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In the expansion phase with a cohort of 182 patients with UC, the ORR was 31.0% (95% CI, 17.6–47.1) overall in the 42 response-evaluable patients. The ORR was 46.4% in the PD-L1-positive subgroup and 0% in the PD-L1-negative subgroup, and disease control rate at 12 months was 57.1% and 28.6%, respectively. Patients showed rapid and durable response. Median follow-up of response-evaluable patients was 6.5 months (range, 0.8–14.8 months). The median time to response was 6.3 weeks (95% CI, 5.6–12.1 weeks) in the 13 responding patients, and median duration of response has not been reached (range, 4.1+ to 49.3+ weeks).16 The updated results showed an ORR of 17.8% (34/191; 95% CI, 12.7–24.0), including seven complete responses. The ORRs were 27.6% (n=27; 95% CI, 19.0–37.5) in PD-L1 high patients and 5.1% (n=4; 95% CI, 1.4–12.5) in PD-L1 low or negative patients. Median time to response was 1.41 months (range, 1.2–7.2). Median duration of response in the as-treated population had not been reached at data cutoff (range, ≥0.9 to ≥19.9 months).17 The median OS was 18.2 months (95% CI, 8.1–not estimable) in the as-treated population and 20.0 months (95% CI, 11.6–not estimable) and 8.1 months (95% CI, 3.1–not estimable) in PD-L1 high and low or negative patients, respectively. The OS rates at 6, 9, and 12 months were 64% (95% CI, 56–71), 57% (95% CI, 47–66), and 55% (95% CI, 44–65), respectively, in the as-treated population.17
Durvalumab showed manageable safety profile. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 6.8% of the patients. Treatment-related AEs leading to death occurred in 2 of 191 patients (1.0%) with one autoimmune hepatitis and one pneumonitis. Regarding adverse events of special interest (AESIs), they occurred in 34.6% and were mostly grade 1 or 2. Their cumulative incidence seemed to plateau at around 32 weeks. Almost 5% experienced treatment-related grade 3/4 AESIs (hepatic and skin events).17
Based on these first results, the Food and Drug Administration (FDA) granted accelerated approval to durvalumab in May 2017 for patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy or who have disease progression<12 months after neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
BIOMARKERS AND COMPANION TEST
Finding robust biomarkers that could help select patients who will benefit from immunotherapy is one of the main challenges with immune checkpoint blockers. Mutational burden and high clonal neoantigens have shown great correlation with efficacy of diverse anti-PD-L1/PD-1 and anti-CTLA4 drugs.18,19 PD-L1 expression was one the first biomarkers investigated in multiple tumor types.20–22 In the Phase I/II trial of durvalumab, PD-L1 testing was required. PD-L1 status was determined using a companion test Ventana 2P263 assay. Tumor was considered PD-L1 high with expression on ≥25% of either IC or TC. The first 20 patients were enrolled regardless of their PD-L1 status but subsequent patients were required to have 5% of PD-L1 expression on TCs.16 FDA approval was also granted with the companion test as a complementary diagnostic for the assessment of the PD-L1 protein in formalin-fixed, paraffin-embedded UC tissue. At ASCO 2018, the results of PD-L1 expression in TC or IC on the outcomes of OS, PFS, objective response rate (ORR), best percentage tumor change, and tumor shrinkage 15 months after last subject randomization were presented. Both tumor-infiltrating ICs and TC PD-L1 were linked to higher ORR, and PD-L1 tumor-infiltrating ICs were associated with better survival in patients treated with durvalumab. Remarkably, PD-L1 tumor-infiltrating ICs had a higher impact on response to durvalumab than PD-L1 TC, demonstrating a significant association with OS, PFS, ORR, and tumor shrinkage. The results of this study for patients treated with durvalumab for bladder cancer suggest that a cutoff/algorithm using PD-L1 TC 25%/PD-L1 tumor-infiltrating IC 25% (TC25%/IC25%) provides optimal predictive value based on efficacy and prevalence of the biomarker (HR =0.46; 90% CI: 0.33–0.64).23
FUTURE PERSPECTIVES
Durvalumab is currently under investigation in combination with other agents such as tremelimumab (anti-CTLA4) in various tumor types (Table 3). First results were presented at ASCO 2018 for the combination of durvalumab and tremelimumab in patients with localized, high-risk, muscle-invasive bladder carcinoma who are ineligible for cisplatin-containing chemotherapy due to decreased renal function, neuropathy, hearing loss, or heart failure (NCT02812420). Patients received durvalumab (1,500 mg) plus tremelimumab (75 mg) on weeks 1 and 5 and then underwent surgery at weeks 9–11. Twelve patients were enrolled and six completed radical cystectomy; three (50%) had pathologically complete response; one (17%) did not respond; two (33%) had upstaging of disease. Only 1 of 12 patients developed grade 3 immune-related toxicity. These promising results showed interesting potential of using immune checkpoint blockers as a neoadjuvant therapy, and results of larger studies are awaited.24
In the first-line setting, the DANUBE trial is ongoing in UC testing the combination of durvalumab and tremelimumab. Results of this Phase III trial will be presented soon and hopefully showed increased response rate. Many questions remain on how to better select patients and also improve the number of patients who will benefit from immune checkpoint blockers.
Main perspectives are thus combination therapies with either other immune checkpoint blockers, epigenetic drugs, chemotherapy or radiation therapy and hopefully find robust biomarkers to increase response rate (Table 3). One option is possibly to combine immune checkpoint blockers and the other option is to adapt treatment based on biomarkers. This is the purpose of the BISCAY trial (NCT02546661), which is designed to combine Durvalumab with other targeted therapies according to biomarkers. This Phase Ib study is a multiarm trial and is evaluating the combination of durvalumab with AZD4547 (selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases), Olaparib, AZD1775 (WEE1 inhibitor), Vistusertib (mTOR inhibitor), or AZD9150 (STAT3 inhibitor) in patients with UC who have progressed after prior treatment.
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