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\begin{document}

\title{Response to Pazopanib-based Combination Regimen in a Case of FGFR3
Amplified Gastric Adenocarcinoma}



\author[1]{Sewanti  Limaye}%
\author[2]{Darshana Patil}%
\author[2]{Dadasaheb Akolkar}%
\author[2]{Navin  Srivastava}%
\author[2]{Revati  Patil}%
\author[2]{Sachin  Apurwa}%
\author[2]{Sanket  Patil}%
\author[2]{Jinumary  John}%
\author[2]{Rahul  Gosavi}%
\author[3]{Prabhu  Nesargikar}%
\author[4]{Prashant  Kumar}%
\author[2]{Vineet  Datta}%
\author[2]{Chirantan Bose}%
\author[2]{Zarrine  Raazi}%
\author[5]{Ajay Srinivasan}%
\author[2]{Rajan Datar}%
\affil[1]{Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute}%
\affil[2]{Datar Cancer Genetics}%
\affil[3]{HCG Cancer Centre}%
\affil[4]{Institute of Bioinformatics}%
\affil[5]{Datar Cancer Genetics }%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
We report a case of an advanced refractory Gastric AD which responded
favourably to a combination regimen of AGI and other chemotherapy agents
which were selected on the basis of multi-analyte tumor profiling. The
treatment was well tolerated with transient manageable adverse events
and yielded radiological partial response.%
\end{abstract}%



\sloppy


\textbf{TITLE}

Response to Pazopanib-based Combination Regimen in a Case of FGFR3
Amplified Gastric Adenocarcinoma.

\textbf{AUTHORS}

Sewanti Limaye\textsuperscript{1}, Darshana Patil\textsuperscript{2},
Dadasaheb Akolkar\textsuperscript{2}, Navin
Srivastava\textsuperscript{2}, Revati Patil\textsuperscript{2}, Sachin
Apurwa\textsuperscript{2}, Sanket Patil\textsuperscript{2}, Jinumary
John\textsuperscript{2}, Rahul Gosavi\textsuperscript{2}, Prabhu
Nesargikar\textsuperscript{3}, Prashant Kumar\textsuperscript{4,5,6},
Vineet Datta\textsuperscript{2}, Chirantan Bose\textsuperscript{2},
Zarrine Raazi\textsuperscript{2}, Ajay Srinivasan\textsuperscript{2},
Rajan Datar\textsuperscript{2}.

\textbf{AFFILIATIONS}

\textsuperscript{1}Kokilaben Dhirubhai Ambani Hospital and Medical
Research Institute, Mumbai -

400053, Maharashtra, India.

\textsuperscript{2}Datar Cancer Genetics, Nasik -- 422010, Maharashtra,
India.

\textsuperscript{3}HCG Cancer Centre, Bengaluru -- 560027, Karnataka,
India.

\textsuperscript{4}Institute of Bioinformatics, Bengaluru - 560066,
Karnataka, India.

\textsuperscript{5}Manipal Academy of Higher Education, Manipal -
576104, Karnataka, India.

\textsuperscript{6}Somaiya Institute of Research and Consultancy,
Somaiya Vidyavihar University, Mumbai - 400077, Maharashtra, India.

\textbf{CORRESPONDING AUTHOR}

Ajay Srinivasan, Datar Cancer Genetics, Nasik -- 422010, Maharashtra,
India.

E-mail: ajays@datarpgx.org. Phone: 0091-7391088107.



\textbf{ABSTRACT}

We report a case of an advanced refractory Gastric AD which responded
favourably to a combination regimen of AGI and other chemotherapy
agents, which were selected on the basis of multi-analyte tumor
profiling. The treatment was well tolerated with transient manageable
adverse events and yielded radiological partial response.

\textbf{KEY CLINICAL MESSAGE}

Angiogenesis Inhibitors (AGI) are not presently used for the treatment
of gastric cancers. We show that personalized combination regimens of
AGI and cytotoxic anti-cancer agents are a safe, effective and viable
treatment strategy in gastric cancers.

