3/7/2018 18 th Multidisciplinary Management of Cancers: A Casebased - - PDF document

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

2018 Developmental Therapeutics Panel Shivaani Kummar MD Stanford Diane Tseng MD PhD Stanford fellow Rahul Aggarwal MD UC San Francisco Pamela Munster MD UC San Francisco Karen Kelly MD UC Davis Tianhong (Tina) Li MD PhD UC Davis Akshiv Malhotra MD Epic Care Ming‐Gui Pan MD Kaiser Permanente

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Case 1: A 45 year old woman with metastatic lung adenocarcinoma and polyarthralgias

2012 2013 2014 2015 2016 2017 Shortness

• f breath

Carbo/pem x 8 cycles

PD

Declines tx, herbal supplements

v PD * Establish care at Stanford

Develops joint pain

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Case 1: A 45 year old woman with metastatic lung adenocarcinoma and polyarthralgias

2012 2013 2014 2015 2016 2017 Shortness

• f breath

Carbo/pem x 8 cycles

PD

Declines tx, herbal supplements

v PD v SD

Develops joint pain

* Establish care at Stanford

Platinum/pem x 6 cycles

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Case 1: A 45 year old woman with metastatic lung adenocarcinoma and polyarthralgias

2012 2013 2014 2015 2016 2017 Shortness

• f breath

Carbo/pem x 8 cycles

PD

Declines tx, herbal supplements

v PD v SD

Develops joint pain

* Establish care at Stanford

Platinum/pem x 6 cycles

Biopsy of LLL: SQSTM1‐NTRK1 translocation detected

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Pre-treatment

LOXO‐TRK‐15002: A Phase II Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects with NTRK Fusion‐Positive Tumors

Larotrectinib 100 mg PO BID

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Pre-treatment After 2 cycles After 6 cycles

LOXO‐TRK‐15002: A Phase II Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects with NTRK Fusion‐Positive Tumors

Larotrectinib 100 mg PO BID

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Pre-treatment After 2 cycles After 12 cycles After 6 cycles After 16 cycles

LOXO‐TRK‐15002: A Phase II Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects with NTRK Fusion‐Positive Tumors

Larotrectinib 100 mg PO BID

RECIST ‐59% PR

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Presented By David Hyman at 2017 ASCO Annual Meeting

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Presented By David Hyman at 2017 ASCO Annual Meeting

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Presented By David Hyman at 2017 ASCO Annual Meeting

18th Multidisciplinary Management of Cancers: A Case‐based Approach

How are NTREK fusions detected? A) Next Generation Sequences (NGS) B) Fluorescence in situ hybridization (FISH) C) Real‐time polymerase chain reaction (RT‐PCR) D) Immunohistochemistry (IHC) E) A, B, and C

18th Multidisciplinary Management of Cancers: A Case‐based Approach

How are NTREK fusions detected? A) Next Generation Sequences (NGS) B) Fluorescence in situ hybridization (FISH) C) Real‐time polymerase chain reaction (RT‐PCR) D) Immunohistochemistry (IHC) E) A, B, and C

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Larotrectinib is effective against which of the following NTREK fusion genes? A) NTREK1 B) NTREK2 C) NTREK3 D) A, B, and C

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Larotrectinib is effective against which of the following NTREK fusion genes? A) NTREK1 B) NTREK2 C) NTREK3 D) A, B, and C

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Presented By David Hyman at 2017 ASCO Annual Meeting

18th Multidisciplinary Management of Cancers: A Case‐based Approach

NTRK fusions have been found in which tumors? A) Highly prevalent tumors (lung, colorectal, thyroid) B) Moderately prevalent tumors (AML, glioblastoma, soft tissue sarcoma, GI stromal tumors) C) Rare pediatric and adult cancer types: juvenile secretory breast cancer, infantile fibrosarcoma, conenital mesoblastic nephroma) D) All of the above

