Response and outcomes after anti-CTLA4 versus anti-PD1 combined with stereotactic body radiation therapy for metastatic non-small cell lung cancer: Retrospective analysis of two single-institution prospective trials

This study compared response rates and outcomes of combined radiotherapy and immunotherapy (iRT) based on the type of checkpoint inhibitor (anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) vs antiprogrammed death-1 (PD1)) for metastatic non-small cell lung cancer (mNSCLC).MethodsWe retrospectively reviewed two prospective trials of radiation combined with anti-CTLA4 or anti-PD1 for patients with mNSCLC. Patients undergoing non-salvage stereotactic body radiation therapy (SBRT) to lung sites were selected from both trials and grouped by the immunotherapeutic compound received. Endpoints included in-field and out-of-field response rates, and overall response rate (complete or partial response) (all by response evaluation criteria in solid tumors). Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method.ResultsMedian follow-up times for the 33 patients (n=17 SBRT+anti-CTLA4, n=16 SBRT+anti-PD1) were 19.6 and 19.9 months. Response rates for out-of-field lesions were similar between anti-PD1 (37%) and anti-CTLA4 (24%) (p=0.054). However, global response rates for all lesions were 24% anti-CTLA4 vs 56% anti-PD1 (p=0.194). The PFS was 76% for anti-CTLA4 vs 94% anti-PD1 at 3 months, 52% vs 87% at 6 months, 31% vs 80% at 12 months, and 23% vs 63% at 18 months (p=0.02). Respective OS values were 76% vs 87% at 6 months, 47% vs 80% at 12 months, and 39% vs 66% at 18 months (p=0.08).ConclusionsBoth anti-CTLA4 and anti-PD1 agents prompt a similar degree of in-field and out-of-field responses after iRT, although the global response rate and PFS were statistically higher in the anti-PD1 cohort. Further dedicated study and biological mechanistic assessment is required.Trial registration numbersNCT02239900 and NCT02444741.radiotherapyimmunotherapyIntroductionImmune checkpoint inhibitors have emerged as a treatment option for several types of recurrent or metastatic cancers.1 The most widely used agents presently are anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and anti-programmed death-1 (PD1) antibodies. Anti-CTLA4, widely studied for melanoma, acts to block the inhibitory signal involving the CTLA4 molecule between antigen-presenting cells and T lymphocytes.2 Anti-PD1 compounds analogously block the inhibitory signal involving the PD1 receptor.3 In both cases, diminishing tumor-mediated immune-attenuating effects results in more robust T-cell activation and immune-mediated neoplastic destruction.4These effects may be augmented by radiation therapy (RT), especially stereotactic body radiation therapy (SBRT), which can enhance antigen release for immune recognition and modulate the tumor stroma to facilitate immune cell infiltration.5 6 RT can also lead to responses in out-of-field (unirradiated) tumors, also known as the abscopal effect. Despite emerging evidence regarding favourable interactions between immunotherapy and RT (combined radiotherapy and immunotherapy (iRT)), whether the various immunotherapeutic compounds lead to different outcomes in combination with radiation is currently unknown. Optimizing the efficacy of immunotherapeutics used in iRT is critical not only because several compounds are available to treat metastatic cancers but also because enhancing treatment efficacy could affect the cost-effectiveness of these agents.7 8To address these gaps in knowledge, we retrospectively analyzed two single-institution prospective clinical trials to evaluate whether combining SBRT with anti-CTLA4 versus with anti-PD1 leads to different response and survival outcomes for patients with metastatic non-small cell lung cancer (mNSCLC).MethodsPatients and study designThis retrospective review of two prospective iRT trials involving RT and anti-CTLA4 or anti-PD1 was approved by the institutional review board, as were the original trials, and written informed consent was obtained from all patients. Full information regarding inclusion/exclusion criteria, workup, follow-up, and RT planning (including dose constraints) is described in detail within the protocol for each study. Briefly, all patients in both trials were required to have ≥1 lesion amenable to RT and ≥1 additional