Factors associated with failure to start consolidation durvalumab after definitive chemoradiation for locally advanced NSCLC.

Introduction: The introduction of consolidation immunotherapy after chemoradiotherapy has improved outcome for patients with locally advanced non-small cell lung cancer. However, not all patients receive this treatment. This study identifies factors associated with failure to start durvalumab as consolidation therapy with the aim of optimizing treatment, supportive care and prehabilitation to ensure that more patients complete the planned treatment. Materials and methods: Patients from two clinical trials and a named patient use program, were included in this study. All patients received platinum-doublet chemotherapy concomitant with radiotherapy to a total dose of 60-66 gray. Patient characteristics, cancer treatment, toxicity, performance status and laboratory data before and after chemoradiotherapy were recorded and patients who never started durvalumab were compared with those who did. Results: A total of 101 patients were included, of which 83 started treatments with durvalumab after chemoradiotherapy. The 18 patients who did not start durvalumab had significantly higher lactate dehydrogenase at baseline and a worse performance status, cumulative toxicity and higher c-reactive protein after completed chemoradiotherapy. Data also suggest that pre-treatment diabetes and reduced hemoglobin and/or diffusion capacity of the lungs for carbon monoxide contribute to the risk of treatment abruption. Conclusion: Treatment plan disruption rate was 18%. Systemic inflammation and performance status were associated with failure to receive durvalumab after chemoradiation. Further studies are needed to confirm findings and prospective trials should investigate whether prehabilitation and supportive treatment could help more patients finishing the planned treatment. Clinical Trial Registration: clinicaltrials.gov, identifier NCT03798535; NCT04392505.

Atezolizumab and stereotactic body radiotherapy in patients with advanced non-small cell lung cancer: safety, clinical activity and ctDNA responses-the ComIT-1 trial.

The introduction of immune checkpoint inhibitors has transformed the treatment landscape of metastatic non-small cell lung cancer. However, challenges remain to increase the fraction of patients achieving durable clinical responses to these drugs and to help monitor the treatment effect. In this phase II trial, we investigated the toxicity, systemic responses and circulating tumour DNA responses in patients (n = 21) with advanced non-small-cell lung cancer treated with atezolizumab and stereotactic body radiotherapy in the second or later line. We found the combined treatment to be safe with grade 3 toxicity reported in three patients. As the best overall response, four patients had a partial response, eight had stable disease and five had progressive disease. Median overall survival time was still not reached after a median follow-up of 26.5 months and 10/15 patients with programmed death-ligand 1 negative tumours were alive >18 months after the start of the study treatment. ctDNA was detectable at baseline in 11 patients. A rapid decline in ctDNA to <30% of baseline levels was seen in three patients, two of which were radiographic responders and one was considered clinically benefiting from therapy for almost 1 year.

[Checkpoint inhibitor-induced myocarditis] / Sjekkpunkthemmerindusert myokarditt.

Immunological checkpoint inhibitors have been revolutionary in the treatment of cancer. A rare but serious adverse effect is the development of heart muscle inflammation (myocarditis). The prevalence of this type of myocarditis is increasing as more cancer patients receive treatment with immune checkpoint inhibitors. Knowledge of immune checkpoint inhibitor-induced myocarditis is important to enable early diagnosis and initiation of treatment. In this article we provide a clinical review of this.

NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients. METHODS: NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy. DISCUSSION: Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1 .