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Home , Cobimetinib, Encorafenib, Fedratinib, Neratinib, Tivozanib, Trilaciclib

Policy # Drug(s) Type of Change Brief Description of Policy Change new Pepaxto (melphalan flufenamide) n/a n/a new Fotivda () n/a n/a new Cosela () n/a n/a Add inclusion criteria: NSCLC UM ONC_1089 Libtayo (‐rwlc) Negative change 2.Libtayo (cemiplimab) may be used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for actionable molecular markers (ALK, EGFR, or ROS‐1) Add inclusion criteria: a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo radia�on (Erbitux + Radia�on) as a single agent for members with a UM ONC_1133 Erbitux () Positive change contraindication and/or intolerance to cisplatin use OR B.Head and Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with .

Add inclusion criteria: UM ONC_1133 Erbitux (Cetuximab) Negative change NOTE: Erbitux (cetuximab) + Braftovi () is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for BRAFV600E positive ..

Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have any residual disease in the breast and/or axillary lymph nodes, Perjeta () use is restricted to node positive stage II and III disease only. ii.Note #2: Perjeta (pertuzumab) use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) and/or pathologic confirmation of ipsilateral (same side) axillary nodal involvement. UM ONC_1134 Products Negative change iii. For curative‐intent, neoadjuvant/adjuvant therapy, Pertuzumab + Trastuzumab is indicated only in patients with node positive disease. The combination may be used in the neoadjuvant setting if there is radiographic and/or pathologic confirmation of ipsilateral axillary/other regional nodal involvement. •Neoadjuvant therapy was given and there was no residual disease found in the breast/axillary nodes at surgery, and there was confirmation of ipsilateral axillary nodal involvement prior to starting neoadjuvant therapy.

Remove inclusion criteria: B.Mul�ple Myeloma (MM) UM ONC_1193 Revlimid (lenalidomide) Negative change ii.Lenalidomide is being used in combina�on with Darzalex/Darzalex Faspro ()/ with or without Velcade (bortezomib). ii.With Darzalex/Darzalex Faspro (daratumumab) +/‐ dexamethasone +/‐ Velcade (bortezomib) NOTE: This is a Preferred Regimen on NCH Pathway based on Level 1 evidence Add inclusion criteria: MM a.Ini�al therapy: UM ONC_1194 Revlimid (lenalidomide) Positive change i.In combina�on with Velcade(bortezomib) +/‐ dexamethasone. Combination with dexamethasone +/‐ Velcade (bortezomib). MDS 2.Revlimid (lenalidomide) is being used as a single agent or in combina�on with hypomethyla�ng agent (i.e. decitabine or azaci�dine ) in members with MDS/Myeloproliferative Overlap Neoplasms (MPN). Policy # Drug(s) Type of Change Brief Description of Policy Change new Pepaxto (melphalan flufenamide) n/a n/aAdd inclusion criteria: C. new Fotivda (tivozanib) n/a n/a NOTE: The preferred drugs, per NCH Policies & NCH Pathway, for the adjuvant therapy of completely resected stage III melanoma are Opdivo new Cosela (trilaciclib) n/a n/a () OR Keytruda (). Please refer to UM ONC_1274 Opdivo (nivolumab) policy or UM ONC_1263 Keytruda (pembrolizumab) Add inclusion criteria: NSCLC policy. Adjuvant is not recommended in this setting. This recommendation is based on randomized data showing inferior outcomes with UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change 2.Libtayo (cemiplimab) may be used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for ipilimumab compared to nivolumab. actionable molecular markers (ALK, EGFR, or ROS‐1) D. Add inclusion criteria: 2.Yervoy (ipilimumab) is being used in combina�on with Opdivo (nivolumab) for 4 cycles followed by single agent nivolumab for Intermediate or a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo radia�on (Erbitux + Radia�on) as a single agent for members with a Poor risk disease (as defined by the IMDC criteria). The recommended dose of Yervoy (ipilimumab) in this setting is 1mg/kg iv every 3 weeks for a UM ONC_1133 Erbitux (Cetuximab) Positive change contraindication and/or intolerance to cisplatin use OR total of 4 cycles. B.Head and Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with chemotherapy. G.Non‐Small Cell Lung Cancer NOTE: The combination of [Yervoy (ipilimumab + Opdivo (nivolumab)] for metastatic Non‐Small Cell Lung Cancer, in the first line/subsequent line Add inclusion criteria: UM ONC_1201 Yervoy (ipilimumab) Negative change setting, is Non‐Preferred per NCH Policy and NCH Pathway. Please refer to the NCH Pathway document for the most current recommended UM ONC_1133 Erbitux (Cetuximab) Negative change NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for regimens/agent for metastatic Non‐Small Cell Lung Cancer. This recommendation is based on the lack of Level 1 evidence ( randomized trials and/or BRAFV600E positive colorectal cancer.. metaanalyses) showing the superiority of the above combination over the recommended regimens for first line therapy of EGFR/ALK negative metastatic NSCLC: a. [carboplatin/cisplatin+pemetrexed+pembrolizumab] for non‐squamous NSCLC and b. Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer [carboplatin/cisplatin+paclitaxel+pembrolizumab] for squamous NSCLC i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have H.Malignant Pleural Mesothelioma any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. 1.Yervoy (ipilimumab) may be used in combina�on with Opdivo (nivolumab), as first line therapy for members with Non‐epithelioid subtype (by ii.Note #2: Perjeta (pertuzumab) use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) and/or pathologic histology) of metastatic/unresectable Malignant Pleural Mesothelioma. Yerovy (ipilimumab) is dosed at 1 mg/kg every 6 weeks until disease confirmation of ipsilateral (same side) axillary nodal involvement. UM ONC_1134 Trastuzumab Products Negative change progression or unacceptable toxicities, in the above setting. iii. For curative‐intent, neoadjuvant/adjuvant therapy, Pertuzumab + Trastuzumab is indicated only in patients with node positive disease. NOTE: Yerovy (ipilimumab) + Opdivo (nivolumab) is not recommended for use in Epithelioid metastatic/unresectable Malignant Pleural The combination may be used in the neoadjuvant setting if there is radiographic and/or pathologic confirmation of ipsilateral axillary/other regional Mesothelioma. This recommendation is based on the lack of a survival benefit of the above regimen compared to [platinum+pemetrexed] in the trial nodal involvement. by Baas et al referenced below. •Neoadjuvant therapy was given and there was no residual disease found in the breast/axillary nodes at surgery, and there was confirmation of ipsilateral axillary nodal involvement prior to starting neoadjuvant therapy. Add inclusion criteria: 2.Neoadjuvant or adjuvant therapy or HER‐2+ breast cancer Remove inclusion criteria:a.Note �1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have B.Mul�pleany residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. Myeloma (MM) UM ONC_1193 Revlimid (lenalidomide) Negative change ii.Lenalidomideb.Note �2: Perjeta use is being used in combina�on with in the neoadjuvant (pre‐opera�ve) Darzalex/Darza se�ng requires radiographic (e.g., breast MRI, CTlex Faspro (daratumumab)/dexamethasone ) with or and/or patholog without Velcadeic confirma�on (bortezomib). of ii.With Darzalex/Darzalex Fasproipsilateral (same side) axillary nodal involvement. (daratumumab) +/‐ dexamethasone +/‐ Velcade (bortezomib) NOTE: This is a Preferred Regimen on NCH Pathway UM ONC_1216 Perjeta (pertuzumab) Negative change based on Level 1 evidencec.Perjeta (pertuzumab) may be used in combina�on with trastuzumab for members with Stage II or III, locally advanced, inflammatory, or early‐ stage node positive breast cancer ( recommendation based on the 6‐year updated analysis of the APHINITY trial which showed a benefit only in node Add inclusion criteria: positive patients). MM •Member has axillary node posi�ve disease (confirmed radiographically and or pathologically). a.Ini�al therapy: • If neoadjuvant