\textbf{KEYWORDS}

Stomach cancer; Gastric Adenocarcinoma; Pazopanib; Encyclopedic Tumor
Analysis; Precision Oncology; Personalized Cancer Treatment; Combination
Regimen



\textbf{INTRODUCTION}

Gastric cancer (GC) is the world's third leading cause of cancer death
and the fifth most serious malignancy for both sexes, responsible for
more than 1 million new diagnoses and nearly 800,000 deaths
annually.\textsuperscript{1} Most GCs are diagnosed at advanced stages
due to late manifestations of symptoms with nausea, vomiting, lack of
appetite, early satiety, weight loss and ascites.\textsuperscript{2,3}

Standard of care systemic treatment options in Gastric adenocarcinomas
have been largely limited to combination 5-Fluorouracil, Platinum
agents, Taxanes and Irinotecan to a smaller extent. These chemotherapy
agents remain the mainstay of systemic treatments and are used in a
perioperative setting despite the advent of various targeted agents and
immune checkpoint inhibitors (ICI). The use of targeted agents in
gastric cancers was initially restricted to Trastuzumab, based on HER2
status determined by IHC. In recent years, other targeted agents such as
Larotrectinib have been approved (as part of labelled pan-solid tumor
indication) in addition to ICIs such as Nivolumab (based on CPS),
Pembrolizumab (based on MSI / MMR status). Angiogenesis inhibitors have
remained largely absent in treatment of gastric cancers until the
approval of Ramucirumab, a monoclonal antibody (mAb) which targets
VEGFR2.

Among other Angiogenesis factors, Fibroblast growth factor receptors
(FGFR) are being studied as potential targets in varied different kinds
of solid tumors including gastric cancers.\textsuperscript{4} FGFR is a
transmembrane receptor family with four members (FGFR 1--4) that bind to
fibroblast growth factors (FGFs)\textsuperscript{5}, and play important
developmental roles, from early embryogenesis to organ formation. A
study of 4,853 tumors by next-generation sequencing (NGS), aberrant
FGFR3 have been identified in 22\% of Urothelial Carcinomas (UC), 4\% of
glioma, 3\% of carcinoma of unknown primary and endometrial carcinoma,
2\% of pancreatic, ovarian, and gastric carcinomas.\textsuperscript{6} A
recent study identified the FGFR3/AKT axis as an escape pathway
responsible for trastuzumab resistance in gastric cancer, thus
indicating the inhibition of FGFR3 as a potential strategy to modulate
this resistance.\textsuperscript{7}

Pazopanib is a non-selective FGFR inhibitor described as a
multi-targeted kinase inhibitor with inhibitory effects on VGEF
(vascular endothelial growth factor), PEGF (platelet endothelial growth
factor), stem-cell factor c-kit, and other factors. It also has been
known to have FGFR directed activity as discussed in a case report which
identified pazopanib as a targeted agent that may be considered for the
treatment of patients with hormone positive, endocrine
therapy--resistant metastatic breast cancer who harbour FGFR1
amplifications.\textsuperscript{8} Pazopanib, has shown promise in mUC
particularly in patients with FGFR gene
amplifications.\textsuperscript{9} Pazopanib is the Standard of Care
treatment (labelled indication) for Renal Cell Carcinomas, Soft Tissue
Sarcomas and Gastrointestinal Stromal Tumors
(GIST).\textsuperscript{10}Pazopanib has been tested with combination
chemotherapy in advanced gastric cancer with promising
results.\textsuperscript{11}

Here, we report a case of gastric cancer that had an excellent durable
response after FGFR3 directed therapy in combination with chemotherapy
designed based on Encyclopaedic Tumor Analysis (ETA) which offers
integrative multi-analyte investigations of the tumor and captures in
depth information about the multi-layered tumor
interactome.\textsuperscript{12}

\textbf{CASE PRESENTATION}

A 55-year-old male patient presented with loss of appetite and icterus.
Upper Gastrointestinal Scopy revealed gastric and duodenal ulcers with
gastric obstruction. HPE of biopsied tumor tissue indicated Gastric
Adenocarcinoma The patient underwent diagnostic laparoscopy which showed
omental and peritoneal deposits which were confirmed by HPE as
metastases. HER2 status was not evaluated by Immunohistochemistry. The
patient received neoadjuvant Standard of Care chemotherapy with
Docetaxel, Cisplatin and 5-Fluorouracil along with 50Gy/28 days of
radiotherapy. Post chemoradiotherapy, PET-CT showed good response to the
treatment with reduced wall thickening in stomach. The patient
subsequently underwent Radical Distal Gastrectomy, with Roux-En-Y
reconstruction. The pathological staging was pT3N0 with a moderately
differentiated gastric adenocarcinoma. The patient received adjuvant
50.4 Gy \#28 CTRT radiation therapy along with oral Tab Capecitabine
till April 2018. On a follow up PET/CT scan at six months, there were
deposits seen along the transverse colon and in the pelvic peritoneum
along with ascites.

