TUMOR BOARD SESSION - cme.cityofhope.org

TUMOR BOARD SESSION

COMPLEX CASES: OPTIMAL MANAGEMENT

OF BRAIN METASTASES

1

Panel & Disclosures

2

Arya Amini, MDAssistant Professor

Department of Radiation OncologyChief of Thoracic Radiotherapy

City of Hope

• Grant/Research Support from Genentech.• Consultant for Reflexion.• On the Speakers Bureau for AstraZeneca, and

Takeda Pharmaceuticals.

Mike Chen, MD, PhDAssociate Professor

Department of SurgeryProgram Director

Neurosurgical Oncology Fellowship ProgramCity of Hope

• Nothing to disclose.

N. Simon Tchekmedyian, MD, FACPProfessor

Department of Medical OncologySenior Medical Director, Orange County

City of Hope

• Stock/Shareholder for BioMarin Pharmaceuticals, Infinity Pharmaceuticals, Inc., Mereo BioPharma Group, Mersana Therapeutics, Inc., Myovant Sciences, and Novo Nordisk.

Case #1: Young Woman With Lung Cancer

▪ 43 year old woman, never smoker, presented elsewhere in April 2011 with persistent nausea and incidental finding of right lower lung nodule.

▪ Biopsy revealed adenocarcinoma.

▪ Right lower lobectomy showed pT1a pN2 lesion (3 + nodes, one in level 4 and 2 in level 7) adenocarcinoma, acinar predominant, with clear margins except that parenchymal margin was positive for tumor cells in lymphatic spaces. EGFR negative. ALK alteration not tested.

▪ Received Carboplatin and Pemetrexed for 4 cycles and was then observed.

▪ In November 2013 a right hilar mass showed adenocarcinoma on core biopsy.

▪ She received Carboplatin, Paclitaxel and radiation therapy with partial response on imaging

3

Patient Seen For Opinion

▪ Consultation done March 2014. Given the presentation, Alk alteration testing requested and

found to be positive.

▪ Crizotinib was recommended but patient declined in part because a “DetoxiGenomic” test

profile suggested she would not tolerate it.

▪ She returned in April 2016. She had started Crizotinib due to lung progression 18 months

earlier and now had lung progression as well as symptomatic brain metastases: 15 supra and

infratentorial lesions, largest 6.7 cm, and midline shift.

▪ Had neurosurgery with resection of largest left temporal lesion and whole brain RT

▪ Patient changed care to our program and Alectinib was started. Alectinib had been approved by

the FDA in December 2015 for patients who progressed on Crizotinib.

4

Subsequent Care and Current Status

▪ On Alectinib for 2 and ½ years, lung progression in November 2018.

▪ Entered on expanded access protocol for Lorlatinib, Cycle 1 Day 1 on 11/15/2018. Had

favorable response. Subsequently went on commercial Lorlatinib and has stayed on it until

present time.

▪ Developed hydrocephalus without tumor recurrence and had VP shunt placed in March 2021.

▪ Remains on Lorlatinib with disease control and preserved cognition.

▪ MRI brain in June 2021 showed improved hydrocephalus and no evidence of brain metastases.

▪ CT chest/abdomen/pelvis in June 2021 showed no evidence of recurrent or metastatic disease.

5

From Left: 1) MRI at diagnosis, 2) Immediate post-op, and 3) Over 5 years

later, after RT, targeted oral therapies and recent VP shunt

6

7

Month

Treatment carbo/pem

Molecular ALK FISH negative

CGP

ALK intron 19

TP53 G154V and R158C

RB1 loss of exons 3-17

crizotinib ceritinib

CGP

ALK intron 19ALK L1152R

TP53 G154V and R158C

RB1 loss of exons 3-17

NF1 G1852fs*17

WBRT alectinib

ALK D5F3 IHC positive

Response SD PR PD PRPD + newCNS metastases PR

2 4 6 8 10 12 140 16

A B

C D

Figure 1. The top panel displays the chronology of treatment, response and molecular pathology. The bottom-right panel shows serial CT chest/abdomen with intravenous contrast A) pre- alectinib, and B) 6 weeks post-alectinib; and serial CT brain with and without contrast, C) pre-alectinib, and D) 6 weeks post-alectinib. Red arrows point to areas of disease and subsequent response. CT, computed tomography; SD, stable disease; PR, partial response; PD, progressive disease; CNS, central nervous system; ALK, anaplastic lymphoma kinase; FISH, fluorescent in situ hybridization; RB1, retinoblastoma-1; TP-53, tumor protein-53, NF-1, neurofibromin-1; CGP, comprehensive genomic profiling; IHC, immunohistochemistry; WBRT, whole brain radiation therapy; carbo, carboplatin; pem, pemetrexed.