therapy was not given and member was found to have axillary node positive disease after surgery. UM ONC_1194 Revlimid (lenalidomide) Positive change i.In combina�on with Velcade(bortezomib) +/‐ dexamethasone. Combination with dexamethasone +/‐ Velcade (bortezomib). MDSAdd inclusion criteria: 2.Revlimid (lenalidomide)3.For relapsed or refractory is bein disease, Kyprolis (carfilzomib) mayg used as a single agent or in combina�on be used for members with hypomethyla�ng who have had prior progression on Velcade(bortezomib) agent (i.e. decitabine or azaci�dine ) in members ‐ UM ONC_1224 Kyprolis (carfilzomib) Negative change with MDS/Myeloproliferative Overlap Neoplasms (MPN).based therapy d.In combina�on with daratumumab +/‐ dexamethasone, if the member has not received prior therapy with daratumumab. Policy # Drug(s) Type of Change Brief Description of Policy Change new Pepaxto (melphalan flufenamide) n/a n/a Add inclusion criteria: new Fotivda (tivozanib) n/a n/a B. Thyroid cancer new Cosela (trilaciclib) n/a n/a NOTE: The preferred oral inhibitor (TKI) for use in metastatic medullary thyroid cancer is Caprelsa (vendatinib) and the preferred TKI Add inclusion criteria: NSCLC for differentiated thyroid cancers (e.g., papillary, follicular, or Hurthle cell thyroid cancer) is Lenvima () over Cometriq (). UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change 2.Libtayo (cemiplimab) may be used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for Above recommendation is based on the lack of Level 1 evidence to support the superiority of cabozantinib over either of the preferred drugs. actionable molecular markers (ALK, EGFR, or ROS‐1) C.Kidney Cancer Add inclusion criteria: NOTE: First line therapy with [Cabometyx (cabozantinib) + Opdivo (nivolumab)] for advanced/metastatic clear cell Renal Cell Carcinoma is not a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo radia�on (Erbitux + Radia�on) as a single agent for members with a recommended per NCH Policy or NCH Pathway. This position is based on the following: UM ONC_1133 Erbitux (Cetuximab) Positive change contraindication and/or intolerance to cisplatin use OR Cometriq or Cabometyx a.Our detailed review of the CheckMate9ER trial showed that the HR for OS for IMDC Favorable Risk disease was 0.84, with wide Confidence UM ONC_1237 Negative change B.Head and Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with chemotherapy. (cabozantinib) Intervals that crossed 1.0 (CI 0.35‐1.97). The HR for PFS for IMDC Favorable Risk disease was 0.62, however, again the Confidence Intervals were wide and crossed 1.0 ( CI 0.38‐1.01) Add inclusion criteria: b.For IMDC Intermediate and Poor risk disease, there is a lack of Level 1 evidence ( randomized trials and/or meta‐analysis) to support the UM ONC_1133 Erbitux (Cetuximab) Negative change NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for superiority of [ Cabometyx (cabozantinib) + Opdivo (nivolumab)] over [Opdivo (nivolumab) + Yervoy (ipilimumab)], ‐ the recommended regimen per BRAFV600E positive colorectal cancer.. NCH Policy and NCH Pathway c.Addi�onally, for IMDC Intermediate and Poor Risk disease, Cabometyx (cabozan�nib) has already been shown to be superior to Sutent (suni�nib) Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer per the CABOSUN trial. Therefore the control arm‐in the CheckMate9ER trial‐ of single agent Sutent () is sub‐optimal control arm. i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have NOTE: The preferred tyrosine kinase inhibitor, per NCH Policy & NCH Pathway for advanced/metastatic RCC, is CABOMETYX (cabozantinib) as a any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. single agent, in the first line setting for IMDC Intermediate/Poor Risk disease, and for subsequent therapy for any risk disease. ii.Note #2: Perjeta (pertuzumab) use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) and/or pathologic confirmation of ipsilateral (same side) axillary nodal involvement. UM ONC_1134 Trastuzumab Products Negative change iii.Add inclusion criteria: For curative‐intent, neoadjuvant/adjuvant therapy, B.HER‐2 Posi�ve Breast Cancer Pertuzumab + Trastuzumab is indicated only in patients with node positive disease. The combination may be used in the neoadjuvant setting 1.For members with recurrent/metastatic HER‐2 positive breast cancer: Kadcyla (ado‐) may be used as a single agent for if there is radiographic and/or pathologic confirmation of ipsilateral axillary/other regional UM ONC_1238 Kadcyla (ado‐trastuzumab) Positive change nodal involvement. members who have experienced disease progression after prior therapy with [a taxane + trastuzumab + pertuzumab +/‐ chemotherapy (e.g. a •Neoadjuvanttaxane) ]. therapy was given and there was no residual disease found in the breast/axillary nodes at surgery, and there was confirmation of ipsilateral axillary nodal involvement prior to starting neoadjuvant therapy. UM ONC_1238 Kadcyla (ado‐trastuzumab) Negative change Remove inclusion criteria: < 2 cm OR ER/PR positive Remove inclusion criteria: Add exclusion criteria: A.Concurrent use with trastuzumab, lapa�nib, pertuzumab, fam‐, or other chemotherapy; UM ONC_1238 Kadcyla (ado‐trastuzumab) Negative change B.Mul�ple Myeloma (MM) endocrine therapy may continue concurrently with Kadcyla if indicated. UM ONC_1193 Revlimid (lenalidomide) Negative change ii.Lenalidomide is being used in combina�on with Darzalex/Darzalex Faspro (daratumumab)/dexamethasone with or without Velcade (bortezomib). ii.With Darzalex/Darzalex FasproAdd inclusion criteria: (daratumumab) +/‐ dexamethasone +/‐ Velcade (bortezomib) NOTE: This is a Preferred Regimen on NCH Pathway based on Level 1 evidenceThe preferred immunomodulatory agent, for first line therapy of newly diagnosed myeloma, and first line therapy for myeloma in first r elapse, per NCH policy and pathway, is Revlimid (lenalidomide) over Pomalyst (pomalidomide) or Thalomid (thalidomide). UM ONC_1239 Pomalyst (pomalidomide) Negative change Add inclusion criteria: i.The member has relapsed or refractory mul�ple myeloma that has failed 2 prior therapies for myeloma including one proteasome inhibitor MM preferably Velcade (unless contraindication/intolerance) & one immunomodulatory agent,preferably Revlimid (unless a.Ini�al therapy: intolerance/contraindication), and Pomalyst (pomalidomide) is being used as a single agent OR in combination with dexamethasone UM ONC_1194 Revlimid (lenalidomide) Positive change i.In combina�on with Velcade(bortezomib) +/‐ dexamethasone. Combination with dexamethasone +/‐ Velcade (bortezomib). MDSRemove inclusion criteria: UM ONC_1239 Pomalyst (pomalidomide) Negative change 2.Revlimid (lenalidomide)B.In combina�on with dexamethasone is being used as and Ninlaro (ixazomib) a single agent or in combina�on with hypomethyla�ng agent (i.e. decitabine or azaci�dine ) in members with MDS/Myeloproliferative Overlap Neoplasms (MPN).D.In combina�on with dexamethasone and Velcade (bortezomib) Add inclusion criteria: B.Myelofibrosis 1.NOTE: The preferred agent, per NCH Policies, is Jakafi (ruxoli�nib) over Inrebic (fedra�nib). This recommenda�on is based on the lack of Level 1 evidence (randomized trial and or meta‐analysis) showing superior outcomes with Inrebic () over Jakafi(). akafi (ruxolitinib) may be used in a member with any of the following: , post‐ myelofibrosis, or post‐essential UM ONC_1242 Jakafi (ruxolitinib) Negative change thrombocythemia myelofibrosis. D.Gra� Versus Host Disease (GVHD) 1.Jakafi (ruxoli�nib) may be used for members with GVHD with or without a cor�costeroid in members 12 years or older who have acute GVHD, following an allogeneic hematopoietic stem cell transplantation, and the member is refractory to primary treatment with methylprednisolone (or a steroid equivalent). Policy # Drug(s) Type of Change Brief Description of Policy Change new Pepaxto (melphalan flufenamide) n/a B.Malignantn/a Melanoma NOTE #1: Per NCH Policy & NCH Pathway, the preferred combination for of metastatic, unresectable, or recurrent BRAF or new Fotivda (tivozanib) n/a n/a V600K positive malignant melanoma