non-contiguous lesion so that response to both in-field and out-of-field radiations could be monitored.The first trial investigated SBRT with anti-CTLA4 (ipilimumab) for metastases from solid tumors to the liver, lung, or adrenal gland (n=143 enrolled). The trial protocol is available in online supplementary file 1. Patients received two cycles of anti-CTLA4 (3 mg/kg every 21 days), followed by SBRT and another two cycles of anti-CTLA4. SBRT was given either as 50 Gy in four daily fractions or as hypofractionated SBRT (60 Gy in 10 daily fractions) if a four-fraction regimen was deemed unfeasible or unsafe.SP110.1136/jitc-2019-000492.supp1Supplementary dataThe other trial enrolled 98 patients with stage IV (metastatic) non-small cell lung cancer (NSCLC). The trial protocol is available in online supplementary file 2. RT and anti-PD1 (pembrolizumab 100 mg every 21 days, followed by 200 mg if tolerated) were given concurrently, followed by an additional anti-PD1. The phase I portion of this study examined the safety of the combined regimen; the phase II component randomized patients to anti-PD1 alone versus SBRT with anti-PD1 (patients with progressive disease (PD) on anti-PD1 only were allowed to undergo salvage RT). SBRT was given as 50 Gy in four daily fractions or, if that regimen was considered unfeasible or unsafe, as wide-field RT (non-SBRT) to a dose of 45 Gy in 15 daily fractions. The patient selection process for both of these trials is shown in figure 1.SP210.1136/jitc-2019-000492.supp2Supplementary dataFigure 1Flowchart of patient selection for this analysis. CTLA4, cytotoxic T-lymphocyte-associated protein 4; F/U, follow-up; NSCLC, non-small cell lung cancer; RT, radiation therapy; SBRT, stereotactic body radiation therapy.Because the goal of this study was to evaluate and compare the effects of each immunotherapeutic agent given with SBRT, we compared the following two groups: (1) patients with mNSCLC from the first trial receiving classical or hypofractionated SBRT to lung sites and anti-CTLA4 (CTLA4 group) and (2) patients with mNSCLC from the other trial who received upfront (non-salvage) anti-PD1 and SBRT (PD1 group).Endpoints and statisticsThe primary endpoint of our study was best treatment response, which was evaluated prospectively in both protocols by using V.1.1 of the response evaluation criteria in solid tumors (RECIST). The same imaging modality (CT of the chest/abdomen/pelvis with or without positron emission tomography) was used before and after treatment, with follow-up scans obtained every 3 months after SBRT. Responses of both in-field and out-of-field lesions (ie, best response of a lesion known but not irradiated) were evaluated together (global response) and separately (in-field vs out-of-field). The overall response rate (ORR) was defined in terms of the RECIST guidelines as partial response (PR)/complete response (CR), and the disease control rate was defined as any response other than PD.The three secondary endpoints were progression-free survival (PFS), defined from the start of RT to the occurrence of a new lesion anywhere in the body or RECIST-defined progression of an existing lesion; overall survival (OS), defined from the start of RT to the date of death from any cause (or censored at last contact); and treatment-related toxicity, which was assessed prospectively per protocol according to the Common Terminology Criteria for Adverse Events V.4.0.Statistical analyses were done with SPSS V.25. First, clinical characteristics of both groups were tabulated and compared by using χ^2 or Mann-Whitney U-test. In-field, out-of-field, and global response rates were compared between groups with Fisher's exact test. Kaplan-Meier analysis was used to plot PFS and OS, and intergroup comparisons were made with log-rank tests.ResultsFrom September 2014 through August 2016, 241 patients were enrolled in either trial; after exclusions, 33 patients were the subject of this analysis: 17 in the SBRT+CTLA4 group and 16 in the SBRT+PD1 group (figure 1). Median follow-up times were 19.6 months (CTLA4) and 19.9 months (PD1) (p=0.212). Baseline characteristics were generally well balanced between groups, although patients in the CTLA4 group seemed to have had more systemic therapies before receiving iRT (mean 2.12 vs 1.13, p=0.157) (table 1).Table 1Patient characteristics.