BackgroundAlectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (Cmin,SS) were below 435 ng/mL. This may suggest that patients should have an alectinib Cmin,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM.MethodsADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib Cmin,SS < 435 ng/mL, arm A will receive increased doses of alectinib till Cmin,SS ≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition.DiscussionThe ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib.Clinical trial registrationClinicalTrials.gov, identifier NCT05525338.
It is increasingly understood that cancers can be recognized by the immune system and that inflammation relates to response. Combining stereotactic radiotherapy (SBRT) to increase release of cancer cell antigens with an anti-CTLA-4 and PD-L1 inhibitor may lead to increased response rates. Due to tumor heterogeneity it may be important to irradiate the primary tumor (addressing trunk mutations), instead of its metastasis (branch mutations). No solid predictive biomarker for response and/or immunotherapy related adverse events (TRAEs) is available. Electronic nose (eNose) technology measures the complete mixture of volatile organic compounds in exhaled breath and can detect lung cancer based on pattern recognition of the breath profile. We hypothesize that eNose is able to predict TRAEs and response in patients with NSCLC. Methods: In 3 sequential cohorts, immunotherapy regimes combined with SBRT were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. All patients were irradiated on the primary tumor (1x20 Gy on 9cc) 1 week after the 1st dose of immunotherapy. The 1st cohort (n=3) received durvalumab. The 2nd and 3rd cohort (both n=6) received a combination of durvalumab and tremelimumab followed by durvalumab monotherapy. Duplicate eNose measurements were performed by using the SpiroNose that contains 7 metal oxide semiconductor sensors. TRAEs were categorized using NCI CTCAE version 4.3. Descriptive statistics were used to summarize baseline characteristics and TRAEs. The relationship between breath profiles and response and TRAEs was analyzed with advanced signal processing, ambient correction and Mann-Whitney U test. Linear discriminant and receiver operating characteristics analysis followed. Pearson correlation and regression assessed duration of response. Findings: Fifteen patients were included as described above. Baseline characteristics of the groups were comparable. Median progression free survival was 2 months, overall survival 10 months (immature). No statistical difference was found in (duration of) response. There was 1 low grade TRAE (CTC 1-2) in cohort 1 and 10 in cohort 2/3. High grade TRAEs (CTC 3) were only present in cohort 2/3 (n=3) and 1 patient discontinued treatment. There was one dose limiting toxicity. At baseline, 12/15 patients performed eNose measurements; 7 with TRAEs and 5 without. The TRAE group had a significant higher sensor 7 signal compared to those without TRAE (p=.042). The cross-validated accuracy for detecting TRAE was 67%. The ROC-AUC was .857 [.638-1]. Interpretation: eNose breath profiles at baseline may predict which patients will develop TRAEs. The small sample size increases the risk of overfitting, therefore another cohort of 34 immuno-monotherapy patients is being analyzed (15 with and 19 without TRAEs, pending). We demonstrated no new safety data. Disclosure: This study was sponsored by a research grant from AstraZeneca. Citation Format: M Benthe Muntinghe-Wagenaar, Hanneke Kievit, Lucie B. Hijmering-Kappelle, Birgitta I. Hiddinga, J Fred Ubbels, Robin Wijsman, Mechteld F. Brasz, Gitte Slingers, Rianne de Vries, Milou M. Schuurbiers, Harry J. Groen, Huib A. Kerstjens, Anthonie J. van der Wekken, Michel M. van den Heuvel, T Jeroen Hiltermann. A phase 1 study to detect adverse events after SBRT and immunotherapy by electronic nose in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 666.
