Janessa Laskin

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Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Adjuvant durvalumab after chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). A post hoc exploratory analysis of PACIFIC revealed no OS benefit in the PD-L1 < 1% subgroup. This retrospective analysis assesses the real-world impact of durvalumab on OS according to PD-L1 tumor proportion score (TPS). Patients with stage III, unresectable NSCLC treated by CRT, with available PD-L1 TPS, from 1 March 2018 to 31 December 2020, at BC Cancer, British Columbia, Canada were included. Patients were divided into two groups, CRT + durvalumab and CRT alone. OS and PFS were analyzed in the PD-L1 ≥ 1% and p = 0.003]. Durvalumab improved OS in the PD-L1 ≥ 1% [HR 0.53 (95% CI 0.34–0.81), p = 0.003, n = 175], but not in the p = 0.4, n = 76]. This retrospective study demonstrates a statistically significant improvement in OS associated with durvalumab after CRT in PD-L1 ≥ 1%, but not PD-L1 < 1% NSCLC. Variables not accounted for may have biased the survival analysis. A prospective study would bring more insight.

(1) Background: Exon 20 insertion mutations (ex20ins) in EGFR and HER2 are uncommon driver mutations in non-small-cell lung cancer (NSCLC), with a poor prognosis and few targeted therapy options, and there are limited real-world data. Here, we report the clinicopathologic features and outcomes for patients with ex20ins NSCLC across British Columbia, Canada. (2) Methods: NSCLC patients with ex20ins in EGFR or HER2 were identified via tumour testing between 1 January 2016 and 31 December 2021 (n = 7233). Data were collected by chart review. Survival analyses were performed using the Kaplan–Meier method using the log-rank test. (3) Results: A total of 131 patients were identified. The median age was 66. Thirty-three percent of patients had brain metastases. For the EGFR cohort, the median OS was 18.6 months for patients who received any systemic therapy (ST) vs. 2.6 months for patients who did not (p < 0.001). Median OS was similar for patients treated with ex20ins-specific tyrosine kinase inhibitors (TKIs) vs. other STs (18.6 vs. 15.9 months; p = 0.463). The median first-line PFS was 4.1 vs. 7.4 months for patients treated with a TKI vs. other ST (p = 0.744). For the HER2 cohort, the median OS was 9.0 months for patients who received any ST vs. 4.9 months for patients who did not (p = 0.015). The median OS was 23.0 months for patients treated with an ex20ins TKI vs. 5.6 months for patients who were not (p = 0.019). The median first-line PFS was 5.4 vs. 2.1 months for patients treated with a TKI vs. other ST (p = 0.343). (4) Conclusions: Overall survival was significantly longer among ex20ins patients who received any systemic therapy vs. those who did not. Overall survival was significantly better among HER2 ex20ins patients who received ex20ins-specific TKIs.

Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual’s cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.

Background: non-small cell lung cancer (NSCLC) outcomes remain suboptimal for early-stage disease despite emerging advances in systemic therapy for the peri-operative period. Next-generation sequencing (NGS) identifies driver mutations for which targeted therapies have been developed that improve survival. The BC lung cancer screening program, which was initiated in May 2022, is expected to identify people with early and late stages of NSCLC. It is crucial to first understand the molecular epidemiology and patterns of time to initiate treatment across its five health authorities (HA) to optimize the delivery of care for NSCLC in BC. In this way, we may harness the benefits of targeted therapy for more people with NSCLC as novel advances in therapy continue to emerge. Objective: to compare (a) the frequency of actionable NSCLC molecular alterations among HAs and (b) the time to treatment initiation. Methods: a retrospective observational study was conducted with prospectively collected data from the BC CGL Database. Adults with late stage NSCLC who underwent targeted NGS were included for the time period from May 2020 to June 2021. Demographics, actionable molecular alterations, PDL-1 expression, and time to treatment across HAs were examined. Using appropriate statistical tests for comparison among HAs, p>0.05 was deemed significant. Results: 582 patients underwent NGS/IHC and analysis during the study period. The mean age was 71 (10.1), and 326 (56%) patients were female. A significantly higher proportion of all EGFRm+ were identified within Vancouver Coastal Health (VCHA) and Fraser Health Authority (FHA) compared to the other health authorities (p < 0.001). This also holds true for common sensitizing EGFRm+ alone (p < 0.001) and for sensitizing EGFRm+ when adjusted for females and smoker status (OR 0.75; 95% CI 0.62, 0.92; p = 0.005). Patients residing within the Northern, Interior, and Island HAs were less likely to receive treatment at the same rate as those in VCHA and FHA HAs. Conclusion: actionable NSCLC driver mutations are present in all regional HAs, with disparity noted in time to initiate treatment between HAs. This provides evidence for the importance of molecular testing for patients in all BC HAs to guide personalized and timely NSCLC treatment.

Purpose: Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of solid tumours with dramatic and durable responses seen across multiple tumour types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers. Experimental Design: We characterised fresh tumour biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pre-treated disease through the Personalized OncoGenomics (POG) program at BC Cancer using whole genome and transcriptome analysis (WGTA). Baseline characteristics and follow up data were collected retrospectively. Results: We found that tumour mutation burden (TMB), independent of mismatch repair status, was the most predictive marker of time to progression (TTP, p=0.007), but immune related CD8⁺ T cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS) (p=0.0014 and 0.0012 respectively). While CD274 (PD-L1) gene expression is comparable to protein levels detected by immunohistochemistry (IHC), we did not observe a clinical benefit for patients with this marker. We demonstrate that a combination of markers based on WGTA provides the best stratification of patients (p=0.00071, OS), and also present a case study of possible acquired resistance to pembrolizumab in a non-small cell lung cancer (NSCLC) patient. Conclusions:Interpreting the tumour-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumour type-specific testing.