13/008 PEARL

The aim of this clinical trial is to determine the activity and safety of treating a site of disease with a single fraction of SABR during immunotherapy with nivolumab in advanced NSCLC progressing after 1 or 2 lines of chemotherapy. Participants will be randomly allocated in a ratio of 2:1 to either nivolumab 240mg every 2 weeks plus SABR (experimental) or nivolumab 240mg every 2 weeks alone (control). Nivolumab is continued until disease progression or prohibitive toxicity. Participants will be assessed regularly for treatment response and side effects during the treatment and follow up phase. Clinical assessments will be performed before each cycle of nivolumab (2 weekly) and CT scans at baseline, week 6, 12, 18, 24 then 12 weekly until progression. Anticancer treatments and survival will be reviewed every 12 weeks after progression. This will enable us to determine the activity and safety of each treatment option in patients with an asymptomatic metastasis.

STIMULI investigated the efficacy and tolerability of the standard treatment (chemotherapy and radiotherapy) alone, compared with the standard treatment followed by nivolumab and ipilimumab (immunotherapy) in patients with limited stage SCLC. The results of STIMULI showed no significant difference between the immunotherapy and observation groups. Overall, there was no difference in the percentage of people with cancer progression at 12 and 24 months after starting immunotherapy or observation. There was also no difference in the percentage of people alive at 24 months, and the amount of tumour shrinkage was no different between the two groups. There was some data to suggest that immunotherapy after a more frequent radiotherapy schedule may be more effective, but this needs to be studied further.

OSCILLATE measured the duration before progression when patients with EGFR-T790 mutation positive advanced NSCLC were treated with osimertinib and gefitinib. It was hypothesised that alternating therapy with the gefitinib and osimertinib would modulate the populations of EGFR-T790M positive and negative tumour clones, delaying the emergence of resistance to osimertinib. Sixty-eight percent of participants in OSCILLATE were able to complete 6 months of treatment without any delays or interruptions due to side effects, suggesting that the alternating approach was safe and feasible. The lung cancer was still under control 12 months after starting treatment in 38% of the participants, but this was not a statistically significant outcome. The side effects of treatment in OSCILLATE were similar to those seen in trials using either drug on its own. Accompanying translational research studies on samples obtained from patients have contributed to current understanding of resistance to EGFR tyrosine kinase inhibitor therapy.

ALKTERNATE evaluated the efficacy, safety and feasibility of alternating lorlatinib and crizotinib for the treatment of ALK-rearranged advanced NSCLC, and provided information on the potential to delay the emergence of drug resistance compared to historical findings of continuous lorlatinib therapy alone.