Due to disease progression, patient was offered Encyclopedic Tumor
Analysis (ETA). The process and details of ETA have been previously
described.\textsuperscript{12} Briefly, ETA includes Next Generation
Sequencing based profiling of gene variants in tumor DNA using a
targeted multigene variant panel, as well as evaluation of
differentially expressed (\textgreater{}20000) transcripts in tumor RNA
and finally in vitro chemoresponse evaluation of viable tumor tissue
derived cells. NGS profiling identified mutations in NOTCH3 (p.G2218G),
ATM (c.1236-2A\textgreater{}T;intronic) and GNAS (p.R201C), in addition
to amplification of FGFR3 gene. In vitro chemoresponse profiling of
viable tumor cells indicated very high sensitivity towards Gemcitabine,
Pemetrexed and Doxoribicin and high sensitivity towards Topotecan and
Epirubicin.

HER2 amplifications were not detected in NGS and HER2 status by IHC was
not ascertainable due to insufficient biopsy (patient was unable to
undergo a repeat biopsy). Prior FFPE blocks / slides were unavailable
for evaluation. Based on ETA findings, the patient was then treated with
a combination of Tab Pazopanib (400 mg, PO, 1 OD) IV Gemcitabine (800
mg, D1 and D8 of 21 Day cycle) and IV Pemetrexed (400 mg, D1 and D8 of
21 Day cycle).

The patient received 5 cycles of ETA guided treatment between Oct 2018
to Feb 2019. The patient underwent 4 follow-up radiological imaging
scans between Oct 2018 and Apr 2019. Significant response to treatment
was observed at day 28 as well as all subsequent imaging scans, with no
new lesions. Thereafter the patient continued to receive maintenance
treatment with Oral Tab Pazopanib. The patient tolerated the treatment
regimen well with minimal and manageable profile of Adverse Events (AE),
which included one Grade III incidence each of Fatigue,
Thrombocytopenia, Sepsis and Pneumothorax. All AEs were transient
(resolved within a week) and did not necessitate treatment suspension or
dose modification. There were no Grade IV AEs.

Patient reported significant improvement in general health and reduction
of symptoms. The patient continued the maintenance regimen for several
months but declined further follow-up or imaging. Unfortunately, the
patient passed away in March 2020 at the beginning of the COVID
pandemic.

A clinical timeline of the patient including all the received
treatments, is shown in figure 1-A, along with the PET CT scan in figure
1-B, showing a significant response to the ETA guided drug treatment.

\textbf{DISCUSSION}

The Cancer Genome Atlas (TCGA) dataset manifests 432 cases of gastric
cancer (SC) harbouring FGFR3 amplification wherein 24 cases showed copy
number gain and 12 cases with copy number loss. Imran et al. have
discussed the originating mutational events at the gene level and the
corresponding consequence in tumour formation and
progression.\textsuperscript{13}

A case study reported in a patient diagnosed with urothelial cancer was
treated with pazopanib whose FFPE tumor harboured amplification of FGFR3
(11 copies), CCND1 (21 copies), and FGF19 (21 copies), and FGFR3
p.(S249C) mutation with estimated mutant allele frequency of 58\%. The
patient showed partial response followed by stable disease to the
targeted therapy given.\textsuperscript{9} Another study by Kim et al.
has reported a gastric cancer patient with liver metastases who
harboured FGFR3-TACC3 novel fusion which is extremely rare in
gastrointestinal cancer.\textsuperscript{14} In this case study, the NGS
analysis of the tumor sample had revealed FGFR3 gene amplification with
10 copies. Pazopanib is widely known to exert its action against VEGFR1,
VEGFR2, VEGFR3, PDGFR\selectlanguage{greek}α \selectlanguage{english}and \selectlanguage{greek}β, \selectlanguage{english}FGFR1, FGFR3, c-KIT, LCK, and macrophage
colony-stimulating factor-1 receptor. \emph{Seung Kim et} .
\emph{al}stated that FGFR2 expression by IHC might be a useful biomarker
for predicting treatment outcomes of patients with metastatic or
recurrent advanced Gastric cancer treated with Pazopanib in combination
with Capecitabine and Oxaliplatin.\textsuperscript{11} Dovitinib, an
FGFR inhibitor under phase II cancer trial is useful against
FGFR3-mutated or overexpressed urothelial cancer.\textsuperscript{15}
The FiGhTeR trial is a phase II, single-arm, open-label study to assess
safety and activity of the FGFR inhibitor pemigatinib as second-line
treatment strategy in metastatic EGJ/GC patients progressing under
trastuzumab-containing therapies.\textsuperscript{16} Pazopanib is
approved for use in advanced renal cell cancer and soft tissue sarcoma
patients who have received prior chemotherapy. Under the Phase II study
of the Arbeitsgemeinschaft internistische Onkologie (AIO) trial,
pazopanib along with 5-fluorouracil, leucovorin, and oxaliplatin (FLO)
is known to show promising outcome in advanced gastric
cancer.\textsuperscript{17} Pazopanib plus fluoropyrimidine and platinum
combination in the first line setting in gastric cancer showed that
median OS ranged from 10.1 months to 10.5 months under prospective phase
II trial of pazopanib.\textsuperscript{18}

