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CCO Independent Conference Highlights of the Virtual 2021 Gastrointestinal (GI) Cancers Symposium

Axel Grothey Headshot
Axel Grothey, MD
Manish A. Shah, MD
Released: March 10, 2021

Hepatobiliary Cancer

KEYNOTE-224: Pembrolizumab Monotherapy for Patients With Advanced HCC and No Previous Systemic Therapy

Manish A. Shah, MD:
The KEYNOTE‑224 study was a phase II efficacy and safety study of pembrolizumab monotherapy in patients with hepatocellular carcinoma (N = 150).[52,53] Patients were split into cohorts based on whether they previously received systemic therapy (n = 104) or were previously untreated (n = 51). In the analysis presented at ASCO GI 2021, Van Laethem and colleagues[52] reported efficacy and safety data for the previously untreated cohort. Patients had confirmed incurable hepatocellular carcinoma and were not eligible for locoregional therapy. In addition, patients had measurable disease and an ECOG PS of 0 or 1. All patients received 200 mg of IV pembrolizumab every 3 weeks for 2 years or until progressive disease, intolerable toxicity, or study withdrawal. The primary endpoint was ORR (using RECIST v1.1 by blinded independent central review), and secondary endpoints were duration of response, disease control rate, time to progression, PFS, OS (RECIST v1.1 by blinded independent central review), safety, and tolerability.

KEYNOTE-224: Baseline Patient Characteristics

Manish A. Shah, MD:
Most of the 51-patient cohort was enrolled in Europe (n = 37; 73%). Alpha fetoprotein above 200 ng/mL, which indicates a higher burden of disease, was present in 19 patients (37%). In total, 34 patients were Barcelona Clinic Liver Cancer stage C (67%), and 24 (47%) had an ECOG PS of 1.

KEYNOTE-224: ORR and DoR

Manish A. Shah, MD:
PR was achieved in 8 patients (16%; 95% CI: 7-29), and disease control was achieved in 29 (57%; 95% CI: 42-71), but no patients achieved full CR. The DoR was ≥ 12 months in 70% of responding patients. Trials for other checkpoint inhibitors also have shown a profound DoR in responding patients with hepatocellular carcinoma. However, many patients do not respond—at least with pembrolizumab—in this setting.

KEYNOTE-224: ORR Across Subgroups

Manish A. Shah, MD:
The ORR was similar across patient subgroups, with no category of patients more or less likely to respond to pembrolizumab.

KEYNOTE-224: Change in Target Lesions from Baseline

Manish A. Shah, MD:
In total, 22 patients (43.1%) had at least some reduction in tumor size from baseline, with 11 patients (21.5%) having a reduction > 30%. Three patients had a nearly complete reduction in tumor volume: 1 hepatitis B positive, 1 hepatitis C positive, and 1 hepatitis negative.

KEYNOTE-224: Time to Progression, PFS, and OS

Manish A. Shah, MD:
The 12-month rate of progression was 31%, with a median time to progression of 4 months (95% CI: 3-8). The 12-month PFS was 24%, with a median PFS of 4 months (95% CI: 2-6). The 12-month OS was 58%, with a median of 17 months (95% CI: 8-NA).

KEYNOTE-224: Treatment-Related AEs

Manish A. Shah, MD:
Pembrolizumab was generally well tolerated, and most patients did not have significant AEs. AEs of any grade occurred in 27 patients (53%), with grade 3-5 AEs occurring in only 7 patients (14%). Only 3 patients (6%) discontinued pembrolizumab due to AEs, and 1 patient (2%) had an AE secondary to immune-related hepatitis that resulted in death.

KEYNOTE-224: Clinical Implications

Manish A. Shah, MD:
It is not clear that this trial changes the current standard of care using atezolizumab and bevacizumab in the first line setting. However, a combination approach for checkpoint inhibition may be beneficial in the first line setting for hepatocellular carcinoma.

Phase II Trial of Infigratinib in Advanced Cholangiocarcinoma With FGFR2 Fusion/Rearrangement

Manish A. Shah, MD:
Earlier, we discussed a FGFR2 inhibitor in the context of advanced gastric/GEJ cancer. In the FIGHT trial, the oral FGFR2 inhibitor bemarituzumab improved median PFS and OS while also improving ORR. In this open-label, single-arm phase II study, the FGFR2 inhibitor infigratinib was evaluated in patients with advanced cholangiocarcinoma (planned N = 160).[54,55]

Enrolled patients had advanced cholangiocarcinoma with FGFR gene fusions or rearrangements and experienced progression or intolerance to gemcitabine-based chemotherapy. Patients were split into cohorts based on which FGFR gene was mutated and previous exposure to selective FGFR inhibitors. Cohort 1 patients (n = 108) had FGFR2 gene fusions or rearrangements and had not previously received a selective FGFR inhibitor. Cohort 2 patients (planned n = 20) had FGFR1&3 gene fusions or rearrangements and/or FGFR mutations and no previous treatment with selective FGFR inhibitors. Cohort 3 patients (planned n = 20) had FGFR2 gene fusions and progressed after receiving a selective FGFR inhibitor other than infigratinib.

