Impact of Targeted/Immunotherapy on Gamma Knife Radiosurgery Veronica Chiang, MD Yale University Department of Neurosurgery IGKRF Scientific Session University of Pennsylvania, Philadelphia June 23-24, 2017 S L I D E 0
Introduction Treatment of melanoma and non-small cell lung cancer has been revolutionized by immunotherapy and targeted therapies Patients living longer How does this affect radiosurgery? S L I D E 2
Targeted versus Immuno-therapy Targeted Therapies Melanoma BRAF: vemurafenib, dabrafenib NSCLC EGFR mutations: gefitinib, erlotinib, afatanib NSCLC ALK rearrangement: crizotinib, alectinib, ceritinib NSCLC ROS rearrangement: crizotinib Systemic Therapy RARELY curative First line therapy for NSCLC if target mutation found CNS penetration rapidly effective Efficacy might be related to drug dose (except osimertinib?) Failure by mutation e.g. T790M mutation for EGFR Immunotherapies Vaccines Anti-CTLA4: ipilimumab Anti-PD1: nivolumab, pembrolizumab Systemic Therapy CAN BE curative First line therapy for melanoma (but not NSCLC) even if target mutation found CNS penetration mechanism unclear More likely due to T-cell infiltration Response and failure dichotomous Dosing oral daily Steroids ok Dosing IV q2weeks until death or 2yrs if successful Steroids strongly discouraged S L I D E 3
BRAF inhibitors and Melanoma Brain Metastases 50% of melanomas have BRAF mutation: 80-90% V600E >70% of melanoma patients will develop MBM often multiple Rochet NM et al. (2011) NEJM 2011;365(25):2439-2441 Single case treated with SRS with progression Vemurafenib 960mg bid significant response in CNS at 1 month Dummer R et al. (2014) Eur J Cancer 2014;50(3):611-621 Prospective, vemurafenib 24 patients, unresectable, previously treated symptomatic MBM 42% partial response (>30% in 37% pts) Retrospective studies: (Dzienis 2014, Harding 2015) Asymptomatic MBM, vemurafenib 50% response in CNS Dabrafenib MBM response 78% (Azer 2014) Median PFS (intracranial and extracranial) 23.6 weeks S L I D E 4
BRAF inhibitors and MBMs and radiation Sambade et al. (2011) Radiother Oncol 2011;98(3):394-399 Showed a range of radiosensitivity of melanoma cells in culture Radioresistence seemed to be related to having BRAF mutation Addition BRAFi resulted in radiosensitization Confirmed by Glazer PM et al. (2013) Mechanism thought to be increase in both G1 and G2 cell cycle arrest BUT Hecht et al. (2015) Ann Oncol 2015;26(6);1238-1244 Normal blood cells exposed to vemurafenib Increased chromosomal aberrations ie radiosensitizes normal cells also?not associated with dabrafenib? BRAF inhibitors and WBRT Significant risk of acute dermatitis Significant radiation recall inflammatory reaction Associated with starting vemurafenib 1-42 days after radiation Less so with dabrafenib and SRS S L I D E 5
Clinical Experience BRAFi and GK-SRS No radiation necrosis or scalp dermatitis 53 GK treatments : 33 concurrent, 4 with drug interruption, 16 before BRAFi started Gaudy-Marqueste et al. Ann Oncol 2014;25(10):2086-2091 Local control 92% 6mos, 75-90% 12mos c/w 50-70% 12mos BRAF neg SRS doses 13-24Gy Distant failure rate 40-60% at median 3-6mos Ahmed et al. JNO 2015;122(1)121-126, Ly et al. JNS 2015;123(2):395-401, Xu et al. 2016 Question of increased rate Radiation Necrosis (Xu/Sheehan 2016, Patel 2016) Concurrent and nonconcurrent If BRAF mutation present and WBRT is best RT option then Dabrafenib/Tremetinib is first line targeted therapy: If CNS disease stabilizes then usually offer SRS ECOG Recommendation: Hold BRAFi 1 day before and after GK and 3 days before and after fractionated SRS S L I D E 6
