GI) cancers, few abstracts were shared with oncologists and other clinicians during the recent 2020 European Society of Medical Oncology (ESMO) Virtual Congress, but those that were presented showed important data in immunotherapy and targeted therapy options, newly introduced in certain disease settings.

Historically, in GI malignancies, chemotherapy and radiation were utilized to improve outcomes for patients. Although these treatments were effective, disease recurrence was always imminent, demonstrating a need for novel therapies.

The key gastrointestinal data from ESMO, which is on track to solve issues with recurrence and improve responses and survival for patients with gastrointestinal malignancies included studies of ripretinib (Qinlock), as well as nivolumab (Opdivo), used as frontline treatment.

Updated Clinical Trial Results in GI Cancers

The INVICTUS Trial

Updated results from the phase 3 INVICTUS trial (NCT03353753)of ripretinib as treatment of patients with advanced gastrointestinal stromal tumors (GIST) were presented at ESMO by John Zalcberg, MD, head of the Cancer Research Program and the NHMRC (MRFF) Practitioner Fellow in the School of Public Health and Preventive Medicine at Monash University in Australia. It was demonstrated in the study that after an additional 9 months of follow-up, ripretinib induced clinically meaningful benefit and was well tolerated in patients with advanced GIST who had been treated with at least 3 prior tyrosine kinase inhibitors (TKIs).¹

“This was an important study. It was a registrational study for ripretinib and it did show that ripretinib is an active agent in this condition, which not only includes improvement in progression-free survival and overall survival, but it also improves quality of life. This was actually approved by the FDA this year,” Zalcberg told Targeted Oncology in an interview.

In the intention-to-treat population of 85 patients in the ripretinib arm and 44 in the placebo arms, there were 38 and 31 overall survival (OS) events, respectively. The median OS was not reached in the ripretinib arm (95% CI, 13.1 to not estimable) versus 6.3 months (95% CI, 4.1-10.0) in the placebo arm (HR, 0.42; 95% CI, 0.26-0.67).

In terms of progression-free survival (PFS), there were 66 events in the ripretinib group compared with 37 in the placebo group. The median PFS was 6.3 months (95% CI, 4.6-8.1) with ripretinib versus 1.0 month (95% CI, 0.9-1.7) with placebo (HR, 0.16; 95% CI, 0.1-0.27).

With a satisfactory objective response rate of 11.8% observed with ripretinib in INVICTUS, the benefit of the agent was clearly established, even with longer-term follow-up.

Treatment-emergent adverse events (TEAEs) were observed in > 15% of patients in the study. Which included grade 3/4 events. The most common TEAEs of any grade observed with ripretinib were alopecia (52%), fatigue (47%), nausea (41%), abdominal pain (40%), and constipation (37%). The most common grade 3/4 TEAEs observed with ripretinib were abdominal pain (7.1%), hypertension (7.1%), fatigue (3.5%), nausea (3.5%), and vomiting (3.5%).

TEAE that required dose reduction occurred in 8.2% of the ripretinib arm compared with 2.3% of the placebo arm. Dose interruptions caused by the occurrence of TEAEs were observed in 26% if the ripretinib arm compared with 21% of the placebo arm. Additionally, 8.2% of the ripretinib arm versus 12% of the placebo arm discontinued treatment due to TEAEs. Finally, 7.1% of the patients who were treated with ripretinib died due to TEAEs versus 23% of the placebo arm.

“In terms of future steps, the current study that is ongoing is called INTRIGUE [NCT03673501]. INTRIGUE is a study of ripretinib versus sunitinib [Sutent] in the second-line setting of advanced GIST,” said Zalcberg.

Primary Clinical Trial Results in GI Cancers

CheckMate 577

Following neoadjuvant chemoradiotherapy (CRT), patients with resected esophageal and gastroesophageal junction (GEJ) cancer received the immunotherapy agent nivolumab in the phase 3 CheckMate 577 clinical trial (NCT02743494). According to initial results presented by Ronan J. Kelly, MD, MBA, during ESMO, nivolumab showed statistically significant andclinically meaningful improvement in disease-free survival (DFS) in this patient population.²

In the overall population of 532 patients in the nivolumab arm and 262 patients in the placebo arm, the median DFS was 22.4 months (95% CI, 16.6-34.0) versus 11.0 months (95% CI, 8.3-14.3), respectively (HR, 0.69; 96.4% CI, 0.56-0.86; P = .0003). Overall, reduction in the risk of disease recurrence or death was 31%. Notably, the benefit with nivolumab was also shown across the subgroup populations explored in the study.

