E-Newsletter - November 2019
Spotlight on Alliance Trials

 

Alliance Trial takes a closer look at genetic testing guiding treatment in brain metastases

Alliance A071701: Genomically-guided treatment trial in brain metastases

This phase II Alliance trial looks at how well genetic testing works in guiding treatment for patients with solid tumors that have spread to the brain. Several genes have been found to be altered or mutated in brain metastases such as NTRK, ROS1, CDK or PI3K. Medications that target these genes such as abemaciclib, GDC-0084, and entrectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Genetic testing may help doctors tailor treatment for each mutation.

Study Rationale
Central nervous system (CNS) disease leads to devastating complications for patients, with profound consequences for quality of life, clinical trial opportunities, and duration of life.[1,2, 3-5] The most common primary histologies that metastasize to the brain are lung, breast and melanoma. Approximately 30 percent of lung cancer patients will have CNS disease at time of diagnosis and an estimated 50 percent will eventually develop brain metastases [6]. Up to 30% of patients with advanced breast cancer and 50 percent of patients with advanced melanoma will develop brain metastases.[7, 8] Effective treatments for brain metastases are limited. Radiation therapy (RT) has historically been the mainstay of treatment, albeit with only a limited survival benefit and risk of cognitive impairment following therapy. [9-12] In the precision medicine era, some tyrosine kinase inhibitors (TKIs) have demonstrated good treatment efficacy for patients whose tumors harbor selected mutations or rearrangements, but this does not reflect the majority of patients.[8]

Furthermore, even patients with targetable mutations in genes such as HER2 and EGFR have high rates of progression in the CNS after initial control of their systemic disease.[13, 14] Targeted or chemotherapeutic agents that cross the blood-brain barrier (BBB) are also used in these patients, but patients inevitably progress in the brain [15] Furthermore, although immunotherapy is rapidly becoming standard of care in patients with metastatic lung cancer, melanoma and other cancers, the majority of patients treated with immunotherapy progress in the CNS.[5, 16] Novel targets are clearly needed. The total annual cost of caring for patients with metastatic CNS disease exceeds $10 billion in the US alone, yet only about 5 percent of all cancer research funding is specifically devoted to the study of metastatic disease.[17] Overall, CNS metastases represent a dreaded and frequent complication for cancer patients and their families: there is an urgent need for more focused efforts to develop improved therapeutic options.

Study Outcomes                          
The primary and secondary objectives are described below.

Primary objectives

  • To determine the activity of a CDK inhibitor in patients with progressive brain metastases derived from lung cancer, breast cancer, and other cancers harboring actionable genetic alterations associated with sensitivity to CDK inhibitors as measured by response rate (Response Assessment in Neuro-Oncology [RANO] criteria).
  • To determine the activity of a PI3K inhibitor in patients with progressive brain metastases derived from lung cancer, breast cancer, and other cancers harboring actionable genetic alterations in the PI3K pathway as measured by response rate (RANO criteria).
  • To determine the activity of an NTRK/ROS1 inhibitor in patients with progressive brain metastases derived from lung cancer harboring actionable NTRK/ROS1 gene fusions as measured by response rate (RANO criteria).

Secondary objectives

  • To evaluate the systemic response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD]) by Brain Metastases (BM)-RANO for central nervous system (CNS) in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the clinical benefit rate (CR + PR + SD) by RECIST for extracranial disease in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the duration of response by BM-RANO in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the duration of response by RECIST in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the progression-free survival for intracranial disease in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the progression-free survival for extracranial disease in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the site of first progression (CNS versus [vs] non-CNS) in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the overall survival in each of the cohorts determined by treatment and primary cancer type.
  • To evaluate the toxicity profile of agents in patients with brain metastases in each of the cohorts determined by treatment and primary cancer type.

Key Eligibility Criteria
Some of the eligibility criteria include:

Pre-registration:

  • Tissue available for biomarker testing

Registration:

  • Histologically confirmed metastatic disease to the brain from any solid tumor defined by one of the following:
    • Untreated measurable lesions in patients who have received surgery and/or stereotactic radiosurgery (SRS) to one or more other lesions
    • Residual or progressive lesions after surgery if asymptomatic.
    • Prior whole-brain radiotherapy (WBRT) and/or SRS and then lesions progressed or new lesions
    • Not previously been treated with cranial radiation (e.g. WBRT or SRS) are eligible, but such patients must be asymptomatic or neurologically stable from their CNS metastases.