is Zelboraf () + Cotellic (). This recommendation is based on the lack of Level new Cosela (trilaciclib) n/a n/a 1 evidence( randomized trials and or meta‐analyses) to show that one anti‐BRAF combination is superior to another. Add inclusion criteria: NSCLC 1.Furthermore, all randomized trials for such combina�on therapy have used a BRAF inhibitor (generally vemurafenib or encorafenib) as the UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change 2.Libtayo (cemiplimab) may be used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for control arm. actionable molecular markers (ALK, EGFR, or ROS‐1) 2. Mekinist () may be used in combination with Tafinlar () as first line, second‐line, or subsequent treatment for metastatic or Add inclusion criteria: UM ONC_1249 Mekinist (trametinib) Negative change unresectable BRAF V600E or V600K mutation positive disease if member is intolerant to/has a contraindication to the preferred combination a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo radia�on (Erbitux + Radia�on) as a single agent for members with a Zelboraf (vemurafenib) + Cotellic (cobimetinib). UM ONC_1133 Erbitux (Cetuximab) Positive change contraindication and/or intolerance to cisplatin use OR 3.Mekinist (trame�nib) + Tafinlar (dabrafenib) may be used in a member with BRAF V600E or V600K mutation positive malignant melanoma as B.Head and Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with chemotherapy. adjuvant treatment after complete resection of the primary lesion and completion of a regional lymph node dissection‐ total duration of adjuvant therapy not to exceed 1 year. Add inclusion criteria: UM ONC_1133 Erbitux (Cetuximab) Negative change NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for C.Non‐Small Cell Lung Cancer (NSCLC) BRAFV600E positive colorectal cancer.. b. Subsequent therapy if anti‐ BRAF V600E targeted therapy was not previously used. Add inclusion criteria:Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer �.Triple Nega�ve Breast Cancer (TNBC)i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have 1.NOTE:any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. The preferred regimen, per NCH Policy and Pathway,is [Tecentriq () + Abraxane (nab‐paclitaxel)] in members with PD‐L1 positive unresectable, recurrent, or metastatic TNBC. This recii.Note #2: Perjeta (pertuzumab) use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) anommendation is based on the lack of long‐term overall survival data from thet d/or pathologic KEYNOTE‐355 trial.confirmation of ipsilateral (same side) axillary nodal involvement. UM ONC_1134 Trastuzumab Products Negative change UM ONC_1263 Keytruda (pembrolizumab) Negative change R.Tumoriii. For curative‐intent, neoadjuvant/adjuvant therapy, Muta�onal Burden‐High (TMB‐H) Cancer Pertuzumab + Trastuzumab is indicated only in patients with node positive disease. iii. Keytruda (pembrolizumab) may be used as a single agent in members with unresectable or metastatic solid tumors with a , a high tumor The combination may be used in the neoadjuvant setting if there is radiographic and/or pathologic confirmation of ipsilateral axillary/other regional mutational burden( high tmb with ≥10 /megabase (mut/mb), that have progressed following prior treatment and have no satisfatactory nodal involvement. alternative treatment options.•Neoadjuvant therapy was given and there was no residual disease found in the breast/axillary nodes at surgery, and there was confirmation of ipsilateral axillary nodal involvement prior to starting neoadjuvant therapy.

UM ONC_1264 Zydelig (idelalisib) Negative change Add exclusion criteria: Remove inclusion criteria: III.NOT RECOMMENDED FOR USE PER NCH POLICY B.Mul�ple Myeloma (MM) UM ONC_1193 Revlimid (lenalidomide) Negative change Add inclusion criteria:ii.Lenalidomide is being used in combina�on with Darzalex/Darzalex Faspro (daratumumab)/dexamethasone with or without Velcade (bortezomib). D.Renalii.With Darzalex/Darzalex Faspro Cell Carcinoma (daratumumab) +/‐ dexamethasone +/‐ Velcade (bortezomib) NOTE: This is a Preferred Regimen on NCH Pathway 1.NOTE:based on Level 1 evidence First line therapy with [Cabometyx (cabozan�nib) + Opdivo (nivolumab)] for advanced/metasta�c clear cell Renal Cell Carcinoma is not recommended per NCH Policy or NCH Pathway. This position is based on the following: Add inclusion criteria: a.Our detailed review of the CheckMate9ER trial showed that the HR for OS for IMDC Favorable Risk disease was 0.84, with wide Confidence MM Intervals that crossed 1.0 (CI 0.35‐1.97). The HR for PFS for IMDC Favorable Risk disease was 0.62, however, again the Confidence Intervals were a.Ini�al therapy: wide and crossed 1.0 (CI 0.38‐1.01). UM ONC_1194 Revlimid (lenalidomide) Positive change i.In combina�on with Velcade(bortezomib) +/‐ dexamethasone. Combination with dexamethasone +/‐ Velcade (bortezomib). b.For IMDC Intermediate and Poor risk disease, there is a lack of Level 1 evidence (randomized trials and/or meta‐analysis) to support the MDS superiority of [Cabometyx (cabozantinib) + Opdivo (nivolumab)] over [Opdivo (nivolumab) + Yervoy (ipilimumab)]‐ the recommended regimen per 2.Revlimid (lenalidomide) is being used as a single agent or in combina�on with hypomethyla�ng agent (i.e. decitabine or azaci�dine ) in members UM ONC_1274 Opdivo (nivolumab) Negative change NCH Policy and NCH Pathway. with MDS/Myeloproliferative Overlap Neoplasms (MPN). c.Addi�onally, for IMDC Intermediate and Poor Risk disease, Cabometyx (cabozan�nib) has already been shown to be superior to Sutent (suni�nib) per the CABOSUN trial. Therefore, the control arm‐in the CheckMate9ER trial‐ with single agent Sutent (sunitinib) is not optimal/standard. L.Malignant Pleural Mesothelioma 1.Yerovy (Iipilimumab) may be used in combina�on with Opdivo (nivolumab), as first line therapy for members with Non‐epithelioid subtype (by histology) of metastatic/unresectable Malignant Pleural Mesothelioma. Yervoy (Iipilimumab) is dosed at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicities, in the above setting. NOTE: Yervoy (Iipilimumab + Opdivo (Nnivolumab) is not recommended for use in Epithelioid metasta�c/unresectable Malignant Pleural Mesothelioma. This recommendation is based on the lack of a survival benefit of the above regimen compared to [platinum+pemetrexed] in the trial by Baas et al referenced below. Policy # Drug(s) Type of Change Brief Description of Policy Change new Pepaxto (melphalan flufenamide) n/a n/a Add inclusion criteria: new Fotivda (tivozanib) n/a n/a B.Malignant Melanoma new Cosela (trilaciclib) n/a n/a 1.NOTE: Per NCH Policy & NCH Pathway, Cotellic (cobime�nib) + Zelboraf (vemurafenib) is the preferred combina�on therapy for BRAF V600E or Add inclusion criteria: NSCLC V600K mutation positive melanoma, both in the first line and subsequent line settings. This recommendation is based on the lack of Level 1 evidence UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change 2.Libtayo (cemiplimab) may be used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for to show the superiority of any one combination of a BRAF inhibitor + a MET inhibitor to be superior than another similar combination. actionable molecular markers (ALK, EGFR, or ROS‐1) 2.NOTE: Per NCH Policy & NCH Pathway, Zelboraf (vemurafenib) in combina�on with a MEK inhibitor (e.g.e.g., cobime�nib) is a non‐preferred Add inclusion criteria: regimen/combination for use as adjuvant therapy in BRAF V600E or V600K mutation positive resected stage III melanoma; Opdivo (nivolumab) for 1 a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo radia�on (Erbitux + Radia�on) as a single agent for members with a year is the preferred option in this clinical setting. This recommendation is based on the lack of Level 1 evidence to support the superiority of the UM ONC_1133UM ONC_1279 Erbitux (Cetuximab)Cotellic (cobimetinib) Positive changeNegative change contraindication and/or intolerance to cisplatin use OR above combination over 1 year of adjuvant therapy with Opdivo (nivolumab) or Keytruda (pembrolizumab). B.Head and Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with chemotherapy. 