Tchekmedyian JTO 2016

Month

Treatment Poziotinib 16mg PO Daily

Molecular

Pause

Response PR PD-lung only Flare Flare

2 3 4 5 6 70 8

B

C D

Figure 1. Chronology of treatment, response, molecular pathology and imaging. Panel A shows the pre-treatment baseline scan, panel B shows the 4 week post-poziotinib scan, panel C represents the flare 3 weeks after poziotinib discontinuation, panel D shows the treatment response after re-initiation of poziotinib on the EAP, panel E shows the second flare two weeks after discontinuing the poziotinib EAP. cfDNA, cell-free DNA; CT, computed tomography; D/C, discontinued; EAP, expanded access program; MR, magnetic resonance imaging; PR, partial response; PD, progressive disease; CGP, comprehensive genomic profiling.

91

Poziotinib 12mg PO Daily

PR

Plasma cfDNA CGP Pre-treatment Month 9

ERBB2 (HER2) A775_G776insYVMA (Exon 20 insertion)

13.5% (variant allele fraction) 35.3%

EGFR Amplification Not Detected 2.5 (plasma copy number)

A) 12/10/18 MR B) 1/9/19 MR C) 6/21/19 MR D) 7/18/19 MR E) 9/28/19 CT

10

D/C

Tchekmedyian JTO CRR 2020

Discussion Points on Case 1

▪ Molecular testing in NSCLC

▪ Role of Systemic Therapy and intracranial response

▪ Role of Surgery for brain metastases

▪ Role of Radiation for brain metastases

o SRS vs Whole Brain

▪ Timing of surgery and/or radiation

10

Case #2

▪ 78 year old female with newly diagnosed NSCLC

▪ Began having falls and left-sided weakness

▪ CT of the brain showed multiple sizable tumors, one in the right anterior frontal convexity and

the other in the right posterior frontal/anterior

▪ CT scan of the chest abdomen and pelvis which showed evidence of a 3.3 cm central left upper

lobe lung mass with a large left pleural effusion and left lung atelectasis.

11

Case #2

12

Case #2

▪ HopeSeq

▪ Adenocarcinoma

13

Case #2

▪ Post-Surgical

14

Case #2

15

Case #3

▪ 34 yo female with metastatic cutaneous BRAF mutant melanoma initially diagnosed in 7/18/11 with punch biopsy of right lower extremity skin lesion. She completed 6 months of adjuvant interferon alpha on 03/09/12. Remained clinically without evidence of disease until 9/17/18, when PET CT showed a new FDG avid 1.6 cm Left lower lung nodule. This was followed by u/s right groin area due patient palpated enlargement, which was confirmed right inguinal adenopathy.

▪ She underwent thorascopic wedge resection on 10/10/18 demonstrating a 1.8 cm tumor involving the lung parenchyma of left lower lobe, which was positive for metastatic melanoma, (2/2) lymph nodes also positive. She completed 3/4 planned cycles of ipilimumab plus nivolumab on 12/03/18. 4th cycle cancelled due to urosepsis and autoimmune hepatitis. She then developed recurrence in the left posterior chest wall in October 2019, and underwent left chest wall excision on 1/10/20, followed by radiation to the area.

16

Case #3

▪ Underwent SRS 2/20 presents to

COH in 5/20 and within a 2-3

weeks was admitted with altered

mental status and seizures. MRI

revealed a hemorrhagic right

temporal lesion, (previously

treated), increasing in size.

17

Case #3: Pre and postop MRI from may 2020

18

Case #3:

Craniotomy #2: developed multiple brain mets

Despite SRS, lesions progressed by July 2020

19

Case #3

▪ With multiple brain lesions and suspected LMC, craniotomy would not be a conventional option.

▪ A shunt and Ommaya reservoir were inserted shortly after the craniotomy.

▪ These were followed by whole brain XRT in 8/2020.

20

Case #3

▪ IT nivolumab given at end of 8/2020.

▪ She initiated pembrolizumab, given every 3 weeks, on 10/19/20, and has now received a total

of 5 cycles. She was also taking encorafenib 450 mg daily with binimetinib 45 mg by mouth 2

times a daily, concurrently with pembrolizumab.

▪ SRS to multiple brain lesions (PTVs 6-9) from 6/2/21 - 6/11/21

21

Case #3: MRI 8/21

22

NERSES SIMON TCHEKMEDYIAN

ntchekmedyian@coh.org

23

ARYA AMINI

aamini@coh.org

MIKE CHEN

mchen@coh.org

Questions