Background

Early analysis¹ of a single arm phase II trial assessed local control (LC) and safety of stereotactic ablative radiotherapy (SAbR) unresectable locally advanced non-small cell lung cancer (LA-NSCLC) patients unfit for concurrent chemo-radiotherapy (ChT-RT). Here we report clinical outcomes of LA-NSCLC patients submitted to exclusive SAbR.

Methods

Between December 31, 2015 and June 30, 2022 71 LA-NSCLC patients were enrolled. 40 (56%) and 31 (44%) received neoadjuvant ChT+SAbR and exclusive SAbR, respectively. The tumor volume included primary tumor (T) and any regionally positive node/s (N). The co-primary study endpoints were LC and safety.

Results

The median age was 80 years (range, 45–88). Twenty (64%) and eleven (36%) patients had PS 0–1 and 2, respectively. Histology was adenocarcinoma (ADC) and squamous cell carcinoma (SCC) in 71% and 29%, respectively. 27 (87%) patients had ultra-central tumor. Median prescribed dose was 45 Gy (range, 35–55) and 40 Gy (35–45) in 5 daily fractions to T and N, respectively. After a median follow-up of 27 months (range, 6–92), 9 (29%) patients had experienced local recurrence (LR) at a median time of 13 months (range, 7–34). The median LR-free survival (FS) was not reached (95% CI, 28 to not reached). The 1-, 2- and 4- year LR-FS rates were 81 ± 7%, 66 ± 9% and 66 ± 9%, respectively. At last follow-up, 23 (74%) patients were alive. Median overall survival (OS) was not reached. The 1, 2, and 4-year OS rates were 97 ± 3%, 74 ± 8% and 70 ± 9%, respectively. Eight (26%) patients developed distant progression (dP). The median dP-FS was not reached (95% CI, 26 to not reached). The 1, 2, and 4-year dP-FS rates were 82 ± 7%, 72 ± 9% and 66 ± 10%, respectively.

Conclusions

LA-NSCLC patients treated with exclusive SAbR had optimal local control and promising overall survival with excellent treatment compliance and absence of ≥G3 toxicity. Our preliminary prospective clinical outcomes provide an attraction to evaluate this approach in patients unfit to ChT, to obtain a “big” cure beyond “little” palliation.

¹ Int J Radiat Oncol Biol Phys. 2022 Oct 24;S0360–3016(22)03459–9. doi: 10.1016/j.ijrobp.2022.10.025.

Clinical trial identification

NCT05291780.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Small cell lung cancer (SCLC) accounts for 14% of lung cancer diagnoses and is characterized by rapid onset of chemoresistance and poor clinical outcomes. SCLC has four major subtypes driven by transcription factors ASCL1, NEUROD1, POU2F3, and YAP1. Recent studies have also shown intratumoral heterogeneity with respect to ASCL1/NEUROD1 balance and MYC amplification – which are potential mechanisms underlying SCLC's aggressive and refractory biology. Unfortunately, patient-derived models of SCLC with which to better characterize the molecular profiles of refractory SCLC are scarce.

Methods

We generated 46 patient-derived (PDX)/circulating tumor cell-derived xenograft (CDX) models derived from 33 patients with treatment-naïve or relapsed SCLC. We performed multi-omic analyses to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these SCLC models.

Results

Our models revealed mutations typical of SCLC (e.g. TP53, RB1), which were maintained in vivo over multiple passages. Consistent with the known distribution of subtypes, most of our samples express ASCL1 or both ASCL1 and NEUROD1. We looked into an inflamed gene signature, including immune checkpoint genes and human leukocyte antigens (HLAs). Seven models showed high expression of HLAs and related antigen presentation genes such as HLA-DRA or HLA-DBP1. To date, there are no reports of an animal model representing POU2F3 subtype. Our cohort included 10 POU2F3-driven models from primary and metastatic tumors from a patient with ES-SCLC. These novel models include high POU2F3 and MYC expression by IHC and RNA-seq; low expression of neuroendocrine (NE) markers; notably high expression of mitochondrial genes such as MT-RNR2 or MT-CO3/1; high expression of REST and BACH2; low expression of DLL3 and ATOH1; and high expression of metabolic genes in comparison to the non-SCLC-P samples such as ABCB6, PGD, or G6PD, highlighting metabolic heterogeneity in our SCLC samples.