TKIs and Lung Cancer Brain Metastases Oncogenic mutations present in 60% adenocarcinomas EGFR/ALK-TKIs are first line treatment for mutation pos metastatic NSCLC PROs for TKI only Phase II studies of EGFR-TKI alone for brain metastases: Objective response rate 65-89% ( afatinib<gefitinib<erlotinib) Median progression-free survival 6.6-14.5 months Median overall survival 15.9-21.9 months No delay in initiating systemic therapy Avoid potential toxicity of local therapy CONS for TKI only Rosell et al 2009, Park et al, 2012, Iuchi et al. 2013 EGFR mutants do not have increased rate of brain mets BUT brain is frequent site of disease recurrence due to low CNS penetration No additional reported toxicity with addition of RT to TKI Depending on who patient sees first, can get different first line Rx S L I D E 7
54yo RHWF w ALK re-arranged NSCLC NED 3 years after diagnosis, Px numbness right hand Options for Management: 5cm 1. Surgery + WBRT 2. WBRT alone 3. SBRT 4. 2-staged SRS 5. Neoadjuvant SRS then surgery 6. CNS-penetrating targeted therapy S L I D E 8
Example of targeted therapy response Start ceritinib f/u MRI 2 weeks S L I D E 9
What is the right answer for this patient? Should WBRT be used upfront? S L I D E 10
What is the right answer for this patient? When is the right time to use SRS? S L I D E 11
TKI only versus TKI-RT at first diagnosis of BrMets - Deferral of upfront RT was detrimental to overall survival - 6 centers : Yale, MSKCC, U Colorado, YCSF, CCF, Vanderbilt - 350 patients - Inclusion: new brain mets, known TKI-sensitive EGFR mutation, naïve to TKI - Exclusion: prior TKI use, TKI resistance, surgical resection, <6mos f/u S L I D E 12
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Progression Free Survival RT group had more symptomatic BrMets WBRT group had larger size and number of BrMets WBRT group had worse dsgpa-based prognosis Rx TKI SRS WBRT PFS 17mos 23mos 24mos S L I D E 14
Rx TKI SRS WBRT OS 25mos 46mos 30mos S L I D E 15
Newest Addition to the TKIs - Osimertinib We Need A Randomized Trial S L I D E 16
Immunotherapy for untreated brain metastases NCT02085070 Non-randomized phase 2 trial using pembrolizumab Inclusion: Melanoma and Lung cancer Lung cancer patient needs PDL-1 positivity At least one untreated or progressive brain metastasis No need for steroids Preliminary results: Melanoma 18 patients 4/18 (22%) with durable CNS response Lung cancer 18 patients 6/18 (33%) with durable CNS response Neurological complications 3 patients with seizures, 1 transient cognitive dysfunction, 1 with significant edema causing herniation Lessons learned: Mechanism of action of IT can cross the blood brain barrier The majority of patients still need radiation to control CNS disease S L I D E 17
Lesson #1 : IT works well in some cases S L I D E 18
Lesson #2: Can go badly quickly in others 1 month 2 months Start trial S L I D E 19
Lesson #3: Adding GK to IT works great!!! surgery GK Start trial watch 6 weeks later S L I D E 20
Lesson #4: GK + IT can work even at lower doses (12Gy) Start trial 6 weeks S L I D E 21
Lesson #5 : sometimes full dose GK + IT a problem 53yo female melanoma Prior SRS x2 without event 2013 new lesion GK 2014 Pembrolizumab Oct 2014 S L I D E 22
Histology GK followed by Anti-PD1 agent S L I D E 23
Concurrent Immunotherapy in Melanoma Qian JM, Yu JB, Kluger HM, Chiang VL. Cancer. 2016 Oct;122(19):3051-8. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. S L I D E 24
Lesson #6: Late Effects of IT + standard dose GK 12/2015 4/2017 NED body 6/2015 1/2016 S L I D E 25
