Mauti LA, et al. ESMO 2017:1615O

Pembrolizumab as second- or further-line treatment in relapsed malignant pleural mesothelioma: A Swiss registry

Background

Programmed death (ligand)-1 (PD-[L]1) checkpoint inhibitors have demonstrated promising activity for patients with malignant pleural mesothelioma (MPM) in early clinical trials,1,2 leading to the off-label use of pembrolizumab in Switzerland as second- or further-line treatment in patients with MPM. Data from a retrospective registry study on pembrolizumab use in patients with MPM in Switzerland were presented at the ESMO 2017 Annual Congress.3

Study design

  • This registry study was a retrospective analysis of data on patients with relapsed MPM who received pembrolizumab in 13 cancer centres in Switzerland.
  • Response outcomes for pembrolizumab were assessed by the local investigators using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • PD-L1 expression was quantified in a central laboratory using antibody SP263 (Ventana).

Key findings

Baseline characteristics and disposition

  • Data were collected on 48 patients who received pembrolizumab for relapsed MPM between September 2015 and April 2017.
  • The median age at diagnosis was 68.5 years (range: 25–86), 96% of patients were male, and 18 patients (39%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at the start of pembrolizumab treatment.
  • Pembrolizumab was the second-line treatment in 31 patients (65%).
  • Platinum chemotherapy and pemetrexed was given to 46 patients (96%) in a prior line of therapy.
  • The median time since diagnosis was 8.7 months (interquartile range: 6.9–18.1).
  • Doses of pembrolizumab included:
    • 10 mg/kg every two weeks (q2w) (5 patients, 10%);
    • 200 mg q2w (1 patient, 2%);
    • 2 mg/kg q2w (4 patients, 8%);
    • 200 mg every three weeks (q3w) (28 patients, 58%); and
    • 2 mg/kg q3w (9 patients, 19%).
  • The median duration of treatment was 3.0 months (95% CI: 2.7–4.1) and treatment is ongoing in eight patients.

Efficacy

  • At a median follow-up of 8.8 months, the overall response rate (ORR) in the total population was 25% (1 complete response and 11 partial responses).
  • The disease control rate (DCR) was 52%, including 13 patients with stable disease.
  • The median progression-free survival (PFS) and median overall survival (OS) in the total population were 3.6 months (95% CI: 2.6–5.5) and 7.2 months (95% CI: 4.9–10.2), respectively. (Figure 1)
    • The 3-month and 6-month PFS rates were 57% (95% CI: 44–73) and 30% (95% CI: 19–47), respectively.
    • The 6-month and 12-month OS rates were 63% (95% CI: 50–79) and 21% (95% CI: 10–47), respectively.
  • Response and survival outcomes by subgroup are listed in Table 1.
  • Of the 28 patients with epithelioid histology, 24 patients (86%) had less than 5% membraneous PD-L1 staining of their tumour cells. (Figure 2)

Figure 1. Survival outcomes in all patients

Table 1. Outcomes by subgroup

Figure 2. PD-L1 quantification and association with histology

Safety

  • Fifteen treatment-related adverse events (TRAEs) were observed in 14 patients (29%).
  • The most common grade 1/2 TRAEs included fatigue (3 patients, 6%), dyspnea (2 patients, 4%), and diarrhea/colitis (2 patients, 4%).
  • Five grade 3/4 TRAEs were observed (one event of each noncardiac chest pain, heart failure, and nephrotic syndrome; two events of hepatitis), four of which were resolved.
  • Seven patients (15%) discontinued pembrolizumab due to TRAEs.

Key conclusions

  • The response rate (ORR 25%) and survival outcomes (in selected patients) with pembrolizumab in this Swiss registry trial were comparable to early clinical trial data with PD-(L)1 inhibitors.1,2,4
  • Survival outcomes in the unselected population (“real-life” setting) were promising compared to available second-line and beyond treatment options (median PFS = 3.6 months, median OS = 7.2 months).
  • Patients with an ECOG PS of 0/1 receiving pembrolizumab in the second line benefitted substantially from treatment (median PFS = 5.3 months, median OS = 10.2 months).
  • Sarcomatoid histology might be predictive of better outcomes with pembrolizumab and higher PD-L1 expression correlated with better outcomes.
  • PD-L1 expression was significantly associated with histology.
  • Ongoing prospective randomized control trials will help to elucidate the role of checkpoint inhibitors in MPM.

References: 1. Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b, trial. Lancet Oncol 2017;18(5):623–30. 2. Kindler H, Karrison T, Tan Y-HC, et al. Phase II trial of pembrolizumab in patients with malignant mesothelioma. WCLC Meeting Abstracts 2016:OA13.02. 3. Mauti LA, Klingbiel D, Schmid S, et al. Pembrolizumab as second or further line treatment in relapsed malignant pleural mesothelioma: A Swiss registry study. ESMO Annual Congress Abstracts 2017:1615O. 4. Quispel-Janssen J, Zago G, Schouten R, et al. A phase II study of nivolumab in malignant pleural mesothelioma (NivoMes): with translational research (TR) biopies. WCLC Meeting Abstracts 2016:OA13.01.