It is increasingly understood that cancers can be recognized by the immune system and inflammation relates to response. Combining stereotactic radiotherapy (SBRT), to increase release of cancer cell antigens, with an anti-CTLA-4 and PD-L1 inhibitor may lead to increased response rates. No solid biomarker in predicting treatment response is available. We set out to study feasibility of combined durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) with SBRT on the primary tumor. The extend of tumor-infiltrating cells has shown to correlate to improved prognosis using checkpoint inhibitor (CPI) treatment of various cancers. We hypothesized that the peripheral blood T-cell activation status may be a predictor of response, progression free survival (PFS) and overall survival (OS). Methods: Three immunotherapy regimes were combined with SBRT in sequential cohorts as ≥2nd line in CPI naïve patients with NSCLC stage IIIB/IV. One week after the 1st dose of CPI, patients were irradiated on the primary tumor (1x 20Gy on 9cc). The 1st cohort (n=3) received durvalumab, the 2nd and 3rd cohort (both n=6) a combination of durvalumab and tremelimumab, followed by durvalumab monotherapy. Exploratory endpoint was the correlation of response with T-cell function. T-cell function was assessed using flow cytometric analysis of peripheral blood T-cells and compared to simultaneously included healthy controls. In short, whole blood was activated ex vivo using Staphylococcal enterotoxin B (SEB) after which the T-cell activation status was assesses by expression of CD69 and cytokines (IL-2, IFN-γ, TNF-α). Patients were divided in above (responders, R) and below median PFS (non-responders, NR). We compared intracellular cytokine production in both CD4+ and CD8+ T-lymphocytes between both groups and with healthy controls (HC) using the Mann-Whitney U test. Findings: Fifteen patients were included as described above. Median PFS was 2 months, OS 10 months (immature). Baseline characteristics of both groups were comparable. T-cell function was assessed in 14 patients and HC at baseline. Data are shown as median (P-value) for R vs NR below. R had a significant higher percentage activated CD8+ T-cells upon SEB stimulation than NR: CD8+CD69+ 15.8 vs 3.5 (0.008) and IL-2+CD8+CD69+ 8.8 vs 2.9 (0.02). There was a trend in TNF-α+CD8+CD69+ 19.8 vs 8.0 (0.11) and IFN-ɣ+CD8+CD69+ 21.4 vs 5.5 (0.22). These differences were all significant for R compared to HC (p<0.03), but not for NR (P>0.66). Interpretation: With a mild antigen independent stimulus (SEB), the CD8+ T-cells of responders were significantly more activated at baseline compared to non-responders and healthy controls. This suggests an elevated pre-treatment T-cell activation status in patients that responded to the treatment and the possibility to use this as a potential biomarker to predict the response to CPI treatment. Disclosure: This study was sponsored by a research grant from AstraZeneca. Citation Format: Hanneke Kievit, M. Benthe Muntinghe-Wagenaar, Lucie B.M. Hijmering-Kappelle, Birgitta I. Hiddinga, J Fred Ubbels, Robin Wijsman, Bart-Jan Kroesen, Marcel J. van der Leij, A. Rutgers, Harry J. Groen, Huib A. Kerstjens, Anthonie J. van de Wekken, T Jeroen Hiltermann. Baseline T-cell function predicts response to SBRT and immunotherapy in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1984.
e21121 Background: Cancers can be recognized by the immune system and immunotherapy (ICI) has become an important treatment for lung cancer. Compared to chemotherapy, combining an anti-CTLA-4 and PD-L1 inhibitor increases response- and survival rates independent of PD-L1 status. We hypothesized that adding stereotactic radiotherapy (SBRT) to increase the release of cancer cell antigens might improve treatment results even further. Because of accumulating tumor heterogeneity it may be important to irradiate the primary tumor (addressing trunk mutations), rather than its metastases (branch mutations). We assessed toxicity of adding SBRT to (dual) ICI. Methods: In 3 sequential cohorts, ICI regimes combined with SBRT were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. All patients were irradiated on an FDG avid part of the primary tumor (1x20 Gy on 9cc) 1 week after the 1st dose of ICI; in case of dual ICI the 1st dose of the 2nd ICI was administered within 1 week following SBRT. Following treatments both ICI were combined. The 1st cohort (n = 3) received durvalumab (D) monotherapy for up to 1 year. The 2nd cohort starting with tremelimumab (T) and the 3rd cohort starting with D (both n = 6) received a combination of D and T (4 cycles) followed by D monotherapy for up to 1 year. The 2nd and 3rd cohort only proceeded when dose limiting toxicities (DLT) occurred in ≤33% of cases in the previous cohort. DLT was defined as any grade ≥3 toxicity that occurred during the first 8 weeks of therapy. Treatment related adverse events (TRAEs) were categorized using NCI CTCAE version 4.3. Descriptive statistics were used to summarize baseline characteristics and TRAEs. Results: Fifteen patients were included from June 2018 to November 2020. Last study visit was in September 2021. Baseline characteristics of the groups were comparable. The median irradiated tumor volume was 9.13 cc (8.98-9.60 cc) with a mean lung dose of 0.44 Gy (0.14-0.73 Gy). The V20 was nihil (0-0.1%) and the V5 1.8% (0-4%). There was 1 DLT in cohort 3 (colitis grade 3). There was 1 low grade TRAE (pneumonitis grade 2) in cohort 1. In cohort 2, 6 low grade TRAEs (CTC 1-2) were observed and 2 high grade (CTC 3) in 1 patient, who discontinued treatment. In cohort 3, 4 low grade and 1 high grade TRAE occurred. Median progression free survival was 2 months, median overall survival 10 months. Conclusions: No additional toxicity was observed by adding SBRT to the primary tumor to (dual) ICI. Clinical trial information: 2017-002797-39. [Table: see text]
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