How current assay approval policies are leading to unintended imprecision medicine

Salgado, Roberto; Bellizzi, Andrew M.; Rimm, David L.; Bartlett, John M.S.; Nielsen, Torsten O.; Moch, Holger; Lænkholm, Anne‐Vibeke; Quinn, Cecily; Cserni, Gábor; Cunha, Isabela W.; Alvarado‐Cabrero, Isabel; Cree, Ian A.

doi:10.1016/s1470-2045(20)30592-1

Cited by 40 publications

(29 citation statements)

References 5 publications

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“…However, its shortcomings as a predictive biomarker need to be well understood in order to put our findings into context [46]. Reproducibility and concordance between the various PD-L1 assays are poor [47][48][49], raising questions regarding the analytical performance of available antibody clones [50]. Nevertheless, PD-L1 positivity per SP142 regardless of PD-L1 status per 22C3 or SP263 seems to be predictive for atezolizumab [13].…”

Section: Discussionmentioning

confidence: 99%

Discordance of PD-L1 status between primary and metastatic breast cancer: A systematic review and meta-analysis

Boman

Zerdes

Mårtensson

et al. 2021

Cancer Treatment Reviews

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Programmed cell death ligand 1 (PD-L1) expression is predictive for benefit from immunotherapy in several human malignancies including triple negative breast cancer. Lower positivity rates but a larger relative benefit from atezolizumab has been implied when PD-L1 status is assessed at metastatic sites. We aimed to study the discordance of PD-L1 expression between primary tumor and metastasis in breast cancer due to its potential clinical utility. Methods: Cochrane Library, Embase, Medline and Web of science were searched for studies reporting on PD-L1 expression in primary and metastatic breast cancer, followed by data extraction. Outcomes included pooled PD-L1 positivity rates in tumor cells, immune cells or both in primary tumor and metastasis, PD-L1 discordance between matched primary tumors and metastasis and direction of discordance. Results: Of 2552 identified entries following de-duplication, 20 studies fulfilled the predefined inclusion criteria. Pooled PD-L1 positivity rate was higher in primary tumors compared to metastasis when assessed in immune cells (51.2% vs 37.1% p < 0.001) and tumor/immune cells (30.1% vs 14.6% p < 0.001), but not in tumor cells (18.7% vs 17.8% p = 0.65). PD-L1 positivity was lowest when assessed in bone metastases (12%) and highest in lymph nodes (60%). Discordance between primary tumors and metastasis was bidirectional, with higher pooled discordance rates when PD-L1 expression was assessed in immune compared to tumor cells (39.5% vs 13.6%, p < 0.001). Conclusion:The observed considerable discordance between PD-L1 status in primary and metastatic breast cancer emphasizes the importance of appropriate tissue sampling when selecting patients for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Discordance of PD-L1 status between primary and metastatic breast cancer: A systematic review and meta-analysis

Boman

Zerdes

Mårtensson

et al. 2021

Cancer Treatment Reviews

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“…Second, there are at least five non-equivalent assays for PD-L1, each with its own scoring system and tumor site indications. For breast cancers, FDA approved two assays: one was the Ventana PD-L1 (SP142) assay (Ventana Medical Systems, Tucson, AZ, United States) and cut-point (1% of TILs) from IMpassion130 trial in 2019, the other one was PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, United States) and its combined positivity score-scoring (CPS) system from the Keynote 355 breast cancer trial in 2020 ( Salgado et al, 2020 ). However, the SP142 assay is poorly reproducible and is much less sensitive than other PD-L1 assays ( Reisenbichler et al, 2020 ), which resulting different positive prevalence rates: in Impassion130, the prevalence of positivity using SP142 was 46%, while using 22C3 this was nearly 80% ( Salgado et al, 2020 ), which might lead to incongruent clinical trial outcomes, lack of comparability and difficulty in seeking the best method to select patients for immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Anti-PD-1/ PD-L1 Monotherapy for Metastatic Breast Cancer: Clinical Evidence

Zhang

Wang

et al. 2021

Front. Pharmacol.

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Background: Success has been reported in PD-1/PD-L1 blockade via pembrolizumab, atezolizumab, or avelumab monotherapy in manifold malignancies including metastatic breast cancer. Due to lack of large-scale study, here we present interim analyses to evaluate the safety and efficacy of these promising strategies in patients with advanced breast cancer.Methods: Six studies including 586 advanced breast cancer patients treated with anti-PD-1/PD-L1 monotherapy agents before July 1, 2020, were included. The anti-PD-1/PD-L1 agents include pembrolizumab, atezolizumab, land avelumab. Statistics was analyzed by R software and IBM SPSS Statistics 22.Results: Global analysis showed that for this monotherapy, the complete response was 1.26%, partial response was 7.65%, objective response rate (ORR) was 9.85%, and disease control rate (DCR) was 18.33%. 1-year overall survival rate and 6-month progression-free survival rate were 43.34 and 17.24%. Overall incidence of adverse events (AEs) was 64.18% in any grade and 12.94% in severe grade, while the incidence of immune-related AEs (irAEs) was approximately 14.75%: the most common treatment-related AEs of any grade that occurred in at least 5% of patients were arthralgia and asthenia; the most common severe treatment-related AEs occurred in at least 1% of patients were anemia and autoimmune hepatitis; the most common irAEs were hypothyroidism. Besides, the incidence of discontinue and death due to treatment-related AEs was about 3.06 and 0.31%, respectively. Additionally, by comparing efficacy indicators between PD-L1–positive and PD-L1–negative groups, an implicated correspondence between efficacy and the expression of PD-L1 biomarker was found: the PR was 9.93 vs 2.69%; the ORR was 10.62 vs. 3.07%; the DCR was 17.95 vs. 4.71%.Conclusion: Anti–PD-1/PD-L1 monotherapy showed a manageable safety profile and had a promising and durable anti-tumor efficacy in metastatic breast cancer patients. Higher PD-L1 expression may be closely correlated to a better clinical efficacy.

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“…At the same time, this test does not take into account PD-L1 expression on tumor cells, which has been recently suggested to provide additional prediction of benefit from immunotherapy in TNBC in the Keynote trials, when combined to PD-L1 expression detection on immune cells (44)(45)(46). Moreover, the SP142 assay has been demonstrated to provide lower sensitivity than other PD-L1 detection assays (47). Considering that PD-L1 has been demonstrated to predict response to immune checkpoint inhibitors in TNBC, and that, along with TILs and BRCA mutational status, seems to be correlated to better response to olaparib in this and other studies (27), further trials of experimental combinations of olaparib and anti-PD-L1 (e.g.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial

et al. 2021

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IntroductionOlaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC.MethodsPatients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG18-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria.Results27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% gBRCA-wt patients. gBRCA-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p<0.001) and CD4/CD8 ratio (p=0.02). Ki67% and TILs did not vary significantly (p=0.67 and p=0.77). A numerical increase in PD-L1 positive cases after olaparib was observed, though non-significant (p=0.134). No differences were observed according to gBRCA status and type of response.ConclusionsEarly-stage TNBC might be a target population for olaparib, irrespective of gBRCA mutations. Future trials should combine TILs, PD-L1 and gBRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.

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How current assay approval policies are leading to unintended imprecision medicine

Cited by 40 publications

References 5 publications

Discordance of PD-L1 status between primary and metastatic breast cancer: A systematic review and meta-analysis

Discordance of PD-L1 status between primary and metastatic breast cancer: A systematic review and meta-analysis

Efficacy and Safety of Anti-PD-1/ PD-L1 Monotherapy for Metastatic Breast Cancer: Clinical Evidence

Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial

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