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Rationale and design of a single-arm, phase 2, multi-center study of chemo-immunotherapy followed by hypo-fractionated RT and maintenance immunotherapy in patients with unresectable stage III NSCLC: the DEDALUS trial.

Published:January 20, 2023DOI:https://doi.org/10.1016/j.cllc.2022.12.015

      Abstract

      Purpose

      This single-arm, phase 2, multi-center, study aims to assess the safety and efficacy of a regimen of induction chemo-immunotherapy followed by de-intensified, hypo-fractionated thoracic radiotherapy (RT) given concurrently with durvalumab and maintenance durvalumab in patients with unresectable, stage III NSCLC.

      Material and methods

      we will enroll 45 patients with unresectable stage III NSCLC, any PD-L1, deemed ineligible for concurrent CRT by a thoracic oncology multidisciplinary team, and candidate to sequential chemoradiation followed by durvalumab.

      Results

      Primary endpoint is safety, defined by the incidence of grade 3 and 4 possibly related adverse events (PRAEs) within six months from the initiation of treatment. The secondary objectives are PFS and OS (median and 12 months). Ancillary endpoints are molecular response evaluated by cfDNA isolation baseline, after chemo-immuno RT and at progression, and radiomics analysis on CT scans at baseline and before maintenance.

      Conclusions

      DEDALUS phase 2 trial explores the safety and efficacy of a novel sequence of chemo-radiation (with de-intensified RT) plus the anti-PD-L1 agent durvalumab in patients with stage III unresectable NSCLC who are candidates to sequential chemoradiation plus maintenance immunotherapy.

      Introduction

      PACIFIC regimen is the gold standard for patients with unresectable locally advanced Non-Small Cell Lung Cancer. This combination led to a 5-years PFS rate of 33.1% and a 5-years OS rate of 42.9%. Updated OS was consistent with a 28% reduction in the risk of death with Durvalumab versus placebo (HR=.72 )
      • Spigel DR
      • Faivre-Finn C
      • Gray JE
      • et al.
      Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.
      . Despite these data, many patients are not eligible to concurrent CRT due to age, comorbidities, or both
      • De Ruysscher D
      • Botterweck A
      • Dirx M
      • et al.
      Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study.
      . Results of PACIFIC-6 trial are promising: PFS is 10,9 months and 12-month PFS rate is 49,6%; median OS is 25 months with a 12-months OS rate of 84,1%
      • Garassino M
      • Faivre-Finn C
      • Mazieres J
      • et al.
      PACIFIC-6: A phase II Study of Durvalumab following sequential chemoradiotherapy in patients with stage III.
      .
      DEDALUS phase 2 study explores the use of a new sequential approach, by: potentiating induction chemotherapy effects through the concomitant use of durvalumab, de-intensifying RT with concurrent durvalumab administration for responding patients and keeping maintenance durvalumab as per PACIFIC regimen.

      Discussion

      Chemo-immunotherapy induction phase

      Regarding the induction phase, the chemotherapy regimen is platinum and etoposide; safety data are available from the CASPIAN trial in SCLC for the combination of cisplatin or carboplatin-etoposide plus durvalumab
      • Goldman JW
      • Dvorkin M
      • Chen Y
      • et al.
      CASPIAN investigators. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label.
      . An higher response rate of this combination compared to CT alone is expected, based on the results of neoadjuvant studies combining chemotherapy plus anti-PD1 agents in resectable stage III NSCLC
      • Forde PM
      • Spicer J
      • Lu S
      • et al.
      Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial.
      . As shown in NADIM trial, in patients who received Nivolumab plus CT as neoadjuvant therapy, the percentage of pCR (pathological complete response) was 24% vs 2,2% with CT alone
      • Forde PM.
      • Spicer J
      • Provencio T
      • et al.
      Neoadjuvant Nivolumab plus Chemotheray in resectable Lung Cancer.
      .
      In the present study, we hypothesized to apply the principles of sequential CT-RT plus durvalumab maintenance, and of neo-adjuvant approaches for resectable NSCLC, using a more robust induction regimen and delivering radiation concurrently with durvalumab.

