Phase 1/2 Trial of Pembrolizumab and Concurrent Chemoradiation Therapy for Limited-Stage SCLC

Welsh, James W.; Heymach, John V.; Guo, Cheng; Menon, Hari; Klein, Katherine; Cushman, Taylor R.; Verma, Vivek; Hess, Kenneth R.; Shroff, Girish S.; Tang, Chad; Skoulidis, Ferdinandos; Jeter, Melenda; Comeaux, Nathan; Patel, Roshal R.; Chen, Fan; Ozgen, Tugce; Nguyen, Quynh Nhu; Chang, Joe Y.; Altan, Mehmet; Zhang, Jianjun; Papadimitrakopoulou, Vassiliki A.; Simon, George R.; Byers, Lauren A.; Glisson, Bonnie S.

doi:10.1016/j.jtho.2020.08.022

Cited by 68 publications

(66 citation statements)

References 30 publications

(35 reference statements)

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“…Welsh et al 26 also recently reported the safety of the addition of pembrolizumab to conventional thoracic radiation as consolidation following induction chemotherapy for extensive-stage SCLC, as well as the combination of pembrolizumab with definitive chemoradiation in patients with limited-stage SCLC. 27 The safety profile established in this study will facilitate our follow-up study that is designed to evaluate whether SBRT to primary non-responsive site will impact the efficacy of chemoimmunotherapy in the front-line treatment of patients with extensive-stage SCLC. We envisage that such a strategy will further improve the modest impact already achieved with front-line chemoimmunotherapy in this disease.…”

Section: Discussionmentioning

confidence: 96%

Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study

Pakkala

Higgins

Sica

et al. 2020

J Immunother Cancer

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BackgroundImmune checkpoint blockade (ICB) targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein 4 has achieved modest clinical activity as salvage therapy in relapsed small cell lung cancer (SCLC). We conducted this signal-finding study to assess the efficacy of ICB with or without radiation in relapsed SCLC.MethodsPatients with relapsed SCLC and ≤2 previous lines of therapy were randomized to (1) arm A: durvalumab (D) 1500 mg/tremelimumab (T) 75 mg (intravenously every 4 weeks without stereotactic body radiation therapy (SBRT)) or (2) arm B: immune-sensitizing SBRT to one selected tumor site (9 Gy × 3 fractions) followed by D/T. Treatment continued until progression or a maximum of 12 months. The co-primary endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). We evaluated circulating lymphocyte repertoire in serial peripheral blood samples and tumor infiltrating lymphocytes (TILs) from on-treatment biopsies as pharmacodynamic markers.ResultsEighteen patients were randomized to arms A and B (n=9 each): median age 70 years; 41.2% women. The median PFS and ORR were 2.1 months and 0% in arm A and 3.3 months and 28.6% in arm B. The median overall survival (OS) was 2.8 months in arm A and 5.7 months in arm B (p=0.3772). Pooled efficacy of D/T±SBRT in 15 Response evaluation criteria in solid tumors (RECIST) evaluable patients across both arms showed the best ORR in terms of partial response in 13.3%, stable disease in 26.6% and progressive disease in 60.0%; the overall median PFS and OS were 2.76 and 3.9 months. The most common adverse events were grade 1 fatigue (66%) and grade 1 elevated amylase (56%) in arm A, and grade 1 fatigue (56%) and pain (44%) in arm B. There was a significant increase in activated CD8(+)ICOS+ T cells (p=0.048) and a reduction in naïve T cells (p=0.0454) in peripheral blood following treatment, along with a significant amount of activated CD8+ICOS+ T cells in TILs from responders.ConclusionsThe D/T combination with and without SBRT was safe but did not show sufficient efficacy signal in relapsed SCLC. Changes in peripheral blood lymphocyte and TILs were consistent with an immunologic response.Trial registration numberNCT02701400.