During his ESMO presentation, Kelly, director of oncology for the Charles A. Sammons Cancer Center and the chief of oncology for the North Texas Division at Baylor Scott & White Health, noted that CheckMate 577 is the first clinical trial to demonstrate a DFS improvement in patients with resected esophageal and GEJ cancer following neoadjuvant CRT.

“We’ve seen data from the UK, Holland, and Germany, but we’ve never had a global study to really show us how these patients do. All of our data has been retrospective data looking at different studies and we piece them together, but here we have disease-free survival in patients who don't have a pathological complete response of only 11 months,” explained Kelly, in an interview with Targeted Oncology.

Looking back, nivolumab was assessed in early studies of esophageal and GEJ cancer to address the high risk of recurrence in this patients population in comparison with standard of care chemotherapy.2 Therefore, results from CheclMate 577 are a step forward in addressing disease recurrence. Kelly stated “I think doctors have known their patients do poorly, but they haven't been able to see it as clearly as this. This is a really important study because it shows the doctors around the world that these patients can’t just be watched. We really need to try to do something.”

CheckMate 649

Patients with advanced gastric and GEJ cancer treated with the frontline combination of nivolumab and chemotherapy achieved a longer OS and PFs compared to those treated with chemotherapy alone, according to primary results from the CheckMate 649 trial (NCT02872116) presented by Markus Möhler, MD, during ESMO.³

In the overall study population of 1581 patients, the median OS was 13.8 months (95% CI, 12.6-14.6) in the nivolumab plus chemotherapy arm compared with 11.6 months (95% CI, 10.9-12.5) in the chemotherapy-only arm (HR, 0.80; 99.3% CI, 0.68-0.94; P = .0002). Among the subgroup population of patients with positive PD-L1 expression (combined positive score [CPS] ≥1), the median OS with the addition of nivolumab was 14.0 months (95% CI, 12.6-15.0) compared with 11.3 months (95% CI, 10.6-12.3) with chemotherapy alone (HR, 0.77; 99.3% CI, 0.64-0.92; P = .0001). Among those with higher PD-L1 expression of CPS ≥5, which was the primary end point, the median OS was 14.4 months (95% CI, 13.1-16.2) with nivolumab and chemotherapy versus 11.1 months (95% CI, 10.0-12.1) with chemotherapy alone (HR, 0.71; 98.4% CI, 0.59-0.86; P < .0001).

The median PFS observed in this study with nivolumab/chemotherapy was 7.7 months (95% CI, 7.1-8.5) with nivolumab in the overall population versus 6.9 months (95% CI, 6.6-7.1) with chemotherapy alone (HR, 0.77; 0.68-0.87). Among patients with higher PD-L1 expression, the median PFS was 7.7 months (95% CI, 7.0-9.2) in the nivolumab arm versus 6.0 months (95% CI, 5.6-6.9) in the chemotherapy arm (HR, 0.68; 98% CI, 0.56-0.81; P < .0001).

“Mostly all prespecified subgroups favored the combination of nivolumab plus chemotherapy. Particularly, I would like to point out that the region and location of the tumor was in favor of nivolumab plus chemotherapy,” Möhler told Targeted Oncology in an interview.

_References:

_{1. Zalcberg JR, Heinrich M, George S. Clinical benefit with ripretinib as _4th line treatment in patients with advanced gastrointestinal stromal tumors (GIST): Update from the phase III INVICTUS study. Presented at: 2020 European Society for Medical Oncology Virtual Congress; September 19-21, 2020. Abstract 1622MO.}

_{2. Kelly RJ, Ajani JA, Kuzdzai J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (ec/gejc) following neoadjuvant chemoradiation therapy (cCT): first results of the CheckMate 577 study. Presented at: 2020 European Society for Medical Oncology Virtual Congress; September 19-21, 2020. Abstract LBA9_PR.}

_{3. Moehler M. Shitara K, Gamido M, et al. Nivolumab (NIVO) plus chemotherapy (Chemo) Versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Presented at: 2020 European Society for Medical Oncology Virtual Congress; September 19-21, 2020. Abstract LBA6_PR.}