RT for brain metastases in ALK+ NSCLC

1. Radiotherapy for Brain Metastasis in
ALK+ NSCLC
Dr. Naveen Mummudi,
Radiation Oncologist,
Tata Memorial Hospital, Mumbai

2. Introduction
• Brain metastases : most frequent malignant disease in the CNS
• Lung cancer : 40-50%
• Breast cancer : 20-30%,
• Melanoma : 5-10%,
• Lymphoma, and various other primary sites like the gastrointestinal tract and
prostate : 4-6%
• Lung cancer - high incidence of brain metastases.
• 10% : present with BM at first diagnosis.
• Around 25–40% : develop during the course of their disease

3. Location
• Cerebral hemisphere 80%
• Cerebellum 20%
• Brain stem 5%
• Most metastasis develop at the gray-white matter junction in
watershed distribution of brain where intravascular tumour cells
lodge in the terminal arterioles.
• Distribution of brain metastases in the brain approximates the
proportion of blood flow such that 80-85% of all metastases in
supratentorial and 15-20 % occur in posterior fossa.

4. Biology of BM
Why certain specific tumour specifically metastasize to brain ?
Different theories…
• Jems Ewing : proposed organ specific propensity due to different
pattern of blood flow.
• Stephen paget: proposed theory of seed and soil
• Tropism to have metastases in brain only
• Fidler tested paget’s theory in murine
• Certain unclear events?

5. Prognostic factors
• Age
• Status of primary
disease
• Extent of extra-
cranial disease
• KPS

6. Treatment strategies
Treatment aims
-To improve Loco-regional control (LRC)
-Good quality of life and neurological function
-Potential increase in OS

8. Decision tree

9. Trials comparing whole brain radiotherapy vs. whole
brain radiotherapy + local treatment
• Local therapy + WBRT compared to WBRT alone
• Improves local control
• Overall survival also

10. Trials comparing local treatment vs. whole brain radiotherapy +
local treatment
• Local therapy + WBRT compared to local therapy alone
• Improves local control
• No overall survival benefit

11. How to improve WBRT outcomes
• Adding Motexafin may give better result in terms of intracranial
control in brain metastasis in NSCLC
• Hippocampal sparing WBRT – RTOG 0933
Gondi, 2013, IJROBP

12. QUARTZ conundrum
• Only adequately powered phase 3, non-inferiority, randomized clinical
trial addressing the efficacy of best supportive care (BSC) plus WBRT
versus BSC alone in patients with NSCLC.
• Primary endpoint was quality-adjusted life-years (QALYs), while secondary
outcomes included OS and quality of life.
Mulvenna, Lancet, 2016

13. Case presentation
• 44 year old male with no co-morbidities,
• a chronic smoker for last 15 yrs reformed since 1 year.
• Diagnosed to have Ca Lung T3N3M1b [Lung, Bone] Alk +ve EGFR:
negative.
• On Crizotinib since April 16
• Previously irradiated for bone mets--- Pall RT to Lt hemipelvis, Lumbar
spine
• Presented with headache & dizziness for last 12 days
• vomiting 3 -4 episodes / day since 7 days
• 8 episodes of GTCS in last 10 days

14. Case presentation

15. ALK + and brain metastases
• Incidence
• 25-40% - ALK inhibitors naïve
• 45-70% - prior ALK inhibitors
Mak KS et al, Neuro Oncol. 2015 Feb;17(2):296-302Toyokawa, Cancer Metastasis Rev (2015) 34:797–805

16. ALK + and brain metastases
• Cystic metastases
• Signet ring histology
• Cystic degeneration
Saraceni, JTO, 2015
Hayashi, JCO, 2014

