BIOLUMA: A phase II trial of nivolumab and ipilimumab in lung cancer—Results from the SCLC TMBhigh cohort.
Authors: Fischer Rieke Nila , George Julie , Calaminus Andreas H. , Schloesser Hans Anton , Weber Jan-Phillip , Brossart Peter , Engel-Riedel Walburga , Griesinger Frank , Grohé Christian , Kern Jens , Nachtkamp Kathrin , Panse Jens Peter , Sebastian Martin , Wiewrodt Rainer Gerhard , Büttner Reinhard , Thomas Roman K. , Wolf Juergen 
Published: June 2024

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Background: Therapeutic options and prognosis for patients with small-cell lung cancer (SCLC) remain poor. Treatment with checkpoint inhibition can achieve remarkable responses, but this holds true for a small percentage of SCLC patients only. While tumor mutation burden (TMB) emerged as possible predictive biomarker for nivolumab and ipilimumab combination therapy in SCLC patients, to our knowledge, tissue-based TMB has never been evaluated prospectively in SCLC patients. Here, we present the results of the cohort 2b of the BIOLUMA trial, which evaluates efficacy and safety of nivolumab in combination with ipilimumab in SCLC patients with high tumor mutation burden. Methods: BIOLUMA is an investigator initiated multicentre non-randomised phase II trial in 2nd line patients with SCLC. The initial all-comer SCLC cohort was amended for inclusion of patients with high TMB only. FFPE tumor tissue was used for TMB pre-screening by whole exome sequencing (WES) at time of first diagnosis. TMBhigh was defined as the upper tertile of total missense mutations. After progression on platinum-based therapy, patients received 4 cycles of nivolumab 1 mg/kg q3w in combination with ipilimumab 3 mg/kg q3w and subsequently nivolumab 240 mg flat dose as monotherapy. Primary endpoint was overall response rate (ORR) of the combination therapy. Additionally, exploratory analyses of sequential tumor biopsies and blood samples were performed at different time points. Results: TMB analysis was feasible for most patients without necessity of performing additional tumor biopsy. Evaluation of TMB on FFPE tumor tissue obtained at first diagnosis was sufficient for TMB analysis in 92.5% of cases. TMB status was determined for 297 patients: 45.8% belonged to the TMB high group, while 54.2% had low or medium TMB. In total, 45 TMBhigh patients were enrolled in the study with 44 subjects evaluable for primary endpoint analysis. Six patients (13.6%) showed response to therapy, of whom in 4 patients (9%) response could be confirmed according to RECIST 1.1 criteria. One patient, who is not evaluable for endpoint analysis experienced a remarkably long lasting PR, which is still ongoing for more than three years. This patient received concomitant palliative radiation during induction with nivolumab and ipilimumab. Disease control rate (DCR) was 20.4% (n=9), three more patients showed unconfirmed SD. Three patients with confirmed PR or SD experienced long lasting treatment benefit, which is still ongoing at data cut-off. Conclusions: This represents the first trial to prospectively evaluate the combination therapy of nivolumab and ipilimumab in TMBhigh SCLC patients. The primary endpoint ORR was not reached. However, we observed an impressive clinical benefit in single patients, which warrants further investigation in order to get more insight into the mechanisms leading to these long-lasting tumor responses. Clinical trial information: NCT03083691 .