Although Trastuzumab is SoC in gastric cancers with HER2 overexpression
(IHC), the same could not be evaluated in this patient due to sample
insufficiency. This conundrum is often experienced in the clinical
setting where IHC analysis of relevant biomarkers is impeded due to
sample insufficiency or non-representative sampling. Though HER2
amplification was not observed on NGS, and HER2 status could not be
ascertained on IHC, NGS profiling successfully identified an alternate
therapeutically targetable indication, i.e., FGFR. Patient showed
sustained response to treatment over the treatment duration leading to
significant regression of the metastatic lesions.

The combination of Gemcitabine and Pemetrexed has been evaluated in
Advanced Non-Small Cell lung Cancer with myelosuppression, especially
neutropenia, as a significant adverse event.\textsuperscript{19,20}

However, in the present case, apart from transient Grade III
Thrombocytopenia and other transient AEs, there were no other
significant or myelosuppressive AEs indicating the safety of the
treatment regimen.

\textbf{CONCLUSION}

In the current study, we identified FGFR3 gene amplification (10 copies)
in a patient with gastric adenocarcinoma. Targeting FGFR3 amplification
with Pazopanib in combination with Gemcitabine and Pemetrexed yielded
significant durable response. These results suggest that ETA-guided
combination regimens of targeted and cytotoxic agents targeting FGFR3 is
an efficient treatment strategy in FGFR3 amplified gastric cancer
patients.

\textbf{ACKNOWLEDGEMENTS}

The authors acknowledge the patient and his family for consenting to
publication of the deidentified case details. The contributions of staff
from HCG Manavata Cancer centre as well as of Datar Cancer Genetics are
acknowledged.

\textbf{AUTHOR CONTRIBUTION}

Sewanti Limaye: Study Design, Study Supervision, Manuscript Writing.

Darshana Patil: Study Design, Study Supervision, Data Analysis,
Manuscript Review.

Dadasaheb Akolkar: Study Design, Study Supervision, Data Analysis.

Navin Srivastava: Study Design, Sample Analysis, Data Analysis.

Revati Patil: Study Design, Sample Analysis, Data Analysis.

Sachin Apurwa: Bioinformatics Analysis, Data Review.

Sanket Patil: Sample Analysis. Data Analysis.

Jinumary John: Data Review, Reporting.

Rahul Gosavi: Data Review, Reporting.

Prabhu Nesargikar: Data Analysis, Data Review.

Prashant Kumar: Data Review, Manuscript Writing.

Vineet Datta: Study Design, Study Supervision, Data Analysis.

Chirantan Bose: Data Review, Manuscript Writing.

Zarrine Raazi: Bioinformatics Analysis, Manuscript Writing.

Ajay Srinivasan: Study Design, Study Supervision, Data Analysis,
Manuscript Review.

Rajan Datar\textsuperscript{:} Study Design, Study Supervision, Funding,
Data Analysis, Manuscript Review.

\textbf{DECLARATION OF CONFLICTING INTERESTS}

SL, PN and PK have no potential conflicts of interest to declare. DP,
DA, NS, RP, SA, SP, JJ, RG, VD, CB, ZR and AS are in full time
employment of the Study Sponsor who offers commercial services in
oncology. RD is the founder and CMD of the Study Sponsor.

\textbf{FUNDING}

This research received no specific grant from any funding agency in the
public, commercial, or not-for-profit sectors.

\textbf{RESEARCH ETHICS AND PATIENT CONSENT}

The patient received personalized treatment as participant of the
RESILIENT trial (CTRI/2018/02/011808), which was previously approved by
the Institutional Ethics Committees of Datar Cancer Genetics as well as
HCG Manavata Cancer Centre. All Study Participants provided written
Informed Consent prior to enrolment and sample collection. Study
participants also consented to publication of deidentified data and
findings. The RESILIENT trial was conducted in accordance with existing
Ethical and Regulatory considerations including the Declaration of
Helsinki.

\textbf{DATA AVAILABILITY}

Data may be made available to qualified researchers upon reasonable
request.

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\par\null

\textbf{FIGURE LEGENDS}

\textbf{Figure 1:} (A) The clinical timeline of 55-year-old male patient
with FGFR3 gene amplification in gastric cancer; locoregional treatment;
progression/recurrence; treatment response/regression; presence of
malignant mass at various sites; (B) PET CT scan- Baseline Vs Partial
Response.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
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