17. ALK + and brain metastases
• Crizotinib
• Brain - most common site of PD after resistance to crizotinib
• Biological change in the tumor - ALK amplification, secondary ALK mutations, and “bypass
tracks” such as increased EGFR phosphorylation and KRAS mutations
• Inadequate central nervous system (CNS) penetration of the drug
• Ceritinib
• has a 20-fold greater potency to inhibit ALK than Crizotinib and a 12-fold greater
potency than Alectinib
• found to cross the intact BBB in rats, although no human data exists
• Alectinib
• Better BBB penetration
• not a substrate of P-glycoprotein (P-gp), a key drug efflux pump typically expressed in
the BBB
Friboulet L, Cancer Discov 2014
Wong, Frontiers in Oncology, 2017

18. ALK + and brain metastases
Wong, Frontiers in Oncology, 2017

19. NCCN guidelines 2017

20. ALK + and brain metastases
Issues
• Presentation
• At initial diagnosis
• Progressive disease
• Oligo-progressive disease
• Better survival
• Survivors – QOL issues related to WBRT toxicity

21. Biological rationale to combine brain radiotherapy
and targeted therapies for brain metastases
• BBB and RT
• data have also shown that endothelial cells actually undergo two waves of
radiation induced cell death after exposure to radiation:
• an early ceramide-mediated apoptosis as described (<24h),
• a delayed DNA damage–induced mitotic death (≥72h) which has been reported to occur
up to one month following RT
• These effects observed for both focal RT to the tumor and WBRT, starting with
radiation doses in the range of 20-30 Gy with fraction size of 2 Gy.
• As for SRS, fraction size over 10 Gy has been suggested to disrupt the BBB
• this BBB disruption following focal RT or WBRT is presumed to lead to an
increase in drug permeability
Dai Y, Radiother Oncol. 2015
Webb TR, Expert Rev Anticancer Ther. 2014

22. Combination of ALKi and RT
• Combination of crizotinib with radiation results in greater inhibition of
tumor growth and microvascular density than by either treatment
alone,
• through an increase in anti-proliferative and pro-apoptotic effects.
Dai Y, Radiother Oncol. 2015
Webb TR, Expert Rev Anticancer Ther. 2014

23. • Most patients (84/90) were treated with brain RT (WBRT or SRS):
• Overall, the authors concluded that ALK+ patients with BM had a prolonged
survival when treated with Crizotinib and brain RT

24. Gamma knife + Crizotinib
Won Chui, World Neurosurg. 2016
• 29 patients - Gamma knife + Crizotinib
• Oligomets / polymets
• The estimated local PFS of the
• oligometastases group were 91.8% at 6 months and 84.2%
at 12 months,
• polymetastases group at 6 and 12 months were 91.6% and
58.2%, respectively
• Conclusion: : GKS combined with crizotinib showed effective
local tumor control and excellent outcome, especially in
oligometastases.

25. Ongoing trial
• NCT02314364 - Trial of Integrating SBRT With Targeted Therapy in
Stage IV Oncogene-driven NSCLC
• SRS + TKI
• EGFR / ALK / ROS
• Primary – 12 month DFS
• November 2021

26. Grey areas in clinical routine
• Treatment decisions based on the mutational status
• Optimal timing for the combination
• Can whole-brain radiotherapy be omitted or delayed in patients with
oncogenic drivers?

27. ALK + and brain metastases
Options
• At presentation
• Asymptomatic – ALKi
• Symptomatic – Oligomets / polymets
• WBRT / SRS + ALKi
• Oligo-progression
• Oligomets - Local therapy + ALKi (same)
• Poly – WBRT +/- SRS + ALKi (same / change)
• Progressive disease
• WBRT + Change of ALKi

28. Summary
• Incidence of CNS mts in ALK+ NSCLC is 35-50%
• ALK+ NSCLCs with CNS mts live longer than differently genotyped
NSCLC pts
• CNS is the most common site of progression on ALKi in pts with and
without CNS mts
• Novel ALK-TKIs may improve prognosis of ALK+ NSCLC.
• Tailored therapy – combination of WBRT / SRS / Surgery

29. Thank you!