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

NTRK fusions have been found in which tumors? A) Highly prevalent tumors (lung, colorectal, thyroid) B) Moderately prevalent tumors (AML, glioblastoma, soft tissue sarcoma, GI stromal tumors) C) Rare pediatric and adult cancer types: juvenile secretory breast cancer, infantile fibrosarcoma, conenital mesoblastic nephroma) D) All of the above

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Presented By David Hyman at 2017 ASCO Annual Meeting

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Presented By David Hyman at 2017 ASCO Annual Meeting

18th Multidisciplinary Management of Cancers: A Case‐based Approach

How would you manage patients who have developed resistance to larotrectinib? A) Consider switching to another first‐generation TRK inhibitor B) Refer to palliative care C) Consider clinical trial with next‐generation TRK inhibitors D) Standard of care chemotherapy

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

How would you manage patients who have developed resistance to larotrectinib? A) Consider switching to another first‐generation TRK inhibitor B) Refer to palliative care C) Consider clinical trial with next‐generation TRK inhibitors D) Standard of care chemotherapy

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Drilon et al. Cancer Discov 2017. Solvent front mutations in TRKA and TRKC lead to steric hindrance for larotrectinib binding * Trial open at Stanford

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Immuno‐Oncology

• Phase 1/2 Multicenter Trial of ICOS Agonist Monoclonal Antibody (mAb) JTX‐2011 Alone or in Combination with Nivolumab in

Adult Subjects with Advanced Refractory Solid Tumor Malignancies

• A Phase 1/1b, Open‐Label, Multicenter, Repeat‐Dose, Dose‐Selection Study of CPI‐444 as Single Agent and in Combination with

Atezolizumab in Patients with Selected Incurable Cancers

• A Phase 1b/2, Open‐Label, Multicenter, Dose‐Escalation and Expansion Trial of Intratumoral of SD‐101 in Combination with

Pembrolizumab in Patients with Metastatic Melanoma or Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Antibody‐Drug conjugate

• An open‐label Phase I dose‐escalation study to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and

pharmacodynamics of the anti‐C4.4a antibody drug conjugate BAY 1129980 in subjects with advanced solid tumors known to express C4.4a

• A Phase 1, Open‐Label, Dose‐Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of

ADCT‐502 in Patients with Advanced Solid Tumors with HER2 Expression Small Molecules

• A Phase 1/2a Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of PLX8394 in Patients with Advanced,

Unresectable Solid Tumors

• A Phase III Study of AL3818 (Anlotinib) Hydrochloride Monotherapy in Subjects with Metastatic or Advanced Alveolar Soft Part

Sarcoma, Leiomyosarcoma and Synovial Sarcoma

• Phase I clinical trial of VX‐970 in combination with the topoisomerase I inhibitor irinotecan in patients with advanced solid

tumors

18th Multidisciplinary Management of Cancers: A Case‐based Approach

History

Case 2: A 63 y/o M, diagnosed in 2014, presented with Gleason 5+4 prostate adenocarcinoma

• Bone and lymph node metastases at diagnosis
• Treated with systemic therapy with Lupron + docetaxel x 6 cycles
• Initial response then recurrence after 12 months on Lupron

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

• Restaging scans with significant interval progression of disease

with bulky nodal metastases

• No visceral metastases
• PSA 142

18th Multidisciplinary Management of Cancers: A Case‐based Approach

What is the reason to consider metastatic tumor biopsy?

A) To evaluate for targetable molecular alterations in his tumor B) To evaluate for evidence of neuroendocrine differentiation C) To evaluate for PD‐L1 expression in the tumor D) A and B E) A, B, and C

18th Multidisciplinary Management of Cancers: A Case‐based Approach

What is the reason to consider metastatic tumor biopsy?

