Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Rizvi, Naiyer A.; Hellmann, Matthew D.; Snyder, Alexandra; Kvistborg, Pia; Makarov, Vladimir; Havel, Jonathan J.; Lee, William; Yuan, Jianda; Wong, Phillip; Ho, Teresa S.; Miller, Martin L.; Rekhtman, Natasha; Moreira, André L.; Ibrahim, Fawzia K.; Bruggeman, Cameron; Gasmi, Billel; Zappasodi, Roberta; Maeda, Yuka; Sander, Chris; Garon, Edward B.; Merghoub, Taha; Wolchok, Jedd D.; Schumacher, Ton N.; Chan, Timothy A.

doi:10.1126/science.aaa1348

Cited by 7,010 publications

(6,253 citation statements)

References 69 publications

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“…9,10,30–32 Although associated with efficacy, TMB has not yet been deemed sufficiently predictive to be of clinical use. Many tumors with high TMB are not responsive to immune checkpoint inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.

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Section: Discussionmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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“…While being an adverse prognostic marker, a nonsynonymous NF1 mutation can be a favorable treatment‐predictive marker, by virtue of its association with increased mutational load. In particular, tumors with high mutational burden (or deficiency in the DNA mismatch repair pathway leading to such an increase) have recently been shown to respond better to immune checkpoint blockade agents (Le et al ., 2015; McGranahan et al ., 2016; Rizvi et al ., 2015; Van Allen et al ., 2015). Furthermore, NF1 ‐mutant melanomas have been found to be dependent on MAPK signaling and to respond to inhibitors targeting key players of this pathway (MEK, ERK) (Maertens et al ., 2013; Nissan et al ., 2014; Whittaker et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF,RAS,NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

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“…However, he has now been receiving nivolumab for > 1 year with a durable complete response and no notable toxicity. IPF is significantly associated with patient characteristics, such as microsatellite instability and smoking history 7, 8, 9. Such characteristics are also associated with a high tumor mutation burden (TMB), a likely independent biomarker for ICI treatment in NSCLC 10.…”

Section: Discussionmentioning

confidence: 99%

Durable response to nivolumab in a lung adenocarcinoma patient with idiopathic pulmonary fibrosis

et al. 2018

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The efficacy and safety of immune‐checkpoint inhibitors in non‐small cell lung cancer patients with idiopathic pulmonary fibrosis (IPF) remain unknown. Herein, we describe the case of a 62‐year‐old man with multiple pleural tumors and carcinomatous pleurisy. High‐resolution computed tomography indicated usual interstitial pneumonia, and a respiratory function test revealed a restrictive disorder and decreased diffusion capacity. He was diagnosed with lung adenocarcinoma and IPF. After failure of initial chemotherapy, he was treated with nivolumab and achieved a complete response without any sign of exacerbation of IPF. The response to nivolumab has persisted for > 1 year. This is the first report of a non‐small cell lung cancer patient with IPF who has been treated with immune‐checkpoint inhibitors for such a long period and achieved a sustained response.

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Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Cited by 7,010 publications

References 69 publications

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

Durable response to nivolumab in a lung adenocarcinoma patient with idiopathic pulmonary fibrosis

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