Conclusions

Our PDX/CDX models and the multi-omic characterization of these models provide a unique system and resource to characterize SCLC biology and inform clinical research treatment strategies for patients with SCLC.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

Bulky tumors remain challenging to treat. Stereotactic body radiation therapy (SBRT) can induce immunogenic cell death (ICD), thus causing T-cell-mediated antitumor effects. Low-dose radiation (LDRT) can inflame the tumor microenvironment (TME) by recruiting T cells. We designed a new radiotherapeutic method (Eclipse RT, E-RT) that combines partial SBRT and LDRT to the same large tumor with αPD-1 and examined it in mice with bulky colon CT26 or Lewis lung carcinoma. The safety and efficacy of ERT/αPD-1 in patients with bulky tumors were also retrospectively analyzed.

Methods

In mice with bulky tumors (about 400 cm³), the whole tumor was irradiated by LDRT (2 Gy × 3 fractions) and/or the tumor center was irradiated by SBRT (10 Gy × 3); αPD1 was given weekly. The dependence of therapeutic effects on CD8⁺ T cells was determined using depleting antibodies. Frequencies of CD8⁺ T cells and M1 macrophages (Mφ) were determined by FACS. Multiplex IHC was applied to analyze CD8⁺ T cells and p-eIF2α (ICD marker) in TME. Kaplan-Meier method was applied to estimate the patients’ progression-free survival (PFS) and overall survival (OS).

Results

ERT/αPD-1 is superior to SBRT/αPD-1 or LDRT/αPD-1 in controlling bulky tumors in both mouse models and it depended on CD8⁺ T cells. In the CT26 model, ERT/αPD-1 cured 3 of 11 mice and induced more CD8⁺ T cells and M1 Mφ compared to other groups. Multiplex IHC analysis showed that ERT/αPD-1 induced higher infiltration of CD8⁺ T cells into the tumor center and periphery compared to other groups, and ERT/αPD-1 induced stronger ICD in the tumor center compared to LDRT/αPD-1. In 39 patients with bulky tumors treated with ERT/αPD-1, 30 patients were diagnosed with stage IV NSCLC and failed lines of therapy. Radiation-induced pneumonitis occurred in 1 of 26 patients receiving thoracic ERT. The overall response rate and the median estimated PFS are 46.9% and 5.6 months, respectively. The minimum estimated OS is 16.8 months and the median estimated OS does not reach yet.

Conclusions

ERT/αPD-1 showed superior efficacy in controlling bulky tumor in two mouse models. ERT/αPD-1 was safe and effective in patients with bulky tumors and it might become a new strategy to treat these patients.

Legal entity responsible for the study

The authors.

Funding

National Natural Science Foundation of China (NSFC).

Disclosure

All authors have declared no conflicts of interest.

Background

Advanced non-small cell lung cancer (aNSCLC) treatment (tx) decision-making is complex, with prognosis and tx influenced by molecular alterations. Data are limited on how epidermal growth factor receptor mutation (EGFRm) subtypes influence tx choice in clinical practice. We aimed to describe disease characteristics and tx patterns in aNSCLC patients (pts) with EGFRm.

Methods

Data were drawn from the Adelphi NSCLC Disease Specific Programme™, a point-in-time survey of oncologists/pulmonologists, collected in Brazil and Taiwan from Jul-Nov 2020. Physicians reported characteristic and tx data for the next 5 consulting adult aNSCLC pts with EGFRm, including pts with point-mutation in exon 21 (exon 21) and/or deletion in exon 19 (exon 19). Data analysis was descriptive.