A) To evaluate for targetable molecular alterations in his tumor B) To evaluate for evidence of neuroendocrine differentiation C) To evaluate for PD‐L1 expression in the tumor D) A and B E) A, B, and C

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Biopsy of Supraclavicular Node Demonstrates Small Cell Neuroendocrine Histology

Adenocarcinoma Small Cell

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Molecular sequencing may explain patient’s depth of response to platinum chemo

• FANCG splice site

mutation predicted to lead to loss of function

• HR dsDNA repair
• Prior studies

indicate synthetic lethality with platinum chemo

18th Multidisciplinary Management of Cancers: A Case‐based Approach

What would you consider next for treatment?

A) Carboplatin + docetaxel B) Pembrolizumab off‐label C) Olaparib off‐label D) Cabazitaxel

18th Multidisciplinary Management of Cancers: A Case‐based Approach

What would you consider next for treatment?

A) Carboplatin + docetaxel B) Pembrolizumab off‐label C) Olaparib off‐label D) Cabazitaxel

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Patient case continued…

• Patient with initial response, then eventual radiographic

progression, patient did not wish to go back on platinum‐ based chemotherapy

• Enrolled on Phase 1 trial of rovalpituzumab tesirine, antibody‐

drug conjugate targeting DLL3

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Phase I open‐label study of Rova‐T in DLL3‐expressing advanced solid tumors

• Rova‐T is an antibody‐drug conjugate

targeting delta‐like protein 3 (DLL3)

• DLL3 is an atypical Notch receptor

family ligand expressed in high‐ grade neuroendocrine carcinoma (NECs), but not normal tissue

Key Eligibility Criteria

• Histologically confirmed,

unresectable, advanced solid tumor

• DLL3 positive
• PD after ≥ 1 prior systemic therapy

– No prior exposure to PBD‐based drug

• ECOG PS 0‐1

N=378 Eight cohorts: ‐ Malignant melanoma ‐ Medullary thyroid cancer (MTC) ‐ Glioblastoma (GBM) ‐ Large‐cell NEC of lung (LCNEC‐lung) ‐ Neuroendocrine prostate cancer ‐ High‐grade gastroenteropancreaticNEC (GEP NEC) ‐ Other NEC ‐ Other solid tumors Part A: Dose Escalation ‐ Rova‐T 0.2‐0.4 mg/kg q6w until PD ‐ N = 144 Part B: Dose Expansion ‐ Rova‐T MTD or lower 1EP: MTD, safety, tolerability 2EP: ORR, DOR, PFS, OS, CBR, PK

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Enriched DLL3 expression in NEPC

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Preliminary Evidence of Anti‐Tumor Activity in Small Cell Lung Ca

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Basket Study Preliminary Results

Aggarwal et al. ESMO 2017

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Case continued

• Patient treated with two cycles of rova‐T
• Had rash on arms, face, and neck, legs, and upper back
• Moderate pleural effusion
• B lower extremity edema

18th Multidisciplinary Management of Cancers: A Case‐based Approach

What would you do next?

A) Thoracentesis B) Lasix C) IV steroids D) Topical steroids

18th Multidisciplinary Management of Cancers: A Case‐based Approach

What would you do next?

A) Thoracentesis B) Lasix C) IV steroids D) Topical steroids

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Case Conclusion

• Patient on prolonged treatment break > 9 months

following two doses of rova‐T

• Eventual disease progression
• Currently on Phase 2 IST of pembrolizumab in high‐

grade NEC at UCSF (PI: E. Bergsland, NCT03136055)

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

UC Davis Tianhong “Tina” Li and Karen Kelly

Case 3: A 65‐year‐old male with refractory, stage IV NSCLC 18th Multidisciplinary Management of Cancers: A Case‐based Approach

Case presentation

A 65‐year‐old Caucasian male, active smoker (smokes 5‐8 cigarettes/day, previously 2.5 PPD for 40 yrs), with chronic obstructive pulmonary disease (COPD) underwent right upper lobe lobectomy with mediastinal lymph node dissection in 1/2010. Surgical pathology revealed stage IIIA (T4N0M0) G3 lung squamous cell carcinoma. He received adjuvant platinum‐based chemotherapy for 4 cycles (4/9/2010‐ 6/22/2010) with poor tolerance. Patient was found to have recurrent metastatic disease ~2 years later.