3.NOTE: Per NCH Pathway & NCH Policy, Zelboraf (vemurafenib) in combina�on with Cotellic (cobime�nib) + Tecentriq (atezolizumab) is non‐ preferred for the treatment of metastatic/recurrent/unresectable BRAF V600E or V600K mutation positive malignant melanoma. This Add inclusion criteria: recommendation is based on the lack of any Level 1 evidence (randomized trial and/or meta‐analysis) to support superior outcomes with the above UM ONC_1133 Erbitux (Cetuximab) Negative change NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for 3‐drug combination compared to Zelboraf (vemurafenib) + Cotellic (cobimetinib). BRAFV600E positive colorectal cancer.. 3.Please refer to the NCH Pathway document for the preferred regimens/op�ons in this disease, both in the ini�al, and subsequent line se�ngs. 4.Cotellic (cobime�nib) may be used in combina�on with Zelboraf (vemurafenib) in The members with has BRAF V600E or V600K mutation positive Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer metastatic, recurrent, or unresectable malignant melanoma in any of the following clinical scenarios. i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. ii.Note #2: Perjeta (pertuzumab)Remove inclusion criteria: use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) and/or pathologic UM ONC_1279 Cotellic (cobimetinib) Positive change confirmation of ipsilateral (same side) axillary nodal involvement.E.Treatment exceeds the maximum limit of 60 3 (20 mg) tablets/month. UM ONC_1134 Trastuzumab Products Negative change iii.Add inclusion criteria: Multiple myeloma For curative‐intent, neoadjuvant/adjuvant therapy, Pertuzumab + Trastuzumab is indicated only in patients with node positive disease. The combination may be used in the neoadjuvant setting 3.NOTE#3: First line daratumumab based regimens are non‐preferrif there is radiographic and/or pathologic confirmation of ipsilateral axillary/other regional ed per NCH Policy and NCH Pathway, for both transplant eligible and transplant Darzalex and Darzalex Faspro nodal involvement. ineligible multiple myeloma. This position is based on the lack of Level 1 evidence ( randomized trial) showing the superiority of daratumumab‐ UM ONC_1280 Negative change (daratumumab) •Neoadjuvantbased first line regimens compared to standard RVd‐ Revlimid Velcade Dexamethasone‐ and long term follow up of the RVd regimen showing therapy was given and there was no residual disease found in the breast/axillary nodes at surgery, and there was confirmation of ipsilateral axillary nodal involvement prior to starting neoadjuvant therapy.excellent long term outcomes. 2.4.Daratumumab may be used in members with relapsed/refractory mul�ple myeloma as a single agent Remove inclusion criteria: Remove inclusion criteria: 1.Daratumumab use is supported for mul�ple myeloma as follows: B.Mul�ple Myeloma (MM) a.First line therapy for members with newly diagnosed, non‐transplant eligible myeloma: UM ONC_1193 Revlimid (lenalidomide) Negative change ii.Lenalidomide is being used in combina�on with Darzalex/Darzalex Faspro (daratumumab)/dexamethasone with or without Velcade (bortezomib). Darzalex and Darzalex Faspro •Daratumumab + Lenalidomide + Steroid (DRd) OR UM ONC_1280 Negative change ii.With Darzalex/Darzalex Faspro (daratumumab) +/‐ dexamethasone +/‐ Velcade (bortezomib) NOTE: This is a Preferred Regimen on NCH Pathway (daratumumab) •Daratumumab + Bortezomib + Steroid (DVd) based on Level 1 evidence 1.Subsequent therapy for relapsed/refractory myeloma: Add inclusion criteria: a.Single agent Daratumumab therapy in members who have experienced disease progression on both a proteasome inhibitor and an MMimmunomodulatory agent OR have experienced disease progression on 3 prior treatment regimens. a.Ini�al therapy: Add inclusion criteria: a.Emplici� () may be used in combina�on with Pomalyst (pomalidomide) with/without dexamethasone in UM ONC_1194 Revlimid (lenalidomide) Positive change i.In combina�on with Velcade(bortezomib) +/‐ dexamethasone. Combination with dexamethasone +/‐ Velcade (bortezomib). UM ONC_1281 Empliciti (elotuzumab) Positive change members with relapsed/refractory multiple myeloma that have received at least 2 prior regimens including and immunomodulatory agent, MDS specifically Revlimid( unless intolerance/contraindication), and a proteasome inhibitor specifically Velcade (unless intolerance/contraindication). 2.Revlimid (lenalidomide) is being used as a single agent or in combina�on with hypomethyla�ng agent (i.e. decitabine or azaci�dine ) in members with MDS/Myeloproliferative Overlap Neoplasms (MPN). Remove inclusion criteria: B.Urothelial carcinoma of the bladder, and other urothelial carcinomas NOTE: Per NCH Policy & NCH Pathway, Keytruda (pembrolizumab) is the preferred agent over other PD‐1 or PD‐L1 inhibitors [i.e. Opdivo (nivolumab), Tecentriq (atezolizumab), Bavencio (), Imfinzi ()], for initial and subsequent therapy in the recurrent/metastatic Negative change setting. 1.For members with locally advanced, metasta�c, or recurrent urothelial cancer Tecentriq (atezolizumab) may be used as a single agent in ANY of UM ONC_1299 Tecentriq (atezolizumab) the following: a.First line treatment in members who are ineligible for cispla�n chemotherapy AND whose tumors express PD‐L1 (CPS or TPS of �/=1%) OR b.As subsequent therapy a�er progression on previous pla�num‐based chemotherapy.

Add inclusion criteria: F.Malignant Melanoma 1. NOTE: Per NCH Policy & NCH Pathway, Cobimetinib + Vemurafenib is the preferred therapy for BRAF V600E mutation positive melanoma over Cotellic (cobimetinib) + Zelboraf (vemurafenib) + Tecentriq (atezolizumab). Please refer to NCH L1 pathway for the preferred treatment in this Negative change setting. UM ONC_1299 Tecentriq (atezolizumab) NOTE: The combination of [Cotellic (cobimetinib) + Zelboraf (vemurafenib) + Tecentriq (atezolizumab)] is not recommended for metastatic malignant melanoma. This position is based on the lack of Level 1 evidence (randomized trials and/or meta‐analyses) showing the superiority of the above 3‐drug combination over the recommended regimen [Opdivo (nivolumab) + Yervoy (ipilimumab)]. Add inclusion criteria: B.Malignant Melanoma 1.NOTE: Per NCH Policy & NCH Pathway, Cotellic (cobime�nib) + Zelboraf (vemurafenib) is the preferred combina�on therapy for BRAF V600E or V600K mutation positive melanoma, both in the first line and subsequent line settings. This recommendation is based on the lack of Level 1 evidence to show the superiority of any one combination of a BRAF inhibitor + a MET inhibitor to be superior than another similar combination. 2.NOTE: Per NCH Policy & NCH Pathway, Zelboraf (vemurafenib) in combina�on with a MEK inhibitor (e.g.e.g., cobime�nib) is a non‐preferred regimen/combination for use as adjuvant therapy in BRAF V600E or V600K mutation positive resected stage III melanoma; Opdivo (nivolumab) for 1 year is the preferred option in this clinical setting. This recommendation is based on the lack of Level 1 evidence to support the superiority of the UM ONC_1279 Cotellic (cobimetinib) Negative change above combination over 1 year of adjuvant therapy with Opdivo (nivolumab) or Keytruda (pembrolizumab). 3.NOTE: Per NCH Pathway & NCH Policy, Zelboraf (vemurafenib) in combina�on with Cotellic (cobime�nib) + Tecentriq (atezolizumab) is non‐ preferred for the treatment of metastatic/recurrent/unresectable BRAF V600E or V600K mutation positive malignant melanoma. This recommendation is based on the lack of any Level 1 evidence (randomized trial and/or meta‐analysis) to support superior outcomes with the above 3‐drug combination compared to Zelboraf (vemurafenib) + Cotellic (cobimetinib). 3.Please refer to the NCH Pathway document for the preferred regimens/op�ons in this disease, both in the ini�al, and subsequent line se�ngs. 4.Cotellic (cobime�nib) may be used in combina�on with Zelboraf (vemurafenib) in The members with has BRAF V600E or V600K mutation positive metastatic, recurrent, or unresectable malignant melanoma in any of the following clinical scenarios.

