GLIO-3 and GLIO-4 Submission from Novocure Inc. (12/19/17 and 9/7/17) Please consider adding tumor treating fields in combination with temozolomide for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma as a category 1 recommendation. Based on the discussion and noted references, there was uniform panel consensus that the following regimen is supported by high-level evidence as an option for postoperative treatment for newly-diagnosed glioblastoma in patients with good performance status (KPS 60): Standard RT + concurrent and adjuvant TMZ + alternating electric field therapy This regimen is now a category 1 recommended option in all of the following pathways: Age 70 y and MGMT promoter methylated (GLIO-3, top pathway) 23 2 1 1 Age 70 y and MGMT promoter unmethylated or indeterminate (GLIO-3, second pathway) 22 3 1 1 Age 70 y and MGMT promoter methylated (GLIO-4, top pathway) 23 2 1 1 Age 70 y and MGMT promoter unmethylated or indeterminate (GLIO-4, second pathway) 22 3 1 1 GLIO-4 For postoperative treatment of newly-diagnosed glioblastoma in patients with good performance status (KPS 60), age 70, request to change Hypofractionated brain RT alone from category 1 to category 2A, and to list Stupp R, Taillibert S, Kanner AA, et al. Maintenance Therapy With Tumor- Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA 2015;314:2535-2543. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26670971. Stupp R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA 2017;318:2306-2316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29260225. Based on the discussion and noted reference, there was uniform panel consensus that Hypofractionated RT + concurrent and adjuvant temozolomide is supported by high-level evidence for postoperative adjuvant treatment of newly-diagnosed glioma in patients age >70 with good performance status (KPS 60) and MGMT promoter methylation (GLIO-4, top pathway). This is a category 1 recommendation. 24 1 0 2 Page 1 of 7
Hypofractionated brain RT + concurrent and adjuvant temozolomide as a category 1 option. PCNS-3 For induction therapy and consolidation therapy for newlydiagnosed primary CNS lymphoma (PCNS-2) and treatment for relapsed or refractory primary CNS lymphoma (PCNS-3), the PCNSL subcommittee revised the recommendations, including changes to the systemic therapy options on BRAIN-D 3 of 8 and 4 of 8 MENI-2 and BRAIN-D 3 of 8 Request to add bevacizumab + everolimus as a systemic therapy option for meningiomas. (BRAIN-D, 3 of 8) Based on the discussion and noted reference, there was not uniform consensus among the panel that Hypofractionated RT + concurrent and adjuvant temozolomide is supported by high-level evidence for postoperative adjuvant treatment of newly-diagnosed glioblastoma in patients age >70, with good performance status (KPS 60), and with MGMT promotor unmethylated or indeterminate (GLIO-4, second pathway). Perry JR, Laperriere N, O'Callaghan CJ, et al. Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med 2017;376:1027-1037. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28296618. Based on the discussion, there was uniform panel consensus supporting the changes made to PCNS-2, PCNS-3, and BRAIN-D 3 of 8 and 4 of 8. Supporting references were added to the reference section of BRAIN-D. Based on the discussion and noted reference, nonuniform panel consensus supported the inclusion of bevacizumab + everolimus as a systemic therapy option for recurrent or progressive meningiomas that are not surgically resectable and RT not possible (MENI-2, third pathway and BRAIN-D 3 of 8). This is a category 2B recommendation. Shih KC, Chowdhary S, Rosenblatt P, et al. A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma. J Neurooncol 2016;129:281-288. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27311730. 19 5 1 2 17 1 5 4 14 8 3 2 Page 2 of 7
BRAIN-D 4 of 8 Submission from Novartis (12/21/17). Please include dabrafenib and trametinib as a treatment option for patients with BRAF V600-mutant melanoma brain metastases in BRAIN-D. supported the inclusion of dabrafenib/trametinib combination as a systemic therapy option for patients with newly diagnosed melanoma brain metastases (LTD-1, LTD-2, and BRAIN-D). This is a category 2A recommendation. supported the inclusion of dabrafenib/trametinib combination as a systemic therapy option for patients with recurrent melanoma brain metastases (LTD- 3, MU-2, and BRAIN-D). Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017;18:863-873. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28592387. 22 2 1 2 21 2 2 2 Page 3 of 7
