FDA Approval Summary: Pembrolizumab for the treatment of tumor mutational burden-high solid tumors

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.

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Abstract 1369: Analysis of association between homologous recombination deficiency and tumor mutational burden in solid tumors

10.1158/1538-7445.am2018-1369 ◽

2018 ◽

Cited By ~ 1

Author(s):

Hua Li ◽

Liqun Wu ◽

Tao Shou ◽

Bo Jiang ◽

Li Zhuang ◽

...

Keyword(s):

Homologous Recombination ◽

Solid Tumors ◽

Homologous Recombination Deficiency ◽

Mutational Burden ◽

Tumor Mutational Burden

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The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) ≥10: a decision centered on empowering patients and their physicians

Annals of Oncology ◽

10.1016/j.annonc.2020.07.002 ◽

2020 ◽

Vol 31 (9) ◽

pp. 1115-1118 ◽

Cited By ~ 7

Author(s):

V. Subbiah ◽

D.B. Solit ◽

T.A. Chan ◽

R. Kurzrock

Keyword(s):

Pediatric Patients ◽

Mutational Burden ◽

Fda Approval ◽

Tumor Mutational Burden

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Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors

Cancer Discovery ◽

10.1158/2159-8290.cd-20-0522 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1808-1825

Author(s):

Dan Sha ◽

Zhaohui Jin ◽

Jan Budczies ◽

Klaus Kluck ◽

Albrecht Stenzinger ◽

...

Keyword(s):

Solid Tumors ◽

Predictive Biomarker ◽

Mutational Burden ◽

Tumor Mutational Burden

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Clinical response and biomarker analysis of a phase II basket trial of toripalimab, a PD-1 mAb in combination with standard chemotherapy as a first-line treatment for patients with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15083 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15083-e15083

Author(s):

Chao Ren ◽

Xiao-Li Wei ◽

Nong Xu ◽

Lin Shen ◽

Guanghai Dai ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Response ◽

Solid Tumors ◽

Squamous Cell ◽

Line Treatment ◽

First Line ◽

Standard Chemotherapy ◽

Mutational Burden ◽

Tumor Mutational Burden

e15083 Background: Platinum based chemotherapy is the standard care for 1st line treatment of metastatic gastric adenocarcinoma (GC), esophageal squamous cell carcinoma (ESSC), nasopharyngeal carcinoma (NPC) and head and neck squamous cell carcinoma (HNSCC). Combinations of PD-1 blockade with chemotherapy have shown promising but mixed results in solid tumors. Predictive biomarkers for chemo-immunotherapy combination as 1st line treatment remain undefined. Methods: Patients (n = 60) included in this analysis were four complete cohorts from a multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in combination with standard chemotherapy for the 1st line treatment of GC, EC, NPC and HNSCC (excluding NPC). Whole exome sequencing (WES), RNA sequencing and immunohistochemistry were performed on tumor biopsy samples. PD-L1 expression and tumor mutational burden (TMB) were evaluated for correlation with clinical efficacy. Results: From Oct 2016 to Feb 2019, 33 GC, 12 ESSC, 12 NPC and 3 HNSCC patients were enrolled and treated with 240mg or 360 mg toripalimab Q3W via IV infusion in combination with Oxaliplatin/Capecitabine (XELOX), Paclitaxel/Cisplatin (PP), Gemcitabine/Cisplatin (GP) and Docetaxel/Cisplatin/5-FU(TPF) respectively. By the data cutoff date of Nov 15, 2019, all patients experienced treatment related adverse event (TRAE). There was one TRAE (heart failure) leading to death. Grade 3-4 TRAEs occurred in 67% patients, mostly attributed to chemotherapy, including 27% neutropenia, 23% thrombocytopenia, 18% leukopenia and 12% anemia. As assessed by investigators according to RECIST v1.1, the ORR/DCR were 54.5%/84.8%, 66.7%/91.7%, 75.0%/83.3% and 33.3%/100% respectively for GC, EC, NPC and HSNCC cohorts. The median duration of response was 8.3, 6.8, 7.7 and 7.1 months respectively. WES showed distinctive patterns of genomic alterations among different cohorts. The clinical response was not correlated with either PD-L1 expression or tumor mutational burden. Conclusions: Toripalimab in combination with chemotherapy as first-line treatments showed promising results for metastatic GC, EC, NPC and HNSCC patients. Two randomized Phase III trials of toripalimab in combination with Paclitaxel/Cisplatin or Gemcitabine/Cisplatin versus chemotherapy alone are ongoing to further evaluate the combination as first-line treatments in metastatic EC and NPC patients. Clinical trial information: NCT02915432 .