Remove inclusion criteria: UM ONC_1279 Cotellic (cobimetinib) Positive change E.Treatment exceeds the maximum limit of 60 3 (20 mg) tablets/month. Add inclusion criteria: Multiple myeloma 3.NOTE#3: First line daratumumab based regimens are non‐preferred per NCH Policy and NCH Pathway, for both transplant eligible and transplant Darzalex and Darzalex Faspro ineligible multiple myeloma. This position is based on the lack of Level 1 evidence ( randomized trial) showing the superiority of daratumumab‐ UM ONC_1280 Negative change (daratumumab) based first line regimens compared to standard RVd‐ Revlimid Velcade Dexamethasone‐ and long term follow up of the RVd regimen showing excellent long term outcomes. 2.4.Daratumumab may be used in members with relapsed/refractory mul�ple myeloma as a single agent Remove inclusion criteria: 1.Daratumumab use is supported for mul�ple myeloma as follows: a.First line therapy for members with newly diagnosed, non‐transplant eligible myeloma: Darzalex and Darzalex Faspro •Daratumumab + Lenalidomide + Steroid (DRd) OR UM ONC_1280 Negative change (daratumumab) •Daratumumab + Bortezomib + Steroid (DVd) 1.Subsequent therapy for relapsed/refractory myeloma: a.Single agent Daratumumab therapy in members who have experienced disease progression on both a proteasome inhibitor and an immunomodulatory agent OR have experienced disease progression on 3 prior treatment regimens. Add inclusion criteria: a.Emplici� (elotuzumab) may be used in combina�on with Pomalyst (pomalidomide) with/without dexamethasone in UM ONC_1281 Empliciti (elotuzumab) Positive change members with relapsed/refractory multiple myeloma that have received at least 2 prior regimens including and immunomodulatory agent, specifically Revlimid( unless intolerance/contraindication), and a proteasome inhibitor specifically Velcade (unless intolerance/contraindication).

Remove inclusion criteria: B.Urothelial carcinoma of the bladder, and other urothelial carcinomas NOTE: Per NCH Policy & NCH Pathway, Keytruda (pembrolizumab) is the preferred agent over other PD‐1 or PD‐L1 inhibitors [i.e. Opdivo (nivolumab), Tecentriq (atezolizumab), Bavencio (avelumab), Imfinzi (durvalumab)], for initial and subsequent therapy in the recurrent/metastatic Negative change setting. 1.For members with locally advanced, metasta�c, or recurrent urothelial cancer Tecentriq (atezolizumab) may be used as a single agent in ANY of UM ONC_1299 Tecentriq (atezolizumab) the following: a.First line treatment in members who are ineligible for cispla�n chemotherapy AND whose tumors express PD‐L1 (CPS or TPS of �/=1%) OR Policy # Drug(s) Type of Change Brief Description of Policy Changeb.As subsequent therapy a�er progression on previous pla�num‐based chemotherapy. new Pepaxto (melphalan flufenamide) n/a n/aAdd inclusion criteria: F.Malignant Melanoma new Fotivda (tivozanib) n/a n/a 1. NOTE: Per NCH Policy & NCH Pathway, Cobimetinib + Vemurafenib is the preferred therapy for BRAF V600E mutation positive melanoma over new Cosela (trilaciclib) n/a n/a Cotellic (cobimetinib) + Zelboraf (vemurafenib) + Tecentriq (atezolizumab). Please refer to NCH L1 pathway for the preferred treatment in this Negative change Add inclusion criteria: NSCLC setting. UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change 2.Libtayo (cemiplimab) may be used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for NOTE: The combination of [Cotellic (cobimetinib) + Zelboraf (vemurafenib) + Tecentriq (atezolizumab)] is not recommended for metastatic UM ONC_1299 Tecentriq (atezolizumab) actionable molecular markers (ALK, EGFR, or ROS‐1) malignant melanoma. This position is based on the lack of Level 1 evidence (randomized trials and/or meta‐analyses) showing the superiority of the Add inclusion criteria: above 3‐drug combination over the recommended regimen [Opdivo (nivolumab) + Yervoy (ipilimumab)]. a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo radia�on (Erbitux + Radia�on) as a single agent for members with a UM ONC_1133 Erbitux (Cetuximab) Positive change Add inclusion criteria:contraindication and/or intolerance to cisplatin use OR 2.Peripheral T‐Cell LymphomaB.Head and Neck Cancers ‐ For recurrent/metasta�c disease as (PTCL) a single agent, or in combination with chemotherapy. a.The member has relapsed or refractory PTCL (including anaplastic large cell , primary systemic type, transformed mycosis fungoides, UM ONC_1308 Folotyn (pralatrexate) Positive change blastic NK cell lymphoma, HTLV1+ lymphoma, extranodal peripheral T.NK‐cell lymphoma) iAdd inclusion criteria: .e. angioimmunoblastic T‐cell lymphoma, peripheral T‐cell UM ONC_1133 Erbitux (Cetuximab) Negative change lymphoma not otherwise specified, anaplastic large cell lymphoma, enteropathy‐associated T‐cell lymphoma, or monomorphic epitheliotropic NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for intestinal T‐cell lymphoma). BRAFV600E positive colorectal cancer.. Add inclusion criteria:NSCLC: Iressa (gefi�nib) may be used as a single agent in members with a known EGFR exon 19 deletions or exon 21 (L858R) UM ONC_1309 Iressa () Negative change sensitizing mutation as subsequent line therapy; may be used as first line therapy in a member who has a contraindication/intolerance to Tagrisso Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer (oOsimertinib).i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have Add exclusion criteria:any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. UM ONC_1311 Lonsurf (trifluridine_tipiracil) Negative change Treatment exceeds the maximum limit of 80 ( 20 mg) ii.Note #2: Perjeta (pertuzumab) use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) anor 60 (15 mg) tablets/month. d/or pathologic Add inclusion criteria:confirmation of ipsilateral (same side) axillary nodal involvement. UM ONC_1134 Trastuzumab Products Negative change B.Non‐Smalliii. For curative‐intent, neoadjuvant/adjuvant therapy, Cell Lung Cancer (NSCLC) Pertuzumab + Trastuzumab is indicated only in patients with node positive disease. 1.Imfinzi (durvalumab) will may beThe combination may be used in the neoadjuvant setting used as a single agent if there is radiographic and/or pathologic confirmation of ipsilateral axillary/other regional for consolidation therapy (for a total of 1 year), after completion of definitive UM ONC_1314 Imfinzi (durvalumab) Negative change chemoradiation, in members with unresectable (not amendable to surgical treatment)nodal involvement. stage II or stage III disease C.Small•Neoadjuvant Cell Lung therapy Cancer was (Extensive given and Stage) there was no residual disease found in the breast/axillary nodes at surgery, and there was confirmation of 2.Imfinziipsilateral axillary nodal involvement prior to starting neoadjuvant therapy. (durvalumab) may be used in combina�on with �carbopla�n + etoposide], for members with extensive stage small cell lung cancer, if there is a history of intolerance to Tecentriq (atezolizumab). Remove inclusion criteria: Add inclusion criteria: B.Mul�ple Myeloma (MM) 2.Breast Cancer UM ONC_1193 Revlimid (lenalidomide) Negative change ii.Lenalidomide is being used in combina�on with Darzalex/Darzalex Faspro (daratumumab)/dexamethasone with or without Velcade (bortezomib). a.The member has early stage (stages I, II, and III) hormone receptor positive, HER2 positive breast cancer, and Nerlynx () is being used as ii.With Darzalex/Darzalex Faspro (daratumumab) +/‐ dexamethasone +/‐ Velcade (bortezomib) NOTE: This is a Preferred Regimen on NCH Pathway a single agent following completion of adjuvant trastuzumab .of ONE year or less OR based on Level 1 evidence b.NOTE: For members with metasta�c HER‐2 + breast cancer, with disease progression on ≥ prior therapies, Tykerb() + UM ONC_1316 Nerlynx (neratinib) Negative change chemotherapy/endocrine therapy, is the preferred anti‐HER‐2 TKIAdd inclusion criteria: ‐ Tyrosine Kinase Inhibitor. This recommendation is based on our analysis of the NALA trial which showed no significant Overall Survival benefit for the use of Nerlynx (neratinib) when compared to Tykerb (lapatinib)MM b.a.Ini�al Nerlynx(neratinib) may be used in a The member with has metastatic HER2 positive metastatic breast cancer with disease progression on ≥ 2 therapy: UM ONC_1194 Revlimid (lenalidomide) Positive change prior regimens for metastatic disease, if the member has an intolerance to Tykerb(lapatinib), and Nerlynx (neratinib) is being used in combination i.In combina�on with Velcade(bortezomib) +/‐ dexamethasone. Combination with dexamethasone +/‐ Velcade (bortezomib). with and the member has received two or more prior anti‐HER‐2 based regimens except lapatinib in the metastatic setting.MDS 2.Revlimid (lenalidomide) is being used as a single agent or in combina�on with hypomethyla�ng agent (i.e. decitabine or azaci�dine ) in members with MDS/Myeloproliferative Overlap Neoplasms (MPN). Add exclusion criteria: UM ONC_1316 Nerlynx (neratinib) Negative change 1.Nerlynx (nera�nib) use a�er disease progression on a Nerlynx (neratinib) based regimen, or disease progression on another anti‐HER‐2 TKI (either as a single agent or in combination with chemotherapy/endocrine therapy‐ specifically Tykerb (lapatinib) or Tukysa () Add inclusion criteria: B.Acute Myeloid (AML) Vyxeos (daunorubicin and 1. NOTE: Per NCH Policy and NCH Pathway, Vyxeos (daunorubicin and cytarabine liposomal) is a non‐preferred drug for the treatment of AML for UM ONC_1326 Negative change cytarabine liposomal) any line of therapy. Generic daunorubicin and cytarabine are the preferred agents in this setting. 1.Vyxeos may be used for induc�on and consolida�on therapy for members aged 60 years or older, who have newly diagnosed, therapy‐related AML or de novo AML with MDS‐associated cytogenetic abnormalities. Add exclusion criteria: A.Members do not have either therapy‐related AML ( related to previous cytotoxic chemotherapy and or radiotherapy e.g. doxorubicin, etoposide) Vyxeos (daunorubicin and or AML with MDS‐related cytogenetic abnormalities. UM ONC_1326 Negative change cytarabine liposomal) B.Members with Acute Promyelocy�c Leukemia C.Members with t(8;21) + or inversion 16 + ( Core Binding Factor posi�ve) AML D.CNS Leukemia Add inclusion criteria: C.Follicular Lymphoma 1.Yescarta (axicabtagene ciloleucel) may be used in adult members with CD19 posi�ve relapsed or refractory follicular lymphoma (FL) with at least UM ONC_1329 Yescarta (axicabtagene ciloleucel) Positive change two or more lines of chemoimmunotherapies, including the combination of an anti‐CD20 monoclonal antibody and an alkylating agent (e.g., R‐ bendamustine, R‐CHOP, R‐CVP).