18th Multidisciplinary Management of Cancers: A Case‐based Approach

• 1. Re‐biopsy for broad tumor genomic profiling by NGS
• 2. Re‐biopsy PD‐L1 IHC
• 3. No biopsy. Blood tumor genomic profiling
• 4. 1 and 2
• 5. All the above
• 6. None of the above

Question 1. Would you recommend tumor biopsy for biomarker testing ? 18th Multidisciplinary Management of Cancers: A Case‐based Approach Patient had the transbronchial FNA biopsy of left upper lobe mass.

Pathology:

• Squamous cell carcinoma with

extensive necrosis FoundationOne Assay:

• TP53 PROTEIN EFFECT:R273C

MUTATION ALLELE FREQUENCY (MAF)= 2.0%

• FGFR1 TRUNCATION (NO MUTATION

ALLELE FREQUENCY AVAILABLE)

Patient received docetaxel for 6 cycles, followed by erlotinib for 15 months and an investigational drug for 6 cycles till Oct 2015 when PD‐1 inhibitor nivolumab

• btained the US FDA approval.

His best clinical response was partial response (PR) and discontinued all these three treatment regiments due to tumor progression.

Case presentation (continued)

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Pre‐Treatment Nivolumab Q2wk x 3

Impression: stable disease by RECIST V1.1 SLIGHT INTERVAL DECREASE IN HYPERMETABOLIC ACTIVITY OF THE KNOWN LEFT LINGULAR MASS AND ASSOCIATED ADENOPATHY WITH NO NEW LESIONS IDENTIFIED.

Fourth line systemic therapy for metastatic disease

Details: On image 76, there is a 1.4 x 1.2 cm precarinal lymph node with SUV Max of 3.1 (previously measured 0.9 x 0.7 cm with SUV Max of 3.2). On image 86, there is a 1.6 x 2.3 cm conglomerate of left hilar lymph nodes with SUV Max

• f 4.8 (prior SUV Max of 5.4).

On image 84, there is a 2.4 x 1.7 cm subcarinal lymph node with SUV Max of 3.4 (previously measured 2.5 x 1.4 cm with SUV Max of 4.9). On image 117, there is a 1.4 x 1.4 cm anterior gastroesophageal lymph node with SUV Max

• f 5.4 (previously measured 1.2 x 0.8 cm with SUV Max of 5.9).

On image 115, there is a 1.2 x 1.3 cm posterior gastroesophageal lymph node with SUV Max

• f 3.4 (previously measured 1.2 x 0.8 cm with SUV Max of 5.9).

There is a focus in the left lobe that measures 2.2 x 1.3 cm with SUV Max of 4.1. There is a 1.0 x 1.7 cm focus at the midline prostate with SUV Max of 3.3. There is a 1.2 x 1.7 focus of increased activity within the right prostate lobe with SUV Max of 3.4. Bilateral rotator cuff tendinopathy as evidenced by low level FDG uptake. Left adrenal gland is mildly prominent with FDG avidity less than that of background liver, suggesting a benign etiology.

18th Multidisciplinary Management of Cancers: A Case‐based Approach Question 2. Would you recommend to continue nivolumab monotherapy ?

1. No 2. Yes 3. I don’t know

18th Multidisciplinary Management of Cancers: A Case‐based Approach Patient continued the nivolumab treatment for 16 cycles. Patient developed pneumonitis. 16 cycles post‐nivolumab

Patient complains of dyspnea on exertion, worsening chronic cough productive of white sputum, fatigue, and joint discomfort. Patient denies hemoptysis, shortness of breath at rest, pleuritic pain, TB exposure, unusual pets, known environmental or asbestos exposure, fever, night sweats, PND, anorexia, anginal chest pain, edema. Radiographically patient had partial response but the lingula and anterior segment of the LUL appear to have tumor progression.

