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Durable Response to Vismodegib in PTCH1 F1147fs Mutant Relapsed Malignant Pleural Mesothelioma: Implications for Mesothelioma Drug Treatment


Malignant pleural mesothelioma (MPM) is an uncommon asbestos-caused malignancy of mesothelial surfaces, most commonly arising from the pleura. Outcomes are universally fatal because of inherent chemoresistance and radioresistance, and inability to achieve complete microscopic surgical resection.1 There have been no new licensed treatments internationally since the approval of cisplatin-pemetrexed in 2004, with ongoing debate about the role of surgery. Several large-scale genomic studies have now established that MPM is characterized by widespread genomic losses, including small-scale and large-scale deletions and inactivation of tumor suppressors.2 Widespread structural variants (SVs) have been recently identified because of chromothripsis, but its biological and clinical role remains largely unknown.3 Activating somatic aberrations in oncogenes such as single nucleotide variants, for example, mutations, or SVs, for example, fusions, are not typically identified, and thus, somatic genotyping by DNA or RNA sequencing is not currently recommended for therapy selection by International Guidelines.4

Case Report

A 54-year-old male with no concurrent significant comorbidities presented in 2013 with a pleural effusion having previously been occupationally exposed to asbestos. Computed tomography (CT) and positron emission tomography-computed tomography (PET-CT) imaging demonstrated right pleural malignant involvement, with no local or distant metastases. There was no family or personal history of BAP1 loss-related diseases or skin stigmata. In May 2013, he underwent video-assisted thoracoscopy, pleural biopsies, and talc pleurodesis, which confirmed epithelioid subtype MPM and then underwent extended pleurectomy-decortication with hilar nodal dissection, intraoperative hyperthermic povidone-iodine lavage, and excision of all macroscopic disease. Postoperative staging was pT3pN0M0, and resection histology confirmed predominantly epithelioid mesothelioma with predominant well-differentiated papillary and tubopapillary patterns, and one microscopic focus of sarcomatoid tumor (Fig 1A). He received adjuvant postoperative radiotherapy to scars (21Gy/3#) followed by six cycles of adjuvant cisplatin-pemetrexed (August-December 2013). Pleural relapse was confirmed on PET-CT in January 2016, and he thereafter received six cycles of carboplatin-pemetrexed-bevacizumab combination (January-May 2016) with initial response and subsequent progression following cycle six. He went on to receive nivolumab in a clinical trial (August 2016-July 2017) with stable disease as best response and then six cycles of vinorelbine monotherapy (April-July 2018) for further progression with stable disease as best response. A surplus representative resection specimen was analyzed by Caris Life Sciences (Phoenix, AZ) that identified PD-L1 0% (SP142), no mismatch repair deficiency by loss of immunohistochemistry staining of MLH1, MSH2, MSH6, and PMS2, indeterminate microsatellite instability (MSI), and tumor mutation burden (TMB). Pathogenic mutations in KMT2D E2678X and PTCH1 F1147fs (NM_000264.4(PTCH1):c.3440_3441delinsG p.(Phe1147*)) were identified, alongside three variants of uncertain significance: ATM E2181K, KMT2D L1600R, and P2938L. The PTCH1 F1147fs variant allele frequency was 24% and was predicted loss of function via nonsense mediated decay (Alamut, Interactive Biosoftware, Rouen, France).
Fig 1. Hematoxlyin and eosin-stained sections of the pleurectomy specimen show epithelioid mesothelioma with a mainly tubular architecture infiltrating skeletal muscle (× 100).
In view of further progression identified on PET-CT in August 2018, maintained performance status of 1, a lack of standard treatment options, and after multidisciplinary team and internal Therapeutics Committee approvals, with full patient discussion, he commenced vismodegib monotherapy at the licensed dose of 150 mg daily in September 2018. PET-CT following cycle two (October 2018) demonstrated an excellent metabolic response by EORTC-PERCIST and radiological response by modified for mesothelioma RECIST v1.1 criteria, underpinning an excellent symptomatic response, which has been maintained until last imaging in March 2020 (Fig 2). He continues on therapy with toxicities of grade 3 alopecia, grade 1 fatigue, grade 1 dysgeusia, and intermittent grade 2 muscle cramps. His treatment timeline is given in Fig 3.
Fig 2. (A) Pre-vismodegib whole-body and axial PET-CT images, respectively, demonstrating pleural sites of disease, and (B) following two cycles of vismodegib and (C) March 2020. A marker lesion is circled on axial PET-CT images. (D) Spider plot jointly demonstrating rapid SUV and sum of maximum diameter reduction during vismodegib therapy. mRECIST, modified response evaluation criteria in solid tumors; SD, stable disease; SUVmax, standardized uptake value maximum; PR, partial response.
Fig 3. Timeline of treatments received.