Add inclusion criteria: ii.Subsequent‐line therapy: Lorbrena () or Alunbrig (Bbrigatinib) (if failed Crizotinib). UM ONC_1347 Lorbrena (lorlatinib) Negative change b.Lorbrena (lorla�nib) may be used as monotherapy in members with recurrent or metasta�c ALK posi�ve NSCLC as subsequent therapy. This recommendation is based on an improved median PFS, ORR, and DOR with Lorbrena (lorlatinib) when compared to Xalkori (crizotinib). Add inclusion criteria: 2.Peripheral T‐Cell Lymphoma (PTCL) a.The member has relapsed or refractory PTCL (including anaplastic large cell lymphoma, primary systemic type, transformed mycosis fungoides, UM ONC_1308 Folotyn (pralatrexate) Positive change blastic NK cell lymphoma, HTLV1+ lymphoma, extranodal peripheral T.NK‐cell lymphoma) i.e. angioimmunoblastic T‐cell lymphoma, peripheral T‐cell lymphoma not otherwise specified, anaplastic large cell lymphoma, enteropathy‐associated T‐cell lymphoma, or monomorphic epitheliotropic intestinal T‐cell lymphoma). Add inclusion criteria:NSCLC: Iressa (gefi�nib) may be used as a single agent in members with a known EGFR exon 19 deletions or exon 21 (L858R) UM ONC_1309 Iressa (gefitinib) Negative change sensitizing mutation as subsequent line therapy; may be used as first line therapy in a member who has a contraindication/intolerance to Tagrisso (oOsimertinib). Add exclusion criteria: UM ONC_1311 Lonsurf (trifluridine_tipiracil) Negative change Treatment exceeds the maximum limit of 80 ( 20 mg) or 60 (15 mg) tablets/month. Add inclusion criteria: B.Non‐Small Cell Lung Cancer (NSCLC) 1.Imfinzi (durvalumab) will may be used as a single agent for consolidation therapy (for a total of 1 year), after completion of definitive UM ONC_1314 Imfinzi (durvalumab) Negative change chemoradiation, in members with unresectable (not amendable to surgical treatment) stage II or stage III disease C.Small Cell Lung Cancer (Extensive Stage) 2.Imfinzi (durvalumab) may be used in combina�on with �carbopla�n + etoposide], for members with extensive stage small cell lung cancer, if there is a history of intolerance to Tecentriq (atezolizumab).

Add inclusion criteria: 2.Breast Cancer a.The member has early stage (stages I, II, and III) hormone receptor positive, HER2 positive breast cancer, and Nerlynx (neratinib) is being used as a single agent following completion of adjuvant trastuzumab .of ONE year or less OR b.NOTE: For members with metasta�c HER‐2 + breast cancer, with disease progression on ≥ prior therapies, Tykerb(lapatinib) + UM ONC_1316 Nerlynx (neratinib) Negative change chemotherapy/endocrine therapy, is the preferred anti‐HER‐2 TKI‐ Tyrosine Kinase Inhibitor. This recommendation is based on our analysis of the NALA trial which showed no significant Overall Survival benefit for the use of Nerlynx (neratinib) when compared to Tykerb (lapatinib) b. Nerlynx(neratinib) may be used in a The member with has metastatic HER2 positive metastatic breast cancer with disease progression on ≥ 2 prior regimens for metastatic disease, if the member has an intolerance to Tykerb(lapatinib), and Nerlynx (neratinib) is being used in combination with capecitabine and the member has received two or more prior anti‐HER‐2 based regimens except lapatinib in the metastatic setting.

Add exclusion criteria: UM ONC_1316 Nerlynx (neratinib) Negative change 1.Nerlynx (nera�nib) use a�er disease progression on a Nerlynx (neratinib) based regimen, or disease progression on another anti‐HER‐2 TKI (either as a single agent or in combination with chemotherapy/endocrine therapy‐ specifically Tykerb (lapatinib) or Tukysa (tucatinib) Add inclusion criteria: B.Acute Myeloid Leukemia (AML) Vyxeos (daunorubicin and 1. NOTE: Per NCH Policy and NCH Pathway, Vyxeos (daunorubicin and cytarabine liposomal) is a non‐preferred drug for the treatment of AML for UM ONC_1326 Negative change cytarabine liposomal) any line of therapy. Generic daunorubicin and cytarabine are the preferred agents in this setting. 1.Vyxeos may be used for induc�on and consolida�on therapy for members aged 60 years or older, who have newly diagnosed, therapy‐related Policy # Drug(s) Type of Change Brief Description of Policy Change AML or de novo AML with MDS‐associated cytogenetic abnormalities. Add exclusion criteria: new Pepaxto (melphalan flufenamide) n/a n/a A.Members do not have either therapy‐related AML ( related to previous cytotoxic chemotherapy and or radiotherapy e.g. doxorubicin, etoposide) new Vyxeos (daunorubicin and Fotivda (tivozanib) n/a or AML with MDS‐related cytogenetic abnormalities.n/a UM ONC_1326 Negative change new cytarabine liposomal)Cosela (trilaciclib) n/a B.Membersn/a with Acute Promyelocy�c Leukemia C.MembersAdd inclusion criteria: NSCLC with t(8;21) + or inversion 16 + ( Core Binding Factor posi�ve) AML UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change D.CNS2.Libtayo (cemiplimab) may be Leukemia used as montherapy in members with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for Add inclusion criteria:actionable molecular markers (ALK, EGFR, or ROS‐1) C.FollicularAdd inclusion criteria: Lymphoma 1.Yescartaa.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemo (axicabtagene ciloleucel) may be used in adult membersradia�on (Erbitux + with CD19 posi�ve Radia�on) asrelapsed or refractory a single agent follicular for members lymphoma wit (FL)h a with at least UM ONC_1329 Yescarta (axicabtagene ciloleucel) Positive change UM ONC_1133 Erbitux (Cetuximab) Positive change two or more lines of chemoimmunotherapies, including the combination of an anti‐CD20 monoclonal antibody and an alkylating agent (e.g., Rcontraindication and/or intolerance to cisplatin use OR ‐ bendamustine, R‐CHOP, R‐CVP). B.Head and Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with chemotherapy.

