FDA Approval Summary: Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer.

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy, an anti­VEGF therapy, and, if RAS wild­type and medically appropriate, an anti EGFR therapy. Approval was based on Study FRESCO-2, a globally-conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival (PFS). A total of 691 patients were randomized (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 (95% CI: 0.55, 0.80; p<0.001). The median OS was 7.4 months (95% CI: 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI: 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with inhibition of the VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI: 0.51, 0.83; p<0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild­type and medically appropriate, an anti-EGFR therapy.

Correlations of response rate and progression-free survival with overall survival in immunotherapy trials for metastatic non-small-cell lung cancer: an FDA pooled analysis.

BACKGROUND: Radiographic changes might not fully capture the treatment effects of immune checkpoint inhibitors (ICIs). We aimed to assess correlations of overall response rate and progression-free survival with overall survival in trials of ICIs for metastatic non-small-cell lung cancer (NSCLC). METHODS: To assess trial-level and patient-level correlations of overall response rate and progression-free survival with overall survival, we conducted a pooled analysis of first-line randomised trials (including patients aged ≥18 years with metastatic squamous and non-squamous NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1) submitted to the US Food and Drug Administration from June 24, 2016, to March 16, 2021. Eligible trials evaluated at least one ICI in the experimental group versus chemotherapy in the control group. At the trial level, we used weighted linear regression to derive coefficients of determination (R2). At the patient level, we used Cox proportional hazards models to compare overall survival between responders versus non-responders per Response Evaluation Criteria in Solid Tumours (version 1.1). FINDINGS: A total of 13 trials including 9285 patients evaluated ICIs alone or in combination with chemotherapy versus chemotherapy alone. At the trial level, the R2 was 0·61 (95% CI 0·32-0·84) for correlation of overall response rate with overall survival and 0·70 (0·40-0·89) for correlation of progression-free survival with overall survival. Correlations ranged from weak to moderate when evaluating subgroups by PD-L1 expression and were consistent across trials evaluating ICIs alone or in combination with chemotherapy. At the patient level, responders had longer overall survival than non-responders (hazard ratio [HR] 0·28 [95% CI 0·26-0·30]). Among responders, overall survival was longer in patients enrolled in experimental groups than in control groups (HR 0·54 [95% CI 0·48-0·61]). INTERPRETATION: Correlations of overall response rate and progression-free survival with overall survival were generally moderate in this pooled analysis. The findings support routine analysis of mature overall survival data, where feasible, in first-line randomised trials of ICIs for metastatic NSCLC. FUNDING: US Food and Drug Administration.

FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements.

On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.

FDA Approval Summary: Ripretinib for Advanced Gastrointestinal Stromal Tumor.

On May 15, 2020, the FDA approved ripretinib for adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with three or more kinase inhibitors, including imatinib. The approval was based on results from INVICTUS (NCT03353753), an international, multi-center, double-blind, placebo-controlled trial. Patients were randomly allocated (2:1) to receive either ripretinib 150 mg once daily (n = 85) or matching placebo (n = 44). The trial demonstrated a statistically significant improvement in progression-free survival (PFS) as assessed by modified RECIST v1.1 by blinded independent central review for patients randomized to ripretinib, with a median PFS of 6.3 months [95% confidence interval (CI): 4.6-6.9] compared with 1.0 month (95% CI: 0.9-1.7) for placebo [HR: 0.15 (95% CI: 0.09-0.25); P < 0.0001, stratified log-rank test]. There was no statistically significant difference in objective response rate in the ripretinib arm, 9% (95% CI: 4.2-18) compared with placebo 0% [(95% CI: 0-8); P = 0.0504, Fisher exact test]. The median overall survival (OS) in the ripretinib arm was 15.1 months (95% CI: 12.3-15.1) compared with 6.6 months (95% CI: 4.1-11.6) in the placebo arm. A formal statistical comparison of OS was not made due to the prespecified hierarchical analysis plan. The most common (≥20%) adverse events with ripretinib, in order of decreasing frequency, were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks of ripretinib include new primary cutaneous malignancies, hypertension, and cardiac dysfunction.

FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma.

The FDA approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently assessed progression-free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second prespecified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4-32.4) versus 8.2 months (95% CI: 6.1-10.2) in the pembrolizumab and SOC arms, respectively [HR: 0.60 (95% CI: 0.45-0.80); two-sided P = 0.0004]. FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in >30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in >30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0-30.6 months) than the duration of treatment in patients receiving SOC (median, 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for first-line treatment with MSI-H advanced colorectal cancer given the study results and different safety profile.

FDA Approval Summary: Selpercatinib for the Treatment of Lung and Thyroid Cancers with RET Gene Mutations or Fusions.

On May 8, 2020, the FDA granted accelerated approval to selpercatinib for (i) adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was granted on the basis of the clinically important effects on the overall response rate (ORR) with prolonged duration of responses observed in a multicenter, open-label, multicohort clinical trial (LIBRETTO-001, NCT03157128) in patients whose tumors had RET alterations. ORRs within the approved patient populations ranged from 64% [95% confidence interval (CI), 54-73] in prior platinum-treated RET fusion-positive NSCLC to 100% (95% CI, 63-100) in systemic therapy-naïve RET fusion-positive thyroid cancer, with the majority of responders across indications demonstrating responses of at least 6 months. The product label includes warnings and precautions for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity. This is the first approval of a drug specifically for patients with RET alterations globally.

Immune Response Evaluation and Treatment with Immune Checkpoint Inhibitors Beyond Clinical Progression: Response Assessments for Cancer Immunotherapy.

PURPOSE OF REVIEW: This review provides a comprehensive assessment of recent literature reports describing atypical response patterns observed with immune checkpoint inhibitors (ICIs), modifications to response evaluation criteria for ICIs, and treatment beyond progression in clinical trials. RECENT FINDINGS: Certain response patterns such as durable response, pseudoprogression, hyperprogression, and dissociated responses can be seen with ICI treatment. These patterns carry differing prognoses and are associated with varied factors. There are multiple modifications of standard Response Evaluation Criteria in Solid Tumors (RECIST) that have been proposed to better characterize immunotherapy response; however, standard RECIST1.1 remains most commonly used in clinical trials. Treatment beyond progression varies in frequency and benefit depending on assessment criteria and cancer type. Future research incorporating modified imaging criteria and biomarker assessments may serve to clarify who will benefit most from treatment beyond progression.

Evaluation of Overall Response Rate and Progression-Free Survival as Potential Surrogate Endpoints for Overall Survival in Immunotherapy Trials.

Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria-based overall response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials.Experimental Design: Thirteen randomized, multicenter, active-control trials containing immunotherapeutic agents submitted to the FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS, and OS were evaluated at individual and trial levels. Patient-level responder analysis was performed for PFS and OS.Results: The coefficient of determination (R²) measured the strength of associations, where values near 1 imply surrogacy and values close to 0 suggest no association. At the trial level, the association between hazard ratios (HR) of PFS and OS was R2 = 0.1303, and between the odds ratio (OR) of ORR and HR of OS was R2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 and 0.1, and individual-level correlations were approximately 0.6. HRs of PFS and OS for responders versus nonresponders were 0.129 [95% confidence interval (CI), 0.11-0.15] and 0.118 (95% CI, 0.11-0.13), respectively.Conclusions: Although responders exhibited longer survival and PFS than nonresponders, the trial-level and individual-level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations. Clin Cancer Res; 24(10); 2268-75. ©2018 AACRSee related commentary by Korn and Freidlin, p. 2239.