LTD-1, LTD-2, BRAIN-D 4 of 8 For patients with newly-diagnosed brain metastases, request to include the following regimens as options for a systemic therapy: Vemurafenib/cobimetinib combination therapy (melanoma) Pembrolizumab monotherapy (melanoma or NSCLC) Alectinib (ALK rearrangementpositive NSCLC) Based on the discussion and noted reference, nonuniform panel consensus supported the addition of vemurafenib/cobimetinib combination as a systemic therapy option for newly-diagnosed melanoma brain metastases. This is a category 2B recommendation. McArthur GA, Maio M, Arance A, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol 2017;28:634-641. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27993793. supported the addition of pembrolizumab monotherapy as a systemic therapy option for newly-diagnosed brain metastases from melanoma or NSCLC. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016;17:976-983. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27267608. supported the addition of alectinib as a systemic therapy option for newlydiagnosed brain metastases from ALK rearrangement-positive NSCLC. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:829-838. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28586279. 19 5 1 2 23 1 1 2 23 1 1 2 Page 4 of 7
LTD-3, MU-2, and BRAIN-D 4 of 8 For patients with recurrent brain metastases (LTD-3, MU-2) request to include the following systemic therapy options (BRAIN-D 4 of 8): Vemurafenib/cobimetinib combination for patients with melanoma Brigatinib for patients with ALK rearrangement-positive NSCLC Uniform panel consensus supported the addition of vemurafenib/cobimetinib combination as a systemic therapy option for patients with recurrent melanoma brain metastases. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer 2014;50:611-621. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24295639 McArthur GA, Maio M, Arance A, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol 2017;28:634-641. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27993793. supported the addition of brigatinib as a systemic therapy option for recurrent brain metastases in patients with ALK rearrangement-positive NSCLC. Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in Patients With Crizotinib- Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol 2017;35:2490-2498. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28475456. 20 3 2 2 23 0 2 2 Page 5 of 7
BRAIN-D 4 of 8 Submission from Bristol-Myers Squibb (06/05/17) to include nivolumab in combination with ipilimumab followed by nivolumab monotherapy as a treatment option for patients with melanoma brain metastases AND nivolumab in combination with ipilimumab or nivolumab alone for patients with melanoma brain metastases. Based on the discussion and noted references, uniform panel consensus supported the inclusion of ipilimumab/nivolumab For patients with newly diagnosed brain metastases from melanoma (LTD-1, LTD-2, BRAIN-D). Tawbi HA-H, Forsyth PAJ, Algazi AP, et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204 (abstract). Journal of Clinical Oncology 2017;35:Abstr 9507. Available at: http://ascopubs.org/doi/abs/10.1200/jco.2017.35.15_suppl.9507. Long GV, Atkinson V, Menzies AM, et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC) (abstract). Journal of Clinical Oncology 2017;35:Abstr 9508. Available at: http://ascopubs.org/doi/abs/10.1200/jco.2017.35.15_suppl.9508. 23 1 1 2 Page 6 of 7
LTD-3, MU-2, and BRAIN-D 4 of 8 Submission from Puma Biotechnology, Inc. (11/30/17) to consider the use of neratinib for the treatment of HER2 + breast cancer patients with brain metastases. supported the inclusion of neratinib + capecitabine as a systemic therapy option for patients with recurrent breast cancer brain metastases (LTD-3, MU-2, BRAIN-D). Freedman RA, Gelman RS, Melisko ME, et al. TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM) (abstract). Journal of Clinical Oncology 2017;35:Abstr 1005. Available at: http://ascopubs.org/doi/abs/10.1200/jco.2017.35.15_suppl.1005. Based on the discussion and noted references, nonuniform panel consensus supported the inclusion of neratinib + paclitaxel (as a systemic therapy option for patients with recurrent breast cancer brain metastases (LTD-3, MU-2, BRAIN-D). This is a category 2B recommendation. Awada A, Colomer R, Inoue K, et al. Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2- Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial. JAMA Oncol 2016;2:1557-1564. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27078022 Awada A, Colomer R, Bondarenko I, et al. Efficacy and CNS progression analysis from the randomized phase 2 trial of neratinib + paclitaxel vs trastuzumab + paclitaxel as first-line treatment for HER2+ metastatic breast cancer (NEfERTT) (abstract). Journal of Clinical Oncology 2015;33:Abstr 610. Available at: http://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.610. 19 3 3 2 16 6 3 2 Page 7 of 7