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Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1091 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1091-1091

Author(s):

Sarah Sammons ◽

Andrew Elliott ◽

Jeremy Meyer Force ◽

Nicholas C. DeVito ◽

Paul Kelly Marcom ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Solid Tumors ◽

Immune Checkpoint ◽

Metastatic Breast ◽

Breast Cancers ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Mutational Burden ◽

Tumor Mutational Burden

1091 Background: Tumor mutational burden (TMB) has emerged as an imperfect biomarker of immune checkpoint inhibition (ICI) outcomes in solid tumors. Despite the approval for pembrolizumab in all TMB-high (TMB-H) solid tumors, the optimal clinical approach to TMB-H or hypermutated advanced/metastatic breast cancer (MBC) is unknown with sparse prospective data. We hypothesize that TMB-H MBC will have unique genomic alterations compared to TMB-low (TMB-L) breast cancer that could inform novel therapeutic approaches. Methods: Tumor samples (N = 5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). TMB was calculated based on recommendations from the Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020), with the TMB-H threshold set to ≥ 10 muts/Mb. IHC was performed for PD-L1 (Ventana SP142 ≥1% immune cells). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. Results: TMB-H was identified in 8.2% (n = 461) of MBC samples, with similar frequencies observed across molecular subtypes (7.8-8.6%, p = 0.85): HR+/HER2- (n = 3087) 7.8%, HR+/HER2+ (n = 266) 8.3%, HR-/HER2+ (n = 179) 7.8%, TNBC (n = 1476) 8.6%. The frequency of TMB-H was significantly increased in lobular (16%) versus ductal (5%) MBC (p < 0.01). TMB-H samples were enriched in genitourinary (42%), soft tissue (20%), and gastrointestinal non-liver (16%) biopsy specimens. Compared to TMB-L tumors, TMB-H tumors exhibited significantly higher mutation rates for TP53 (60 v 52%), PIK3CA (55 vs 31%), ARID1A (34 vs 11%), CDH1 (27 vs 11%), NF1 (22 vs 9%), RB1 (14 vs 5%), KMT2C (12 vs 7%), PTEN (12 vs 7%), ERBB2 (7 vs 2.9%), and PALB2 (3.3 vs 1%) genes (p < 0.05 each). Copy number alteration and fusion rates did not differ between TMB-H and TMB-L breast cancers. PI3K/AKT/MTOR, TP53, Histone/Chromatin remodeling, DNA damage repair (DDR), RAS, and cell cycle pathway alterations were detected in > 25% TMB-H MBCs (p < 0.05 each). dMMR/MSI-High (7.2 vs 0.3%, p < 0.01) and PD-L1 positivity (36 vs 28%, p < 0.05) frequencies were significantly increased in TMB-H tumors. DNA signature analyses including APOBEC and homologous recombination repair deficiency, as well as gene expression profiling to assess immune-related signatures and tumor microenvironment are underway. Conclusions: TMB-H breast cancers contain a unique genomic profile enriched with targetable mutations such as PIK3CA, ARID1A, NF1, PTEN, ERBB2, and PALB2. Concurrent predictive biomarkers of response to immune checkpoint inhibition such as MSI-H and PDL-1 positivity are also more prevalent in TMB-H MBC. These findings suggest novel combination strategies within TMB-H MBC could be explored.

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