      Hypo-fractionated RT plus durvalumab

      In the RTOG 0617 trial, a 2-by-2 factorial design was used to compare standard dose (60 Gy) to high dose (74 Gy) radiation delivered with concurrent platinum-based chemotherapy with or without cetuximab in the treatment of locally advanced, unresectable NSCLC. After a median follow-up of 5 years in surviving patients, radiation dose escalation was associated with a worse 5-year OS of 23% versus 32% (p=.004) compared with the standard dose
      • Bradley JD
      • Paulus R
      • Komaki R
      • et al.
      A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small-cell lung cancer: results on radiation dose in RTOG 0617.
      .
      Jin et al. hypothesized that an increased inherent dose of radiation to the host immune system in the high-dose arm of RTOG 0617 may have hindered tumor response and contributed to the poorer outcomes seen in the experimental arm
      • Jin JY
      • Hu C
      • Xiao Y
      • Zhang H
      • et al.
      Higher Radiation Dose to the Immune Cells Correlates with Worse Tumor Control and Overall Survival in Patients with Stage III NSCLC: A Secondary Analysis of RTOG0617.
      .
      In retrospective series
      • Amini A
      • Lin SH
      • Wei C
      • Allen P
      • Cox JD
      • Komaki R.
      Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non-small cell lung cancer.
      • Pollom EL
      • Qian Y
      • Durkee BY
      • et al.
      Hypofractionated intensity-modulated radiotherapy for patients with non-small cell lung cancer.
      , a radiation schedule of 45 Gy in 15 fractions, when compared with higher dose regimens, did achieve comparable response rates, locoregional control, and OS; treatment toxicity was also not found to be different. More recently, a mono-institutional retrospective study tested 45 Gy in 15 fractions delivered with intensity-modulated radiation therapy (IMRT), with excellent compliance, and efficacy was superimposable for local control, PFS and OS
      • Ladbury CJ
      • Rusthoven CG
      • Camidge DR
      • Kavanagh BD
      • Nath SK.
      Impact of Radiation Dose to the Host Immune System on Tumor Control and Survival for Stage III Non-Small Cell Lung Cancer Treated with Definitive Radiation Therapy.
      .
      These results sustain the feasibility, efficacy, and tolerance profile of a hypo-fractionated 45 Gy regimen; a reduced radiation dose should also be associated with a lower incidence of grade 3 lymphopenia, improving immunotherapy efficacy
      • Abravan Azadeh
      • Faivre-Finn Corinne
      • Kennedy Jason
      • McWilliam Alan
      Marcel van Herk. Radiotherapy-Related Lymphopenia Affects Overall Survival in Patients With Lung Cancer.
      .
      Finally, mean heart dose would be drastically reduced by a combination of modern RT techniques (IMRT) and lower prescription dose; as cardiac exposure is known to be associated with late mortality
      • Banfill K
      • Giuliani M
      • Aznar M
      • et al.
      IASLC Advanced Radiation Technology Committee. Cardiac Toxicity of Thoracic Radiotherapy: Existing Evidence and Future Directions.
      , our experimental regimen would potentially reduce long-term, treatment-related mortality.

      Maintenance phase

      Durvalumab will be administered at a flat dose of 1500 mg every four weeks for a maximum of 12 months from the end of radiotherapy (or until progression or discontinuation due to adverse events).

      Study endpoints

      The primary endpoint is to assess the safety and tolerability, as defined by Grade 3 and Grade 4, possibly related adverse events (PRAEs) within six months from the initiation of treatment.
      The secondary endpoint is to assess the efficacy of the proposed treatment strategy in terms of PFS (median PFS and PFS at 12 months according to RECIST 1.1).
      Other secondary endpoints are OS (median OS and OS at 12 months) and quality of life (through administration of EORTC QLQ-C30 and LC13 questionnaires at different time points).
      An exploratory endpoint is to correlate radiomic signatures extracted from baseline and post-RT computed tomography scans to PFS and a correlation between Minimal Residual Disease (MRD) evaluated with cfDNA levels and PFS and OS.