Results

Of 471 pts, 26% (n = 124) had exon 21 and 35% (n = 167) had exon 19. Median age was 65.0 years, 57% were female and 87% had adenocarcinoma. At aNSCLC diagnosis, 77% were stage IV and 69% had an Eastern Cooperative Oncology Group performance status of 0–1. EGFR tyrosine kinase inhibitor (TKI) monotherapy (mono) was the most common first-line (1L) tx; 41% of pts received first generation (1G), 21% second generation (2G) and 16% third generation (3G) EGFR TKI regardless of mutation type. 26% of exon 21 and 27% of exon 19 pts received 2G EGFR TKI, while 9% and 21%, respectively, received 3G EGFR TKI. Of pts who completed 1L tx (n = 55), most (84%) had partial response regardless of mutation type (94% of exon 21, n = 15; 84% of exon 19, n = 21). Median time to discontinuation (TTD) of 1L was 14.2 months (mo) overall (n = 61); 17.1 mo in exon 21 (n = 16) and 16.0 mo in exon 19 (n = 27). Median time to next tx was 15.0 mo overall (n = 61); 19.0 mo in exon 21 (n = 15) and 17.0 mo in exon 19 (n = 27). Median real-world progression free survival (excluding death; rwPFS) was 15.1 mo overall (n = 61); 19.2 mo in exon 21 (n = 15) and 16.6 mo in exon 19 (n = 27).

Conclusions

Pts with EGFRm generally received EGFR TKI mono, including those with exon 21 and exon 19. Exon 21 pts had longer TTD and rwPFS (no formal comparison was made between groups). Future research should examine whether different sensitizing EGFR mutations have an impact on pt outcomes.

Legal entity responsible for the study

Adelphi Real World.

Funding

Adelphi Real World.

Disclosure

H. Bailey: Financial Interests, Institutional, Full or part-time Employment: Adelphi. H. Burlison: Financial Interests, Institutional, Full or part-time Employment: Adelphi. S. Chandrasekar: Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Institutional, Full or part-time Employment: Pfizer. C.H. Wong: Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Institutional, Full or part-time Employment: Pfizer. C. Forshaw: Financial Interests, Institutional, Full or part-time Employment: Adelphi. K. Duncan: Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Institutional, Full or part-time Employment: Pfizer.

Background

In advanced stage non-small cell lung cancer (NSCLC), tumor proportion score (TPS) is typically used to predict the efficacy of immune checkpoint inhibitors (ICI). However, in other cancer types, the combined positive score (CPS), which covers PD-L1 expression on both tumor and surrounding immune cells, is used. We investigated the predictive value of CPS in comparison to TPS in advanced NSCLC.

Methods

A monocenter retrospective study was performed in advanced NSCLC patients treated with ICI monotherapy between 2015 and 2021. H&E and PD-L1 were stained on baseline tumor biopsies to score PD-L1 by both TPS and CPS. Positivity for TPS and CPS was defined as a score of 1% or above. Progression-free survival (PFS) and overall survival (OS) were assessed for TPS and CPS scores.

Results

Amongst the 187 included patients, PD-L1 positivity was found in 112 patients (59.9%) by TPS and 135 patients (72.2%) by CPS. In terms of PFS, no significant differences were observed between TPS⁻ and TPS⁺ or CPS⁻ and CPS⁺ patients (HR 0.86, p = 0.37 and HR 0.72, p = 0.065, respectively). There was no significant difference in OS between TPS⁻ and TPS⁺ patients (HR 0.81, 95%CI 0.59–1.12, p = 0.20). However, CPS⁺ patients did show a longer OS than CPS⁻ patients (HR 0.62, 95%CI 0.44–0.87, p = 0.006). OS was superior in both TPS⁻/CPS⁺ and TPS⁺/CPS⁺ as compared to TPS⁻/CPS⁻ cases (HR 0.52, p = 0.018 and HR 0.64, p = 0.015, respectively). Cases that were TPS⁻/CPS⁺ had a comparable OS to TPS⁺/CPS⁺ cases (11.3 vs 9.7 months, p = 0.016).

Conclusions

To our knowledge, this is the largest real-world population study comparing TPS and CPS in NSCLC. We showed that CPS differentiated OS better than TPS in advanced NSCLC patients with ICI monotherapy. Remarkably, this was driven by the performance of the TPS⁻/CPS⁺ subgroup, indicating that CPS may be a better predictive biomarker for ICI efficacy. These findings support the notion that ICI also have an anti-cancer efficacy through inhibiting the immune suppressive immune cells in the tumor microenvironment.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Hashemi: Other, Institutional, Other, Research contracts to the institution, outside of the current study: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, GSK, MSD, Novartis, Roche, Takeda. All other authors have declared no conflicts of interest.