Add inclusion criteria: Add inclusion criteria: UM ONC_1133 Erbitux (Cetuximab) Negative change NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, for ii.Subsequent‐line therapy: Crizotinib Lorbrena (lorlatinib) or Alunbrig (Bbrigatinib) (if failed Crizotinib). UM ONC_1347 Lorbrena (lorlatinib) Negative change BRAFV600E positive colorectal cancer.. b.Lorbrena (lorla�nib) may be used as monotherapy in members with recurrent or metasta�c ALK posi�ve NSCLC as subsequent therapy. This recommendation is based on an improved median PFS, ORR, and DOR with Lorbrena (lorlatinib) when compared to Xalkori (crizotinib). Add inclusion criteria: B.HER‐2 Posi�ve Breast Cancer i.Note #1: For adjuvant (post‐opera�ve) use in members who did not receive neoadjuvant therapy/received neoadjuvant therapy and did not have Add inclusion criteria: Talzenna (talazoparib) is not recommended for use when a PARP inhibitor is indicated for use in BRCA1/2 + metastatic breast any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. UM ONC_1349 Talzenna (talazoparib) Negative change cancer. This recommendation is based on data from the phase III EMBRACA trial, reported April 2020, in which Talzenna (talazoparib) did not show a ii.Note #2: Perjeta (pertuzumab) use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) and/or pathologic statistically significant overall survival benefit for patient with metastatic breast cancer with a germline BRCA 1/2 mutation. confirmation of ipsilateral (same side) axillary nodal involvement. UM ONC_1134 Trastuzumab Products Negative change iii.Remove inclusion criteria:2.Breast Cancer For curative‐intent, neoadjuvant/adjuvant therapy, Pertuzumab + Trastuzumab is indicated only in patients with node positive disease. UM ONC_1349 Talzenna (talazoparib) Positive change The combination may be used in the neoadjuvant setting a.NOTE #1: The preferred PARP inhibitor, per NCH policy andif there is radiographic and/or pathologic confirmation of ipsilateral axillary/other regional NCH pathway, is OLAPARIB for recurrent or metasta�c, germline BRCA 1/2 muta�on nodal involvement. positive HER2 negative breast cancer. •Neoadjuvant therapy was given and there was no residual disease found in the breast/axillary nodes at surgery, and there was confirmation of UM ONC_1349 Talzenna (talazoparib) Negative change Add exclusion criteria: III.NOT RECOMMENDED FOR USE PER NCH POLICY ipsilateral axillary nodal involvement prior to starting neoadjuvant therapy. Remove exclusion criteria: 1.No history of intolerance to/contraindica�ons to Olaparib. UM ONC_1349 Talzenna (talazoparib) Positive change Remove inclusion criteria: 2.Dosing exceeds single dose limit of Talzenna (talazoparib) 1 mg. B.Mul�ple Myeloma (MM) 3.Treatment exceeds the maximum limit of 120 (0.25 mg) or 30 (1mg) capsules/month. UM ONC_1193 Revlimid (lenalidomide) Negative change ii.Lenalidomide is being used in combina�on with Darzalex/Darzalex Faspro (daratumumab)/dexamethasone with or without Velcade (bortezomib). ii.With Darzalex/Darzalex FasproAdd inclusion criteria: (daratumumab) +/‐ dexamethasone +/‐ Velcade (bortezomib) NOTE: This is a Preferred Regimen on NCH Pathway based on Level 1 evidence2.Myelofibrosis (MF) UM ONC_1366 Inrebic (fedratinib) Negative change a.NOTE: The preferred agent, per NCH Policies, is Jakafi (ruxoli�nib) over Inrebic (fedra�nib). This recommenda�on is based on the lack of Ldue Add inclusion criteria: to level 1 evidence ( randomized trial and/or meta‐analyses) showing auperior outcomes with Inrebic (fedratinib) over Jakafi (ruxolitinib). MM a.Ini�alRemove inclusion criteria: therapy: UM ONC_1366 Inrebic (fedratinib) Positive change UM ONC_1194 Revlimid (lenalidomide) Positive change i.Ind.The combina�on member has with Velcade(bortezomib) failed prior therapy with +/‐ Jakafi dexamethasone. (ruxoli�nib). Combination with dexamethasone +/‐ Velcade (bortezomib). MDSAdd exclusion criteria: UM ONC_1366 Inrebic (fedratinib) Negative change 2.Revlimid (lenalidomide)1.Inrebic (fedra�nib) use a�er is bein diseaseg used as progression with the a single agent or in sam combina�one regimen with hypomethyla�ngor another JAK2 inhibitor [e.g., Jakafi (ruxolitinib)]. agent (i.e. decitabine or azaci�dine ) in members with MDS/Myeloproliferative Overlap Neoplasms (MPN).Remove exclusion criteria: UM ONC_1366 Inrebic (fedratinib) Positive change 2.Concurrent use with another 2 (JAK2) inhibitor (e.g., Ruxoli�nib). Add inclusion criteria: 2.Urothelial Carcinoma i.Documented FGFR3 mutation or FGFR2/3 fusion genomic alterations in tumor tissue (using the FDA approved companion diagnostic: therascreen or another appropriate genomic test) ii.Disease progression on/intolerance to on platinum‐based chemotherapy AND disease progression on/intolerance to Immune Check Point UM ONC_1374 Balversa () Negative change Inhibitor therapy (e.g., atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab) OR iii.If ineligible for pla�num containing therapy, the member had disease progression on/intolerance toon Immune Check Point Inhibitor therapy (e.g., atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab). iii.NOTE: Above recommenda�ons are based on the lack of Level 1 evidence ( randomized trial and/or meta‐analysis) showing superiority of Balversa (erdafetinib) over Immune Checkpoint Inhibitor therapy in the second line setting. Add exclusion criteria: UM ONC_1374 Balversa (erdafitinib) Positive change 5.Treatment exceeds the maximum limit of 360 (4 mg), 30 (5mg), 90 (3mg) tablets/month. Add inclusion criteria: UM ONC_1395 Clolar (clofarabine) Positive change Clolar(clofarabine) is being used as a single agent or as part of a multi‐agent regimen.

Add inclusion criteria: 2.Melanoma a.NOTE: The preferred BRAF and MEK inhibitor combina�on regimen, per NCH policy and NCH pathway, for unresectable/metasta�c BRAF UM ONC_1397 Mektovi () Negative change mutation positive melanoma is the combination of Cotellic (cCobimetinib) + Zelboraf (vVemurafenib) over Mektovi (bBinimetinib) + Braftovi (eEncorafenib). Rationale: Lack of Level 1 evidence (randomized trial and/or meta‐analysis) showing superior outcomes with binemetinib + encorafenib over cobimetinib + vemurafenib b.The member has BRAF V600E or V600K activating mutation and unresectable or metastatic melanoma Remove exclusion criteria: UM ONC_1397 Mektovi (binimetinib) Positive change 3.Treatment exceeds the maximum limit of Mektovi 180 90 (15 mg) tablets per month. Add exclusion criteria: 1.Disease progression with another combination of a BRAF (i.e. vemurafenib, dabrafenib) inhibitor + MEK inhibitors (i.e. UM ONC_1397 Mektovi (binimetinib) Positive change trametinib or cobimetinib). UM ONC_1398 Pemazyre () Negative change Add exclusion criteria: 2.No confirmatory test available to confirm the presence of an FGFR‐2 gene fusion/gene rearrangement Add inclusion criteria: Acute Myeloid Leukemia UM ONC_1416 Onureg (azacitidine oral) Positive change 1.Onureg (azaci�dine) may be used as a single agent as maintenance therapy in a member with AML in first complete remission following induc�on therapy (with or without consolidation therapy). Remove inclusion criteria: B.Acute Myeloid Leukemia UM ONC_1416 Onureg (azacitidine oral) Positive change Note: Vidaza (azacitidine) + Venclexta () is the preferred induction and consolidation regimen in members who are newly diagnosed and who are not candidates for intensive therapy in treatment of AML. Add inclusion criteria: Talzenna (talazoparib) is not recommended for use when a PARP inhibitor is indicated for use in BRCA1/2 + metastatic breast UM ONC_1349 Talzenna (talazoparib) Negative change cancer. This recommendation is based on data from the phase III EMBRACA trial, reported April 2020, in which Talzenna (talazoparib) did not show a statistically significant overall survival benefit