Thoracic radiotherapy plus Durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy - employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy: study protocol of the TRADE-hypo trial

Abstract

Background: Non-small cell lung cancer is the most common cause of cancer death worldwide, highlighting the need for novel therapeutic concepts. In particular, there is still a lack of treatment strategies for the group of elderly and frail patients, who are frequently not capable of receiving standard therapy regimens. Despite comprising the majority of lung cancer patients, this group is underrepresented in clinical trials. This applies also to elderly and frail patients suffering from unresectable stage III NSCLC, who are unfit for chemotherapy, and, therefore, cannot receive the standard therapy comprising of radiochemotherapy and the recently approved subsequent durvalumab consolidation therapy. These patients often receive radiotherapy only, which raises the concern of undertreatment. The TRADE-hypo trial aims at optimizing treatment of this patient group by combining radiotherapy with concomitant durvalumab administration, thereby employing the immune-promoting effects of radiotherapy, and determining safety, feasibility, and efficacy of this treatment.

Methods/ design: In this prospective phase II clinical trial, durvalumab therapy will be combined with either conventionally fractionated (CON-group) or hypofractionated (HYPO-group) thoracic radiotherapy. A safety stop-and-go lead-in phase will assess safety of hypofractionated radiotherapy with respect to severe pneumonitis in small patient cohorts before opening full enrollment. Tumor tissue, blood and stool samples will be collected before and during the study period to investigate the immunological mechanisms responsible for checkpoint inhibitor efficacy and immune-promoting effects of radiotherapy.

Discussion: Preclinical data suggests that irradiation-induced immunogenicity can be further increased if applied in a hypofractionated setting, potentially boosting the expected synergistic effect with immune checkpoint inhibition in restoring the immune anti-tumor response. If proven safe and efficient, a hypofractionated radiation schedule can provide a considerably more practicable option for the patient. Taking into consideration the intend to develop a combination treatment strategy that can be made available to patients soon after proving to be efficient and the potentially elevated toxicity of a hypofractionated radiotherapy approach, this trial was designed as a two-trials-in-one design. An accompanying translational research program is planned striving to gain insights into the tumor-host biology and to identify suitable biomarkers to predict therapy response.

Trial registration: Clinicaltrials.gov , NCT04351256 . Registered 17 April 2020, Eudra-CT, 2019-002192-33 . Registered 24 October 2019.

Keywords: Anti-PD-L1 monoclonal antibody; Geriatric risk profile; Hypofractionated radiation; Immune checkpoint inhibition; NSCLC; Non-small cell lung cancer; Radioimmunotherapy.

Conflict of interest statement

The TRADE-hypo trial receives funding from AstraZeneca/ MedImmune. However, AstraZeneca/ MedImmune has not been involved in study design, data collection, management, data analysis and interpretation, or in the decision to submit this protocol for publication. All authors declare that they have no competing interests.

Figures

Fig. 1

Study design of the TRADE-hypo trial. Patients will be enrolled according to eligibility criteria and treated with either a hypofractionated TRT regimen (HYPO-group) or conventionally fractionated TRT (CON-group) in combination with durvalumab. For the HYPO-group, a safety stop-and-go phase with a 6 + 6 design precedes full enrollment. Whenever this arm is open for recruitment, patients will be allocated to this arm until the cohort is closed; whenever HYPO-arm is closed for Stop/ Go decision evaluation based on the toxicity assessment of this regimen 8 weeks after the end of TRT, patients are allocated to the CON-arm. When the study proceeds to expansion phase, patients will be allocated to treatment arms by randomization using “biased coin” algorithm. An efficacy interim analysis will be performed after 18 patients have been enrolled in each arm

Fig. 2

Cohort design of the safety stop-and-go lead-in phase (HYPO-group). The safety lead-in phase follows a 6 + 6 design in order to carefully evaluate the toxicity of the treatment in the HYPO-group with respect of the occurrence of a grade 3/4 pneumonitis (“event”) within 8 weeks after the end of TRT. Two events in the first six patients, two events in the first 12, or two events in the first 18 patients will result in termination of the HYPO-group (“Stop”). If no event is observed within the first two safety cohorts, i.e. the first 12 patients, the HYPO-arm will be opened for full enrollment with close toxicity assessment with respect to pneumonitis grade 3/4, and terminated as soon as two events are reported within the subsequent six patients (“Go*”). Full enrollment in the HYPO-arm will only take place if the criteria for the non-toxicity scenario are met, i.e. ≤ 1 event in n = 18 patients (“Go”)