18th Multidisciplinary Management of Cancers: A Case‐based Approach Question 3: How would you manage the immune‐related toxicities ?

1. Discontinue nivolumab, observe 2. Discontinue nivolumab, add steroids 3. Continue nivolumab and add steroids 4. Refer for pulmonary consultation

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Patient underwent bronchoscopy with bronchoalveolar lavage (BAL) failed to reveal pathogen. Transbroncial biopsy was performed (see next page, A and C). LUL biopsy confirmed residual tumor that was stained positive for PD‐L1 IHC positive (see next page, B and D). Patient was started on prednisone 60 mg for symptomatic, presumed nivolumab‐induced organizing pneumonia, which was tapered off over a 2‐month period. A follow‐up chest CT scan reveals residual consolidation within the left upper lobe consistent with known malignancy, and improvement in inflammatory appearing components in the central LUL. Unchanged size and appearance of known metastatic mediastinal and gastrohepatic ligament lymph nodes.

Case presentation (continued)

18th Multidisciplinary Management of Cancers: A Case‐based Approach

H& E stain PD‐L1 IHC

Histological assessment and PD‐L1 IHC of different lung pathologies

Transbroncial biopsy Tumor biopsy

PD‐L1 positive macrophages PD‐L1 positive tumor cells

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Early Immune‐Related Adverse Events (irAEs) at 2 weeks are associated with a better outcome in Advanced NSCLC Patients Treated with Nivolumab: the First Prospective Cohort Study

Teraoka S et al., Journal of Thoracic Oncology 12 (12), Pages 1798‐1805 (December 2017)

Any irAEs Rash Pyrexia Diarrhea Rash and pyrexia were strong early predictive factors of efficacy.

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Evaluation of immune‐related adverse effects (irAEs) (pneumonitis) to PD1/PD‐L1 inhibitor therapy

• Be alert for the possibility for all patients
• Need a multidisciplinary discussion
• The need for bronchoscopy and trans‐bronchial biopsy for tissue diagnosis and

rule out other pathologies

• Treatment indication: No evidence of steroids use compromises clinical efficacy1
• Rechallenge later?

1Garant A et al., Critical Reviews in Oncology / Hematology 120 (2017) 86–92

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

• Q4. Patient received afatinib for two months followed by external beam radiation

therapy to the LUL lung lesion and hepatogastric lymph nodes. At progression, which treatment would you recommend?

• 1. Retreat with nivolumab
• 2. Change to pembrolizumab and platinum-based

chemotherapy combination

• 3. Change to a PD-L1 inhibitor such as atezolizumab
• 4. A combo immunotherapy regimen on a clinical trial
• 5. Non-immunotherapy trial

Radiation

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Major Factors Contributing to Resistance to Immune Checkpoint Blockage (ICB) Therapy

Pitt JM, et al. Immunity. 2016; 44 (6): 1255-1269

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Permission to use from Dr. Siwen Hu-Lieskovan

Rational Combinations to Overcome Resistance to ICBs

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Tumor debulking and releasing tumor antigens Not systemically immunosuppressive Upregulation of immunogenic cell surface markers ‐ ICAM-1 ‐ MHC-1 ‐ Fas Secretion of danger signals & cytokines

• IFN-
• TNFα
• IL-1β

Induction of Immunogenic cell death ‐ Calreticulin ‐ HMGB-1

Immunomodulatory Effects of Radiotherapy

Daly ME et al., J Thorac Oncol. 2015; 10: 1685–1693

Increased homing of immune cells to tumors ‐ Normalization of tumor vasculature ‐ Secretion of chemo-attractants (cxcl16) ‐ Endothelial expression of VCAM-1 ‐ Improved T-cell homing to tumors Improved antigen presentation by APC’s ‐ Irradiated tumors prime dendritic cells ‐ Improved antigen presentation via TLR-4 Depletion of immunosuppressive cells Shifting TAM polarization to M1

