In June, the United States (US) Food and Drug Administration (FDA) approved 10 new indications for cancer treatment, including five new indications for immune checkpoint inhibitors.

Avelumab for Maintenance Treatment in Urothelial Cancer (UC).

Avelumab (Bavencio®,EMD Serono, Inc. and Pfizer Inc.) was approved for the maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy. The approval was based on results from the randomized, open-label, phase III JAVELIN Bladder 100 trial that enrolled 700 patients. Patients received either avelumab plus best supportive care (BSC) or BSC alone. The main efficacy outcome measures were overall survival (OS) in all patients, and in patients with PD-L1-positive tumors. Median OS in all patients was 21.4 months in the avelumab arm versus 14.3 months in the BSC alone arm (hazard ratio (HR) 0.69; P=0.001). Among patients with PD-L1-positive tumors (51%), the HR for OS was 0.56 (P<0.001). For more details on these results see ACE OncoBlog, 05 June 2020.

A New Indication for Nivolumab in Esophageal Squamous Cell Carcinoma (ESCC).

Accelerated approval was granted to nivolumab (Opdivo®, Bristol-Myers Squibb Co.) for the treatment of patients with unresectable advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy, based on survival data from the randomized, active-controlled, open-label ATTRACTION-3 trial. The trial included 419 patients, who received either nivolumab or investigator’s choice of taxane chemotherapy consisting of docetaxel or paclitaxel. Median OS for patients receiving nivolumab was 10.9 months compared with 8.4 months in patients receiving taxane chemotherapy (HR 0.77; P=0.0189). The OS benefit was observed regardless of tumor PD-L1 expression level.

Three New Indications for Pembrolizumab:

First-Line Therapy for Colorectal Cancer (CRC).

Pembrolizumab (Keytruda®, Merck & Co.) received approval for the first-line treatment of patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) CRC. Approval was based on the results from the open-label, active-controlled, randomized, phase III KEYNOTE‑177 trial that enrolled 307 patients. Patients received either pembrolizumab or investigator’s choice of mFOLFOX6/FOLFIRI ± bevacizumab or cetuximab. The main efficacy outcome measures were progression-free survival (PFS) and OS. Median PFS was 16.5 months in the pembrolizumab arm versus 8.2 months in the chemotherapy arm (HR 0.60, P=0.0004). At the time of the PFS analysis, the OS data were not yet mature. For more details on these results see ACE OncoBlog, 19 June 2020.

Treatment of Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma(cSCC).

Pembrolizumab was approved for the treatment of patients with recurrent or metastatic cSCC that is not curable by surgery or radiation, based on efficacy data from the non-randomized, open-label, single-arm phase II KEYNOTE-629 trial. The trial enrolled 105 patients, who received pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 24 months. The primary endpoint was objective response rate (ORR) per blinded independent central review (BIRC) and secondary endpoints included response duration (DOR). Pembrolizumab treatment resulted in a clinically meaningful ORR of 34.3%; median DOR was not reached.

Second-Line Therapy and Beyond in Unresectable or Metastatic Tumor Mutational Burden High (TMB-H) Solid Tumors.

Accelerated approval was granted to pembrolizumab for the treatment of adult and pediatric patients with unresectable or TMB-H solid tumors (as determined by the FDA-approved FoundationOne CDx assay [Foundation Medicine, Inc]) that have progressed following prior treatment and who have no satisfactory alternative treatment options. Approval was based on results from a retrospective analysis of data from a multicenter, non-randomized, open-label phase II KEYNOTE-158 trial that included 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors. A total of 102 patients had tumors identified as TMB-H. ORR per BIRC in these patients was 29%, with 4% complete response (CR) and 25% partial response (PR). The median DOR was not reached, with 57% of patients having response durations ≥12 months and 50% of patients having response durations ≥24 months.

Lurbinectedin, a New Second-Line Option for Metastatic Small Cell Lung Cancer (SCLC).