Hedgehog (Hh) signaling is critical for cell growth and differentiation during embryogenesis, and aberrant reactivated adult canonical signaling has been demonstrated as a key pathway for carcinogenesis in medulloblastoma and basal cell carcinoma (BCC) through somatic mutation in PTCH1 or SMO. Under physiological conditions, the Hh ligand binds to the transmembrane patched protein receptor (encoded by PTCH1 at chromosome location 9q22.2), which acts to negatively regulate the G-protein-coupled receptor smoothened (SMO). The inhibition of SMO is then released, leading to translocation of GLI transcription factors (GLI1-3) to the nucleus and expression of Hh target genes.5 Canonical mechanisms leading to aberrant Hh signaling are ligand-dependent or ligand-independent with the classical ligand-independent mechanism occurring in BCC, where somatic loss-of-function mutations in PTCH1 lead to constitutively active SMO in an oncogene-addicted manner.6
Although Hh signaling is required for embryonic mesothelial development, it is inactive in the adult mesothelium.7,8 Nevertheless, dysregulated Hh signaling has previously been implicated in MPM carcinogenesis, with increased expression of GLI1 and HHIP8 and in vitro studies of SMO inhibitors demonstrating inconsistently impaired cell growth.8-10 Indeed, in solid-tumor phase I trials of vismodegib (GDC-0449) and sonidegib (LDE225), which included 5 MPM cases, responses were only limited to BCCs and medulloblastoma cases, with no clinical benefit (no response or stable disease) in MPMs,11,12 and to the best of our knowledge, no case of MPM with response to vismodegib or sonidegib monotherapy has been reported to date. This lack of benefit for SMO inhibitors in MPM is typically underpinned by the lack of Hh signaling dependency identified in MPM to date. Specifically, MPM does not feature as part of basal cell nevus syndrome or Gorlin syndrome, cancer predisposition syndromes driven by germline loss-of-function PTCH1 mutations, and/or gain-of-function SMO mutations. Indeed, multiple somatic genomic studies of MPM have been performed, characterizing the disease by recurrent areas of losses and tumor suppressor inactivation.13
Nevertheless, according to cancer genomics repositories, Hh-activating variants, although very rare, do occur in MPM and their role in determining SMO inhibitor benefit has not been determined. cBioPortal interrogation14,15 of 196 MPM samples across three studies for PTCH1 and SMO variants currently identifies no SMO mutations and eight cases with five different pathogenic loss-of-function PTCH1 variants from two data sets2,13 alongside three cases with two PTCH1 missense variants, one of which was deleterious or probably damaging by SIFT/PolyPhen analysis (Fig 4). Additional review of 222 MPM cases genotyped by CARIS Life Sciences recently reported one other pathogenic PTCH1 variant (A58fs) and no SMO deleterious variants.16 Whether any of these patients have been treated with or responded to SMO inhibitors has not published. The PTCH1 F1147fs variant we identified is novel, has not yet been reported in MPM, maps to the highly conserved transmembrane domain, and is predicted to result in PTCH1 loss-of-function, likely accounting for our patient’s dramatic, durable, and near-complete response to vismodegib.
Fig 4. PTCH1 mutations identified from cBioPortal analysis of mesothelioma specimens.
Biomarker-driven therapy for MPM is not recommended by international guidelines and is yet to be routinely implemented on the basis of clinical trial data to date. The only approved predictive biomarkers in MPM with licensed therapeutics are microsatellite instability-high (MSI-H) and TMB-high (≥ 10 mut/Mb) for which pembrolizumab is licensed by the US Food and Drug Administration, with previous studies demonstrating MSI-H rates of 1.7%-2.4%17,18 and a TMB-high (≥ 10 mut/Mb) rate of 9.6%16 in MPM. A variety of other predictive biomarkers, especially for immune checkpoint inhibitors, remain nonvalidated and the focus of ongoing research. Given the lack of benefit of SMO inhibitors in MPM, these have not been developed further in this indication. Our case, alongside the small rate of PTCH1 loss-of-function mutations identified in cBioPortal, accounts for a somatic mutation frequency of 4.6%, a rate comparable to ALK fusions in advanced non–small-cell lung cancer, for which four ALK inhibitors are now licensed.
We have therefore identified a novel likely loss-of-function mutation in PTCH1 in MPM, predictive of clinically meaningful and durable response to vismodegib in a tumor type not otherwise sensitive, adding weight for the routine comprehensive molecular analysis of MPM to identify such rare individuals who may have long-term durable benefit in an otherwise rapidly fatal disease, and to develop SMO inhibitors further in this indication.