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

UC Davis Cancer Center: Combinational strategies for patient who failed first generation PD1/PD‐L1 inhibitors (phase I/II trials)

• PD‐1 and CTLA‐4

PHII‐155: a Phase 2 Study of MEDI4736 (durvalumab) and Tremelimumab Alone or in Combination with High or Low‐Dose Radiation in NSCLC (NCI#10021)

• PD‐1/PD‐L1 and chemotherapy

A Phase 1, Open‐Label, Multicenter, Safety Study of Nivolumab (BMS‐936558) in Combination with nab‐Paclitaxel Plus or Minus Gemcitabine in Pancreatic Cancer, nab‐Paclitaxel / Carboplatin in Stage IIIB/IV NSCLC or nab‐Paclitaxel in Metastatic Breast Cancer

• PD‐L1 and Radiation

UCDCC#270: A Pilot Study of Avelumab and Stereotactic Ablative Radiotherapy in Non‐Responding and Progressing NSCLC Patients Previously Treated With a PD‐1 Inhibitor

• TGFβ‐PD‐L1 antibody conjugate:

A Phase I, Open‐label, Multiple‐ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of MSB0011359C in Subjects with Metastatic or Locally Advanced Solid Tumors and Expansion to Selected Indications Combination with immune‐modulators:

• Phase 1, Open‐Label, Dose‐Escalation and Cohort Expansion First‐in‐Human Study of the Safety, Tolerability, Activity and Pharmacokinetics of REGN3767

(anti‐LAG‐3 mAb) Administered Alone or in Combination with REGN2810 (anti‐PD‐1 mAb) in Patients with Advanced Malignancies

• UCDCC#269: A Pilot Study of Intralesional IL‐2 and Hypofractionated Radiotherapy in Patients with Metastatic NSCLC Who Are Refractory to PD‐1/PD‐L1

Blockade

• UCDCC#263 Phase II Trial of TG4010 (a modified vaccinia expressing MUC1 and interleukin 2A) plus Nivolumab in Previously Treated Patients with

Metastatic NSCLC

18th Multidisciplinary Management of Cancers: A Case‐based Approach

6 weeks post‐treatment

Pre‐treatment

Patient received MEDI4736 (durvalumab) and Tremelimumab x 1 on a clinical trial.

18th Multidisciplinary Management of Cancers: A Case‐based Approach

A Ribas Cancer Discovery 2015;5:915- 919

Summary

Permission to use from Dr. Siwen Hu-Lieskovan

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Case 4: 43 year old lady with metastatic adenocarcinoma of unknown primary

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Case history

Initially presented with back pain and found to have a large sacral mass‐ 06/2015 Biopsied and showed Adenocarcinoma of upper GI/pancreatobiliary origin‐ stable MSI testing Refused Colonoscopy, negative EGD in hospital. PET showed left lung mass, lytic lesions in ribs and left adrenal gland metastasis, retroperitoneal adenopathy Got Radiation to sacral mass and then started on palliative chemo Responded to chemo but multiple psychosocial issues‐ So it was stopped

18th Multidisciplinary Management of Cancers: A Case‐based Approach

2015 2016 2017

mFOLFOX6 x 10 cycles Refused further chemo

Back pain and night sweats 2018 Foundation one testing

Started on Palbciclib + Letrozole

18th Multidisciplinary Management of Cancers: A Case‐based Approach Foundation 1 testing showed CCND3 amplification‐ NCI MATCH trial would have put her on Palbociclib based on this but she was not eligible due to psychosocial issues Started on Palbociclib plus letrozole in February 2016 18th Multidisciplinary Management of Cancers: A Case‐based Approach

Follow up‐

Latest PET scan and MRI brain in December 2017 showing stable disease.