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Section: Discussionmentioning

confidence: 96%

Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study

Pakkala

Higgins

Sica

et al. 2020

J Immunother Cancer

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“…P r e v i o u s r e s e a r c h h a s s h o w n t h a t c o n c u r r e n t chemoradiation resulted in better survival outcomes than sequential chemoradiation (23). Concurrent chemoradiation plus pembrolizumab is also a promising strategy for treating LS-SCLC (24). However, the question arises as to whether postoperative radiotherapy is necessary to the comprehensive therapy of LS-SCLC patients who undergo resection followed by ACT.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of prognostic predictors for patients with limited-stage small-cell lung cancer who underwent resection followed by adjuvant chemotherapy

et al. 2021

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Background: The prognosis of patients with limited-stage small-cell lung cancer (LS-SCLC) who undergo resection followed by adjuvant chemotherapy (ACT) is uncertain. Thus, we combined clinicopathological characteristics and next-generation sequencing (NGS) to answer this question.Methods: In total, the data of 51 LS-SCLC patients who had undergone complete surgical resection and postoperative ACT were retrospectively collected. NGS examinations with a 68-gene panel were performed for each specimen. Patients' genetic status and potentially clinical correlations were statistically evaluated.Progression-free survival (PFS) and overall survival (OS) were plotted using Kaplan-Meier curves. The independent prognostic factors for the primary cohort were investigated using univariable and multivariable cox proportional hazard regression analyses. Subgroup analyses were also conducted based on retinoblastoma protein 1 (RB1) status.Results: Combined SCLC (c-SCLC) had similar clinical and pathological characteristics to that of pure SCLC (p-SCLC). TP53 and RB1 were 2 major genetic mutations present in both p-SCLC and c-SCLC. c-SCLC had a unique genetic profile that was related to the PI3K/AKT/mTOR and WNT/β-catenin signaling pathways. There was no prognostic difference between c-SCLC and p-SCLC. However, the pathological node (N) stage of lymphovascular invasion (LVI), which was related to PFS and age, corelated with OS. Neither pathological subtypes nor genetic mutations affected the survival outcomes. Notably, RB1 mutated c-SCLC resulted in poorer DFS compared to that of p-SCLC among LS-SCLC patients who underwent resection followed by ACT.Conclusions: Our examination of LS-SCLC patients who underwent resection followed by ACT showed that c-SCLC and p-SCLC had a clinical and prognostic similarity and a genetic peculiarity. Thus, it is essential that a new classification system be proposed for SCLC. Such a system is especially needed for LS-SCLC.

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“…A recent phase I/II trial in 40 LD-SCLC patients has reported that cCT-RT and pembrolizumab (started concurrently with cCT-RT and continued for up to 16 cycles) was well tolerated (15% grade 2-3 pneumonitis, 43% grade 1-2 esophagitis) and yielded a favorable outcome (RR: 79%, median PFS: 19.7 months and OS: 39.5 months). 41 These data formed the basis for several trials evaluating combined-modality therapy for LD-SCLC patients as summarized in Figure 3. This includes ongoing clinical trials assessing the efficacy and safety of ICI, either as consolidation treatment or concurrent with cCT-RT, which will hopefully contribute to elucidate the efficacy of this strategy in SCLC.…”

Section: Immunotherapy In Ld-sclcmentioning

confidence: 99%

Small cell lung cancer: a slightly less orphan disease after immunotherapy

et al. 2021

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Small cell lung cancer (SCLC) is an aggressive malignancy accounting for 15% of all diagnosed cases of lung cancer. After >15 years without any clinically relevant therapeutic advances, extensive-disease SCLC has become the second thoracic malignancy for which immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm to improve overall survival. Today, atezolizumab or durvalumab in combination with platinum-etoposide chemotherapy is considered the new standard of care in the first-line setting in SCLC. However, the magnitude of benefit with this immunechemotherapy strategy in SCLC is more modest than that observed in metastatic non-small-cell lung cancer patients. The immunosuppressive phenotype of SCLC plays an important role in hampering ICI efficacy and may explain the differences in outcomes between these two types of lung cancer. In this review, we provide a summary of recent therapeutic advances in SCLC in light of ICIs, as well as current challenges of this strategy in patients who are elderly, have poor performance status or brain metastases. We also address future perspectives of immunotherapeutic strategies currently in clinical development for these patients.

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Phase 1/2 Trial of Pembrolizumab and Concurrent Chemoradiation Therapy for Limited-Stage SCLC

Cited by 68 publications

References 30 publications

Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study

Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study

Comprehensive analysis of prognostic predictors for patients with limited-stage small-cell lung cancer who underwent resection followed by adjuvant chemotherapy

Small cell lung cancer: a slightly less orphan disease after immunotherapy

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