All patient cohorts received 125 mg PO of infigratinib once a day for 21 days out of a 28-day cycle. The primary endpoints were ORR per blinded independent central review (RECIST v1.1) and DoR. Secondary endpoints were PFS, disease control rate, best overall response, OS, safety, and pharmacokinetics.

Infigratinib in Advanced Cholangiocarcinoma With FGFR2 Fusion/Rearrangement: Outcomes

Manish A. Shah, MD:
Infigratinib monotherapy resulted in a 23.1% confirmed ORR, of which 1 patient (0.9%) had CR, 24 patients (22.2%) had PR, and 66 patients (61.1%) had stable disease. The ORR is higher in patients who received a maximum of 1 previous line of treatment vs 2 or more (34.0% vs 13.8%). Still, the disease control rate is remarkably high at 84.3%—a clear indication of infigratinib’s activity in this patient population.

Eye disorders are a toxicity of special interest for FGFR inhibitors, as mentioned in the discussion of the trial of bemarituzumab in gastric cancer. In this cohort, 70.4% of patients experienced eye disorders with infigratinib treatment, and 16.7% developed central serous retinopathy or retinal pigment epithelial detachment. Changes in calcium phosphate homeostasis were also common, affecting 85.2% of patients.

Infigratinib: Clinical Implications

Manish A. Shah, MD:
These results are very interesting, and represent potentially the first biomarker driven treatment for HCC. Clinically, we can diagnose HCC by appropriate imaging and an elevated AFP level in the correct setting. However, if these data hold up in a phase III study, it would require that we change our practice by testing for the FGFR gene fusion or rearrangement on a tissue or liquid biopsy sample.

ClarIDHY: Ivosidenib vs Placebo in Previously Treated Cholangiocarcinoma with IDH1 Mutation

Manish A. Shah, MD:
The ClarIDHy study was an international, double-blind, randomized phase III trial enrolling 187 patients with previously treated cholangiocarcinoma.[56,57] Adult patients with centrally confirmed IDH1 mutation by next-generation sequencing were enrolled if they had 1-2 previous therapies and an ECOG PS of 0 or 1. Patients were randomized 2:1 to receive the IDH1 inhibitor ivosidenib (n = 126) or placebo (n = 61). Stratification was based on the number of previous therapies. Ivosidenib was received orally at 500 mg daily in 28-day (± 2 days) cycles. Patients in the placebo group were permitted to cross over at radiographic disease progression. Crossover ultimately occurred in 43 patients, for a total ivosidenib group of 166 patients. The primary endpoint was PFS by blinded independent radiology center. Key secondary endpoints were PFS by local review, OS, ORR, safety, QoL, and pharmacokinetics/pharmacodynamics. Zhu and colleagues[48] reported the final results at ASCO GI 2021.

ClarIDHY: PFS by IRC and Final OS

Manish A. Shah, MD:
Median PFS was 2.7 months for ivosidenib and 1.4 months for placebo (HR: 0.37; 95% CI: 0.25-0.54; P < .0001), meeting the primary endpoint. The 12‑month PFS by blinded independent radiology center was 22% for ivosidenib vs not estimable for placebo; the last patient on placebo progressed at 5 months. The final median OS was 10.3 months for ivosidenib vs 7.5 months for placebo, with a 12-month OS rate of 43% for ivosidenib vs 36% for placebo (HR: 0.79; 95% CI: 0.56-1.12; P = .093). The difference was not significant for unadjusted HR, which did not account for patient crossover. It is important to note, however, that when the effect from patient crossover was factored in using rank-preserving structural failure time, the difference in median OS was statistically significant (HR: 0.49; 95% CI: 0.34-0.70; P < .0001).

ClarIDHY: Treatment-Emergent AEs in > 15% of Patients

Manish A. Shah, MD:
The most common treatment-emergent AEs in the total ivosidenib group were nausea (38.0%), diarrhea (33.1%), and fatigue (28.9%). The rate of vomiting was also high at 19.9%. The most common grade ≥ 3 toxicities were ascites (ivosidenib: 9.0%; placebo: 6.8%), anemia (ivosidenib: 7.2%; placebo: 0%), and increased bilirubin (ivosidenib: 5.4%; placebo: 1.7%). Overall, ivosidenib was well tolerated by patients and was associated with a slight reduction in discontinuation due to treatment-emergent AEs vs placebo (6.6% discontinuation with ivosidenib vs 8.5% in the placebo group). However, treatment-emergent AEs leading to dose reduction (3.0% vs 0%) and interruptions (30.1% vs 18.6%) were more common for ivosidenib vs placebo.

ClarIDHY: Clinical Implications

Manish A. Shah, MD:
Treatment with ivosidenib resulted in statistically significant improvement in PFS and numerical improvement in OS for patients with previously treated cholangiocarcinoma with IDH1 mutation, despite a high rate of crossover from the placebo arm (about 70%). I think IDH1 is an important target in cholangiocarcinoma that highlights the importance of knowing targets across GI malignancies to improve patient care and outcomes.

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