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

CCND3(cyclin D3) amplification

18th Multidisciplinary Management of Cancers: A Case‐based Approach

Oral CDK inhibitor Received accelerated approval by FDA for HR+ metastatic breast cancer in February 2015 in combination with Letrozole based on phase II PALOMA‐1 study

Palbociclib

18th Multidisciplinary Management of Cancers: A Case‐based Approach

• Which of the following is/are CDK4/6 inhibitors?

A) Abemaciclib B) Palbociclib C) Ribociclib D) Flavopiridol E) A, B and C F) All of the above

Question

18th Multidisciplinary Management of Cancers: A Case‐based Approach

• Which of the following is/are CDK4/6 inhibitors?

A) Abemaciclib B) Palbociclib C) Ribociclib D) Flavopiridol E) A, B and C F) All of the above

Question

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

Genta et al. Transl Can Res 2016.

18th Multidisciplinary Management of Cancers: A Case‐based Approach

• Which of the CDK 4/6 inhibitors has the highest CNS penetration?

A) Abemaciclib B) Palbociclib C) Ribociclib

Question

18th Multidisciplinary Management of Cancers: A Case‐based Approach

• Which of the CDK 4/6 inhibitors has the highest CNS penetration?

A) Abemaciclib B) Palbociclib C) Ribociclib

Question

18th Multidisciplinary Management of Cancers: A Case‐based Approach

First‐in‐human clinical trial of abemaciclib, an inhibitor of CDK4/6

• Enrolled 33 patients in dose‐escalation
• Enrolled 192 patients in tumor‐specific cohorts
• Breast cancer (n = 47, single‐agent)
• Hormone receptor positive breast cancer (n = 19, abemaciclib + fulvestrant)
• Non‐small cell lung cancer (n = 68)
• Glioblastoma (n = 17)
• Melanoma (n = 26)
• Colorectal cancer (n = 15)

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

First‐in‐human clinical trial of abemaciclib, an inhibitor of CDK4/6 Breast cancer

18th Multidisciplinary Management of Cancers: A Case‐based Approach

First‐in‐human clinical trial of abemaciclib, an inhibitor of CDK4/6 Breast cancer Lung Cancer

18th Multidisciplinary Management of Cancers: A Case‐based Approach

First‐in‐human clinical trial of abemaciclib, an inhibitor of CDK4/6 Breast cancer Lung Cancer Colorectal, Glioblastoma, Melanoma

18th Multidisciplinary Management of Cancers: A Case‐based Approach

First‐in‐human clinical trial of abemaciclib, an inhibitor of CDK4/6 Breast cancer Lung Cancer Colorectal, Glioblastoma, Melanoma Adverse events:

• Neutropenia (23% all grades)
• Fatigue (41% all grades)
• Diarrhea (63% all grades)

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18th Multidisciplinary Management of Cancers: A Case‐based Approach

CDK4/6 Inhibitors: Current and future directions

• Breast cancer
• Phase II/III studies showing efficacy as monotherapy (MONARCH 1) and in combination with endocrine therapy

(MONARCH 2, MONARCH 3); FDA approved

• Lung cancer
• Phase II JUNIPER trial against erlotinib in KRAS‐mutant NSCLC in second line
• LUNG‐MAP, UK National Lung Matrix trials, SIGNATURE basket trial treating patients with CDK4/6 activated tumors

(CDK4/6 amplification or mutation, CCND1 or CCND3 amplification, or CDKN2A mutations)

• Mantle cell lymphomas
• t(11;14) translocations lead to increased cyclin D1 expression
• Phase I trial of ibrutinib and palbociclib in mantle cell lymphomas (Martin et al. ASH Annual Meeting 2016)
• Liposarcoma
• CDK4 amplifications reported
• Phase II trial of palbociclib in advanced liposarcoma (Dickson et al. Jama Onc 2016)

18th Multidisciplinary Management of Cancers: A Case‐based Approach

CDK4/6 Inhibitors: Current and future opportunities

• Evaluation of potential to treat brain metastases
• Combination with growth signaling pathways:
• PI3K
• MAP kinase
• Her2
• B cell receptor signaling pathways