Phase I dose escalation of pembrolizumab given concurrently with palliative thoracic radiotherapy (RT) for NSCLC

Abstract

Background: Pembrolizumab is used routinely in advanced NSCLC. Combination strategies, such as with RT are of great interest. We report on safety and tolerability of an open-label phase 1 trial for cohort 1 of pembrolizumab with 2 schedules of palliative RT. Methods: All cohort 1 patients started with a pembrolizumab dose of 100mg given 2 weeks prior to RT, and then received pembrolizumab 100mg 2-weekly concurrently with RT, followed by maintenance dose 200mg pembrolizumab 3-weekly. The RT was either 20 Gy/5# (low dose RT - LD) or 36 Gy/12# (high dose RT - HD). Cohort 2 pembrolizumab dose will be 200mg, for all doses, with the same RT schedules. Dose limiting toxicity (DLT) period, 2 months from completing RT, is defined as grade (G) 2 pneumonitis, G4 oesophagitis or G2 myelitis. Results: 3/6 pts in the LD and 6/8 pts in the HD were evaluable for DLTs. Mean age was 61 years, 64% were female, 71% were smokers, ECOG performance status was 1 in 100%. 57% were of non-squamous histology with no driver mutations, and 64% were PD-L1 positive (TPS ≥1%). All pts had adverse events (AEs); G3-4 AEs were seen in 66.7% in the LD and 37.5% in the HD. There were no DLTs. In the LD, G3 AEs included: anaemia (n=1), back pain (n=1), bronchitis (n=1), dyspnoea (n=1), fatigue (n=1), hypokalaemia (n=1), hypophosphataemia (n=1), and syncope (n=2). In the HD, 1 pt had drug induced liver injury (G1 ALT, G3 ALP, G2 AST, G1 bilirubin, G4 GGT), and so the cohort was expanded by a further 3 pts. No DLTs were seen. G3 AEs included: pneumonia (n=1), back pain (n=1), dehydration (n=1), radiation dermatitis (n=1), diarrhoea (n=1), hyperglycaemia (n=1), and hypokalaemia (n=2). 1 pt had G4 urosepsis. In the LD and HD, pts also had RT dermatitis (G1 n=11, G2 n=2), RT esophagitis (G1 n=10, G2 n=4), and RT pneumonitis (G1 n=6). With a median follow-up of 7.9 months, median PFS was 1.3 months in the LD and 3.7 months in the HD (HR 0.28, P=0.056). Median OS was 5.2 months in the LD and 8.3 months in the HD (HR 0.59, P=0.441). Disease control rate (DCR) was 37.5% in the LD (3 SD) and 62.5% in the HD (3 PR, 2 SD; P=0.592). DCR did not correlate with PD-L1 status (P=1.00). Conclusions: Combining pembrolizumab and palliative thoracic RT appears to be safe and tolerable with both RT doses. This trial continues to recruit to cohort 2.