Delayed RN can occur years later 10/2015 1/2016 GK 12/2014 3/2017 S L I D E 26
Late Effect of Immunotherapy and GK 300 consecutive GK patients treated 2010-2012 180 survived >6 months Mean age 59 years 55% male 39% lung cancer, 31% melanoma 39 with diagnosis of RN by imaging or histology Tumor Volumes: Mean 3.89cc (RN) versus 7.13cc (no-rn) Treatment Dose: Single fraction 18-22Gy to 45-60% isodose lines Median follow-up: 11.7mos (range 6-48 mos) S L I D E 27
Results: Uni-variate Analysis Systemic therapy Total (180) RN (39) % IT only 32 12 37.5 TT only 20 5 25.0 CT only 83 14 16.9 IT+TT 4 2 IT+CT 4 0 TT+CT 31 5 16.1 IT+TT+CT 2 0 None 4 1 Receiving any IT showed a trend towards increasing the risk of RN Receiving any CT significantly decreased the risk of RN Systemic Therapy OR 95%CI P-value IT 2.07 0.96 4.47 0.06 TT 1.04 0.49 2.26 0.12 CT 0.38 0.18 0.78 0.01 S L I D E 28
Is it the same for lung cancer? S L I D E 29
64yo male EGFR WT NSCLC GK 10/2015 nivolumab 11/2015 - HA 12/2015 S L I D E 30
IT and 12Gy SRS? 12Gy SRS After 6 weeks IT S L I D E 31
Brain metastases response to GK varies by disease S L I D E 32
Conclusions Brain metastasis treatment got complicated Need to be aware of patient systemic therapy plans Need to weigh efficacy and toxicity of drug only versus drug plus radiation Need to participate in clinical trials to answer the question of treatment sequence Need to understand mechanisms of interaction that result in efficacy and toxicity S L I D E 33
Thank You S L I D E 34
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Comparing TKIs to chemotherapy agents Small molecule inhibitors C6H10N6O Erlotinib C22H23N3O4 TKIs - Small molecules Cross cell membranes to inhibit cytoplasmic tyrosine kinases for growth factors Pemetrexed C20H21N5O6 S L I D E 37
Interaction between Targeted Therapy and Radiation in the CNS Drug Gefitinib Erlotinib Crizotinib Systemic Interaction Neutropenia, mucositis, GI bleed and perforation, dermatitis, rash, pneumonitis CNS specific Interaction Few?increased ICH No data on osimertinib Herceptin (Trastuzumab)?cardiac None Vemurafenib Dabrafenib/Tremetinib?radiosensitization in tumor? Radiosensitization of healthy tissues increased RT-induced chromosomal aberrations Acute radiodermatitis, Radiation recall pneumonitis (start vem 1-42d post RT) SRS avoid skin toxicity but radionecrosis increase? 1 case radiation recall myelitis S L I D E 38
Having mutation and GK allows patients to get full benefit of expected survival due to improved local control Tumors with EGFR and ALK mutations are more radiosensitive The addition of radiation to TKI systemic therapy provides better LC Median OS after development of Brain Mets was 49.5mos Despite 74% presenting with BrMets No history of TKIs before development BrMets assoc with improved OS (p<0.001) S L I D E 39
BZ MR4378561 (excellent systemic response) 53yo right handed white male with newly diagnosed diffusely metastatic BRAF wild type melanoma. Initially presented with leg pain and now found to have pathological fracture and widespread melanoma. Was being considered for T-IL therapy at NIH but MRI brain shows 3 lesions likely consistent with brain metastases which makes him ineligible for this treatment. Patient neurologically asymptomatic and no deficits noted on exam except difficulty with use of left leg secondary to cancer involvement. MRI brain shows 5mm lesion right frontal, 3mm lesion lateral right temporal and 8mm lesion adjacent right orbital apex. 8/26 4/15 no FLAIR changes 6/3-1 bigger, 1 new?1 resolved? 7/1 all bigger 1 new 8/5 crani then GK S L I D E 40