for patient with metastatic breast cancer with a germline BRCA 1/2 mutation. Remove inclusion criteria:2.Breast Cancer UM ONC_1349 Talzenna (talazoparib) Positive change a.NOTE #1: The preferred PARP inhibitor, per NCH policy and NCH pathway, is OLAPARIB for recurrent or metasta�c, germline BRCA 1/2 muta�on positive HER2 negative breast cancer. UM ONC_1349 Talzenna (talazoparib) Negative change Add exclusion criteria: III.NOT RECOMMENDED FOR USE PER NCH POLICY Remove exclusion criteria: 1.No history of intolerance to/contraindica�ons to Olaparib. UM ONC_1349 Talzenna (talazoparib) Positive change 2.Dosing exceeds single dose limit of Talzenna (talazoparib) 1 mg. 3.Treatment exceeds the maximum limit of 120 (0.25 mg) or 30 (1mg) capsules/month. Add inclusion criteria: 2.Myelofibrosis (MF) UM ONC_1366 Inrebic (fedratinib) Negative change a.NOTE: The preferred agent, per NCH Policies, is Jakafi (ruxoli�nib) over Inrebic (fedra�nib). This recommenda�on is based on the lack of Ldue to level 1 evidence ( randomized trial and/or meta‐analyses) showing auperior outcomes with Inrebic (fedratinib) over Jakafi (ruxolitinib). Remove inclusion criteria: UM ONC_1366 Inrebic (fedratinib) Positive change d.The member has failed prior therapy with Jakafi (ruxoli�nib). Add exclusion criteria: UM ONC_1366 Inrebic (fedratinib) Negative change 1.Inrebic (fedra�nib) use a�er disease progression with the same regimen or another JAK2 inhibitor [e.g., Jakafi (ruxolitinib)]. Remove exclusion criteria: Policy #UM ONC_1366 Drug(s) Inrebic (fedratinib) Type of ChangePositive change Brief Description of Policy Change 2.Concurrent use with another Janus Kinase 2 (J AK2) inhibitor (e. g ., Ruxoli�nib). Add inclusion criteria: new Pepaxto (melphalan flufenamide) n/a n/a 2.Urothelial Carcinoma new Fotivda (tivozanib) n/a n/ai.Documented FGFR3 mutation or FGFR2/3 fusion genomic alterations in tumor tissue (using the FDA approved companion diagnostic: therascreen new Cosela (trilaciclib) n/a n/aor another appropriate genomic test) Add inclusion criteria: NSCLCii.Disease progression on/intolerance to on platinum‐based chemotherapy AND disease progression on/intolerance to Immune Check Point UM ONC_1374 Balversa (erdafitinib) Negative change UM ONC_1089 Libtayo (cemiplimab‐rwlc) Negative change 2.Libtayo (cemiplimab) may beInhibitor therapy (e.g., atezolizumab used as, avelumab, montherapy in membersdurvalumab, nivolumab, or pembrolizumab) OR with locally advanced, recurrent/metastatic NSCLC, with PD‐L1 ≥ 50%, negative for actionable molecular markers (ALK, EGFR, or ROS‐1)iii.If ineligible for pla�num containing therapy, the member had disease progression on/intolerance toon Immune Check Point Inhibitor therapy Add inclusion criteria: (e.g., atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab). a.As a part of primary/de�ni�ve/cura�ve‐intent concurrent chemoiii.NOTE: Above recommenda�ons are based on the lack of Level 1 radia�on (Erbitux +evidence ( randomized trial and/or Radia�on) as a single meta‐analysis) showing sup agent for members witeriorityh a of UM ONC_1133 Erbitux (Cetuximab) Positive change contraindication Balversa (erdafetinib) over Immune Checkpoint Inhibitor therapy in the second line setting.and/or intolerance to cisplatin use OR B.Head andAdd exclusion criteria: Neck Cancers ‐ For recurrent/metasta�c disease as a single agent, or in combination with chemotherapy. UM ONC_1374 Balversa (erdafitinib) Positive change 5.Treatment exceeds the maximum limit of 360 (4 mg), 30 (5mg), 90 (3mg) tablets/month. Add inclusion criteria: Add inclusion criteria: UM ONC_1133UM ONC_1395 Erbitux (Cetuximab)Clolar (clofarabine) Negative changePositive change NOTE: Erbitux (cetuximab) + Braftovi (encorafenib) is NCH preferred L1 pathway for second‐line or subsequent therapy in the metastatic setting, Clolar(clofarabine) is being used as a single agent or as part of a multi‐agent regimen. for BRAFV600E positive colorectal cancer.. Add inclusion criteria: Add inclusion criteria: 2.Melanoma B.HER‐2 Posi�ve Breast Cancer i.Note #1: For adjuvant (post‐opera�ve)a.NOTE: The preferred BRAF and MEK inhibitor use in members who did combina�on regime notn, receive per NCH neoadjuvant policy and NCH therapy/received pathway, for neoadjuvantunresectable/metasta�c therapy and did not BRAF have UM ONC_1397 Mektovi (binimetinib) Negative change any residual disease in the breast and/or axillary lymph nodes, Perjeta (pertuzumab) use is restricted to node positive stage II and III disease only. mutation positive melanoma is the combination of Cotellic (cCobimetinib) + Zelboraf (vVemurafenib) over Mektovi (bBinimetinib) + Braftovi ii.Note #2: Perjeta (pertuzumab)(eEncorafenib). Rationale: Lack of Level 1 evidence (randomized trial and/or meta‐analysis) showing superior outcomes with binemetinib + use in the neoadjuvant (pre‐opera�ve) se�ng requires radiographic (e.g., breast MRI, CT) and/or pathologic confirmation of ipsilateral (same side) axillary nodal involvement.encorafenib over cobimetinib + vemurafenib UM ONC_1134 Trastuzumab Products Negative change iii.b.The For curative‐intent, neoadjuvant/adjuvant therapy, member has BRAF V600E or V600K activating mutation and unresectable or metastatic melanoma Pertuzumab + Trastuzumab is indicated only in patients with node positive disease. The combination may be used in the neoadjuvant setting Remove exclusion criteria: if there is radiographic and/or pathologic confirmation of ipsilateral axillary/other regional UM ONC_1397 Mektovi (binimetinib) Positive change nodal involvement. 3.Treatment exceeds the maximum limit of Mektovi 180 90 (15 mg) tablets per month. •NeoadjuvantAdd exclusion criteria: therapy was 1.Disease given andprogression there was with another combination of no residual disease found in thea BRAF (i.e. vemurafenib, dabrafenib) inhibitor breast/axillary nodes at surgery, and there was confirmation of + MEK inhibitors (i.e. UM ONC_1397 Mektovi (binimetinib) Positive change ipsilateral axillary nodal involvement prior to starting neoadjuvant therapy.trametinib or cobimetinib). UM ONC_1398 Pemazyre (pemigatinib) Negative change Add exclusion criteria: 2.No confirmatory test available to confirm the presence of an FGFR‐2 gene fusion/gene rearrangement Remove inclusion criteria: Add inclusion criteria: Acute Myeloid Leukemia B.Mul�ple Myeloma (MM) UM ONC_1416 Onureg (azacitidine oral) Positive change 1.Onureg (azaci�dine) may be used as a single agent as maintenance therapy in a member with AML in first complete remission following induc�on UM ONC_1193 Revlimid (lenalidomide) Negative change ii.Lenalidomide is being used in combina�on with Darzalex/Darzalex Faspro (daratumumab)/dexamethasone with or without Velcade (bortezomib). therapy (with or without consolidation therapy). ii.With Darzalex/Darzalex Faspro (daratumumab) +/‐ dexamethasone +/‐ Velcade (bortezomib) NOTE: This is a Preferred Regimen on NCH Pathway Remove inclusion criteria: B.Acute Myeloid Leukemia based on Level 1 evidence UM ONC_1416 Onureg (azacitidine oral) Positive change Note: Vidaza (azacitidine) + Venclexta (venetoclax) is the preferred induction and consolidation regimen in members who are newly diagnosed and Add inclusion criteria: who are not candidates for intensive therapy in treatment of AML. MMAdd exclusion criteria: UM ONC_1416 Onureg (azacitidine oral) Negative change a.Ini�alC.Treatment therapy: exceeds the maximum limit of 14 (300 mg) or 14 (200 mg) tablets/month. UM ONC_1194 Revlimid (lenalidomide) Positive change i.In combina�on with Velcade(bortezomib) +/‐ dexamethasone. Combination with dexamethasone +/‐ Velcade (bortezomib). MDS 2.Revlimid (lenalidomide) is being used as a single agent or in combina�on with hypomethyla�ng agent (i.e. decitabine or azaci�dine ) in members with MDS/Myeloproliferative Overlap Neoplasms (MPN).