Accelerated approval was granted to lurbinectedin (Zepzelca™, Pharma Mar S.A.) for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Efficacy was demonstrated in an open-label, multi-cohort phase II single agent study where 105 patients with metastatic SCLC, who had disease progression on, or after, platinum-based chemotherapy, received lurbinectedin. The main efficacy outcome measures were investigator assessed ORR and DOR. ORR was 35%, with a median DOR of 5.3 months.

Subcutaneous Formulation of Pertuzumab and Trastuzumab with Hyaluronidase for HER2-Positive Breast Cancer (BC). 

A new fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase–zzxf(Phesgo™, Genentech, Inc.) for subcutaneous injection was approved for use in two indications. The first indication is in combination with chemotherapy for neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage BC, as part of a complete treatment regimen for early BC, and also as adjuvant treatment of patients with HER2-positive early BC at high risk of recurrence. The second indication is in combination with docetaxel for the treatment of patients with HER2-positive metastatic BC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Efficacy and safety were evaluated in the open-label, randomized phase III FeDeriCa trial, in which 500 patients with operable or locally advanced HER2-positive BC received chemotherapy with concurrent administration of either the combination of pertuzumab and trastuzumab and hyaluronidase–zzxfas subcutaneous injection, or pertuzumab plus trastuzumab IV, during the neoadjuvant and adjuvant therapies. The subcutaneous formulation of pertuzumab and trastuzumabwas shown to be non-inferior to combination of pertuzumab plus trastuzumab IV, and the pathological CR rate was 59.7% versus 59.5%, respectively. The safety profile was also comparable except for increased administration-related reactions with subcutaneous application.

Selinexor as Late Line Treatment for Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL).

Accelerated approval was granted to selinexor, a first-in-class oral selective inhibitor of nuclear export (Xpovio®, Karyopharm Therapeutics) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Approval was based on results from the open-label, single-arm phase II SADAL trial that included 127 patients. Patients received selinexor until disease progression or unacceptable toxicity. ORR, per IRC was 28%, which met the primary endpoint, 12% achieved a CR and 17% a PR. The median DOR was 9.3 months, and 23 months for patients with CR. The prescribing information for selinexor contains warnings and precautions for thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremia, serious infection, neurological toxicity, and embryo-fetal toxicity.

Tazemetostat for Second-Line Therapy and Beyond in Relapsed or Refractory Follicular Lymphoma (R/R FL).

Tazemetostat (Tazverik™, Epizyme, Inc.), an EZH2 inhibitor, was granted accelerated approval for the treatment of patients with R/R FL who are EZH2 mutation positive, per Cobas EZH2 Mutation Test (Roche Molecular Systems, Inc.), and have received at least two prior systemic therapies. Additionally, patients with R/R FL who have no satisfactory alternative treatment options may also receive this treatment. Approval was based on results from the open-label, single-arm, multi-center, phase II study that included EZH2 mutation positive patients and wild-type EZH2 patients.ORR and DOR, the major efficacy outcomes, were assessed by IRC. ORR in 42 patients with EZH2 mutant R/R FL was 69%, with 12% CR and 57% PR; median DOR was 10.9 months. ORR in 53 patients with EZH2 wild-type R/R FL was 34%, with 4% CR and 30% PR; median DOR was 13 months.

Gemtuzumab Ozogamicin (GO) Indication for Newly Diagnosed AML Extended.

TheFDA extended the approval of gemtuzumab ozogamicin (Mylotarg™, Wyeth Pharmaceuticals LLC) for newly-diagnosed CD33-positive AML to include pediatric patients aged ≥1 month. Efficacy and safety data from the randomized phase III AAML0531 trial, which included patients aged 0 – 29 years with newly-diagnosed AML, supported this approval. Patients received either chemotherapy alone or chemotherapy with GO. The main efficacy outcome measure was event-free survival (EFS), measured from the date of trial entry until induction failure, relapse, or death by any cause; the EFS HR was 0.84. At 5 years, the estimated percentage of patients free of induction failure, relapse, or death was 48% in the chemotherapy plus GO arm versus 40% in the chemotherapy alone arm. However, there were no differences in overall survival between the two arms.