      Statistical Plan

      Since the primary objective is to estimate the safety of the whole sequence, the safety and efficacy analysis set will include all patients who initiated treatment.
      Descriptive statistics will be obtained for all variables assessed in the study population. Mean and standard deviation will be used for normally distributed variables, the mean and interquartile range for skewed distributions, proportions for categorical variables. Whenever relevant, two-sided 95% confidence intervals will be calculated and serve as the basis for sample size calculations in future trials.
      The proportion of patients experiencing grade 3 or 4 PRAEs (according to CTCAE) within six months from enrollment will be calculated together with the corresponding 95% confidence intervals (CI) in the safety set, in the modified and the long-term safety set.
      The Kaplan-Meier estimates for reaching grade 3 or 4 PRAEs over the six months following enrolment will be produced; the observation will start at the date of consent and end at grade 3-4 PRAE, or the date of the last follow-up, whichever comes first. Patients who die will be counted as PRAE (scenario 1) or censored (scenario 2). We do not anticipate performing competing risk time-to-PRAE analyses considering the small sample size. The resulting estimates will be compared to the literature results for comparable treatment strategies available at the analysis time.
      For the secondary endpoints, the cumulative proportion of patients alive at the end of the study period will be described, together with its corresponding 95% CI. Analogously, we will report on patients alive with no progression. These will be computed using the Kaplan-Meier estimates, with the corresponding 95% CI at each month. Results will be compared to literature for comparable treatment strategies available at the time of analysis. Quality of life scores will be computed and compared over time using a mixed regression model.
      All analyses will be performed using the Stata software (version 17 or later, StataCorp, College Station, TX, USA)
      Figure 1.
      Figure 1
      Figure 1– Study design. Abbreviations: CT: chemotherapy; RT: radiotherapy; CR: complete response; PR: partial response; SD: stable disease; ECOG PS: Eastern Cooperative Oncology Group Performance Status; MRD: minimal residual disease; cfDNA: circulating-free DNA Primary endpoint: safety, defined by the incidence of grade 3 and 4 possibly related adverse events (PRAEs). Secondary endpoint: progression free survival and overall survival (median and 12 months).

      Sample Size

      The incidence of PRAE with this innovative schedule is unknown. According to previous studies which combine chemo-radio-immunotherapy in this setting, we considered an estimated proportion of PRAEs ≥ G3 within six months not to exceed 35% as acceptable. The sample size was evaluated in 45 patients, with an expected rate of PRAEs of 20%, which corresponds to an upper limit of the confidence interval of 34.6% (9.6-34.6%).
      A sample of 45 patients would allow detecting a difference in PFS at 12 months of 20% in favor of the experimental regimen, based on expected PFS with standard therapy of nearly 0% with a statistical power of 87 % and one-sided alpha error = 0.05.

      Ancillary studies

      Radiomics: CT scan will be acquired baseline and at the end of RT-durvalumab. Lesion segmentation will be performed on the radiotherapy treatment planning suite. All radiomic analysis will be carried out at University of Pavia Radiomic Lab.
      Liquid Biopsy: monitoring of minimal residual disease (MRD) by inspecting evolving molecular features in a longitudinal series of liquid biopsy specimens at different timing points (baseline, post CRT and at PD). This activity will be aimed to identification of evolving molecular hallmark in terms of variation of mutated allele frequencies (MAF) previously detected on matched tissue specimens.

      Conclusions

      DEDALUS trial will assess the safety and efficacy of a schedule of chemo-immunotherapy with de-escalated, hypo-fractioned radiotherapy and durvalumab, followed for responders by durvalumab maintenance. The trial is currently recruiting (estimated completion date: June 2025).

      Declaration of Competing Interest

      Funding: the study is sponsored by Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and supported by an institutional research grant from Astra Zeneca, Cambridge, UK.

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