Authors' Disclosures of Potential Conflicts of Interest

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to or
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Sanjay Popat

Honoraria: Boehringer Ingelheim, AstraZeneca, Roche, Takeda, Chugai Pharma
Consulting or Advisory Role: Boehringer Ingelheim, Roche, Novartis, Pfizer, AstraZeneca, Bristol-Myers Squibb, MSD, Guardant Health, AbbVie, EMD Serono, Takeda, Paradox Therapeutics, Incyte
Research Funding: Boehringer Ingelheim, Epizyme, Bristol-Myers Squibb, Clovis Oncology, Roche, Lilly, Takeda
Travel, Accommodations, Expenses: Boehringer Ingelheim, Merck Sharp & Dohme, Roche

Bhupinder Sharma

Honoraria: Takeda
Travel, Accommodations, Expenses: Takeda

Andrew G. Nicholson

Honoraria: Pfizer, 3M Excellence, European Society of Oncology, UpToDate
Consulting or Advisory Role: AbbVie, Navify, Oncologica
Research Funding: Pfizer

Klaus Schuster

Employment: Caris Life Sciences, VAMED
Stock and Other Ownership Interests: Caris Life Sciences
Research Funding: Caris Life Sciences

Dean Fennell

Honoraria: Bristol-Myers Squibb, Bayer, Boehringer Ingelheim, Inventiva, RS Oncology, NovoCure, Targovax
Consulting or Advisory Role: Consulting or Advisory Role, Roche, Inventiva, Targovax, NovoCure
Speakers' Bureau: Boehringer Ingelheim, Bristol-Myers Squibb
Research Funding: Boehringer Ingelheim, Bayer, Astex Pharmaceuticals, Fuji Pharma, lab21
Travel, Accommodations, Expenses: Bristol-Myers Squibb, MSD Oncology
No other potential conflicts of interest were reported.


The patient provided signed written consent to publish anonymized images in this manuscript.


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Information & Authors


Published In

JCO Precision Oncology
Pages: 39 - 43
PubMed: 34994590


Published online: January 08, 2021


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Sanjay Popat, FRCP [email protected]
Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
Section of Clinical Studies, Institute of Cancer Research, London, United Kingdom
National Centre for Mesothelioma Research, National Heart & Lung Institute, Imperial College London, London, United Kingdom
Bhupinder Sharma, FRCR
Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
Suzanne MacMahon, PhD
Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
Section of Clinical Studies, Institute of Cancer Research, London, United Kingdom
Andrew G. Nicholson, FRCPath
National Centre for Mesothelioma Research, National Heart & Lung Institute, Imperial College London, London, United Kingdom
Department of Histopathology, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom
Rajaei K. Sharma, BSc, PGCert
College of Medicine and Health, University of Exeter, Exeter, United Kingdom
Klaus Schuster, MD
Caris Life Sciences, Basel, Switzerland
Loic Lang Lazdunski, FRCS
Lung Centre, BUPA Cromwell Hospital, London, United Kingdom
Dean Fennell, FRCP
Leicester Mesothelioma Research Programme, Leicester Cancer Research Centre, University of Leicester and University Hospitals of Leicester NHS Trust, Leicester, Leicestershire, United Kingdom


Sanjay Popat, FRCP, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom; Twitter: @drsanjaypopat; @royalmarsdenNHS; @ICR_London; @NCMRimperial; e-mail: [email protected].

Author Contributions

Conception and design: Sanjay Popat
Administrative support: Rajaei K. Sharma, Klaus Schuster
Provision of study materials or patients: Loic Lang Lazdunski, Sanjay Popat
Collection and assembly of data: Sanjay Popat, Bhupinder Sharma, Andrew G. Nicholson, Klaus Schuster, Loic Lang Lazdunski, Dean Fennell
Data analysis and interpretation: Sanjay Popat, Bhupinder Sharma, Suzanne MacMahon, Rajaei K. Sharma, Loic Lang Lazdunski, Dean Fennell
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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Sanjay Popat, Bhupinder Sharma, Suzanne MacMahon, Andrew G. Nicholson, Rajaei K. Sharma, Klaus Schuster, Loic Lang Lazdunski, Dean Fennell
JCO Precision Oncology 2021 :5, 39-43

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