  • Measurable CNS disease (>10 mm)

  • Ability to obtain MRIs

  • No surgery within 2 weeks prior to or after registration.

  • No chemotherapy within 14 days prior to registration.

    • For melanoma, progression after immunotherapy or for BRAF positive melanoma, BRAF/MEK inhibitors
    • For lung cancer, failed EGFR therapies.
    • For HER2-positive breast cancer received prior HER-2 directed therapy in the metastatic setting
    • For triple negative breast cancer (TNBC), at least one chemotherapy in the metastatic settingFor ER/PR+ breast cancer, at least one endocrine therapy in the metastatic setting
    • Breast cancer patients who have received ribociclib or palbociclib are eligible as long as there is documentation of CDK4 pathway alteration on a biopsy at the point of progression post-ribociclib or palbociclib.

Description of Treatment
Patients will be randomized into one of three groups. Those in Group 1 (CDK gene mutation) will receive abemaciclib orally twice daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Those in Group 2 (PI3K gene mutation) will receive PI3K inhibitor GDC-0084 orally once daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Those in Group 3 (NTRK/ROS1 gene mutation) will receive entrectinib orally once daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Refer to the study protocol, which can be found on the Alliance website at www.AllianceNCTN.org, for complete information on the trial design, treatment plan, and patient eligibility.

References

  1. Brastianos, P.K., W.T. Curry, and K.S. Oh, Clinical discussion and review of the management of brain metastases. J Natl Compr Canc Netw, 2013. 11(9): p. 1153-64.
  2. Brastianos, H.C., D.P. Cahill, and P.K. Brastianos, Systemic therapy of brain metastases. Curr Neurol Neurosci Rep, 2015. 15(2): p. 518.
  3. Koshy, M., et al., Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neurooncol, 2012. 107(1): p. 207-12.24.
  4. Lagerwaard, F.J., et al., Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys, 1999. 43(4): p. 795-803.25.
  5. Brastianos, P.K. and D.P. Cahill, Management of brain metastases in the era of targeted and immunomodulatory therapies. Oncology (Williston Park), 2015. 29(4): p. 261-3.26.
  6. Cagney, D.N., et al., Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: A population-based study. Neuro Oncol, 2017.
  7. Dagogo-Jack, I., S.L. Carter, and P.K. Brastianos, Brain Metastasis: Clinical Implications of Branched Evolution. Trends Cancer, 2016. 2(7): p. 332-337.
  8. Dagogo-Jack, I., et al., Treatment of brain metastases in the modern genomic era. Pharmacol Ther, 2017. 170: p. 64-72.
  9. Ray, S., et al., Comparative analysis of survival, treatment, cost andresource use among patients newly diagnosed with brain metastasis by initial primary cancer. J Neurooncol, 2013. 114(1): p. 117-25.30.
  10. Mehta, M.P., et al., The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol, 2010. 96(1): p. 71-83.31.
  11. Bhangoo, S.S., M.E. Linskey, and S.N. Kalkanis, Evidence-based guidelines for the management of brain metastases. Neurosurg Clin N Am, 2011. 22(1): p. 97-104, viii.
  12. Gaspar, L.E., et al., The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol, 2010. 96(1): p. 17-32.33.
  13. Weickhardt, A.J., et al., Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors inoncogene-addicted non-small-cell lung cancer. J Thorac Oncol, 2012. 7(12): p. 1807-14.
  14. Shaw, A.T., et al., Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med, 2013. 368(25): p. 2385-94.
  15. Johung, K.L., et al., Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis.J Clin Oncol, 2016. 34(2): p. 123-9.34. Chubachi, S., et al., A Case of Non-Small Cell Lung Cancer with Possible "Disease Flare" on Nivolumab Treatment. Case Rep Oncol Med, 2016. 2016: p. 1075641
  16. Chubachi, S., et al., A Case of Non-Small Cell Lung Cancer with Possible "Disease Flare" on Nivolumab Treatment. Case Rep Oncol Med, 2016. 2016: p. 1075641.
  17. Sleeman, J. and P.S. Steeg, Cancer metastasis as a therapeutic target. Eur J Cancer, 2010. 46(7): p. 1177-80.

Study chair: Priscilla Brastianos, MD, Massachusetts General Hospital
E-mail: pbrastianos@partners.org
Activated: 8/15/19
Link: http://bit.ly/AllianceA071701
ClinicalTrials.gov Identifier: NCT03994796

 

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