Estimation of the Percentage of US Patients with Cancer Who Benefit from Genome‐Driven Oncology

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Supplementary Online Content

Marquart J, Chen EY, Prasad V. Estimation of the percentage of US patients with cancer who benefit from genome‐driven oncology. JAMA Oncology. Published online April 17, 2018. doi:10.1001/jamaoncol.2018.1660

eAppendix 1. Yearly Cancer Statistics eAppendix 2. Data Sources by Malignancy eAppendix 3. Pie Charts Estimating Patients Eligible for Genomically Targeted Therapy eAppendix 4. Pie Charts Estimating Patients Who Could Benefit from Genomically Targeted Therapy eAppendix 5. Pie Charts Estimating Patients Eligible for Genomically Informed Therapy eAppendix 6. Pie Charts Estimating Patients Who Could Benefit from Genomically Informed Therapy eAppendix 7. Pie Charts Estimating Patients Eligible for and who could Benefit from Adjuvant Therapy eFigure 1. Percent of US metastatic Cancer Patients Who May be Eligible for and Benefit from Genomically Informed Treatment eFigure 2. Growth of Genome Targeted and Informed Therapy Over Time With Fitted Linear Regression

This supplementary material has been provided by the authors to give readers additional information about their work.

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eAppendix 1. Cancer Statistics by Year: 2006: https://www.ncbi.nlm.nih.gov/pubmed/16514137 2007: https://www-ncbi-nlm-nih-gov/pubmed/17237035 2008: https://www-ncbi-nlm-nih-gov/pubmed/18287387 2009: https://www-ncbi-nlm-nih-gov/pubmed/19474385 2010: https://www-ncbi-nlm-nih-gov/pubmed/20610543 2011: https://www.ncbi.nlm.nih.gov/pubmed/21685461 2012: https://www.ncbi.nlm.nih.gov/pubmed/22237781 2013: https://www.ncbi.nlm.nih.gov/pubmed/23335087 2014: https://www.ncbi.nlm.nih.gov/pubmed/24890451 2015: https://www.ncbi.nlm.nih.gov/pubmed/25559415 2016: https://www.ncbi.nlm.nih.gov/pubmed/26742998 2017: https://www.ncbi.nlm.nih.gov/pubmed/28055103 2018: https://www.ncbi.nlm.nih.gov/pubmed/29313949

eAppendix 2. Data Sources by Malignancy: Below are the detailed breakdowns and evidence used for each malignancy, the mutations involved in genomically targeted and informed therapy, as well as the drugs approved for the specific targets.

Non‐Small Cell Lung Cancer(NSCLC): ‐Yearly Statistics from Cancer Statistics section, 2018 Lung Cancer deaths = 154,050 ‐NSCLC frequency = 85% Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864624/

Mutations: EGFR: Frequency: 15%(10‐20%), Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346098/ Best Overall Response Rate: 2006‐2012: 10.6% Gefitinib, FDA drug label 2013‐2018: 65%, Osimertinib and Erlotinib, from FDA drug label Drugs Approval Dates Erlotinib 4/16/10, 5/14/13, 10/18/16(Originally approved in 2004) Afatinib 7/12/13, 1/12/18 Gefitinib 7/13/15(Originally approved in 2003) Osimertinib 11/13/15, 3/31/17

ALK: Frequency: 4.5%(2‐7%), Source: https://www.ncbi.nlm.nih.gov/pubmed/20979469 Best Overall Response Rate: 2011‐2012: 56%(50‐61%) Crizotinib, FDA drug label 2013‐2016: 65% Crizotinib, FDA drug label

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2017‐2018: 79%, Alectinib, from FDA drug label Drugs Approval Dates Crizotinib 8/26/11, 11/20/13 Ceritinib 4/29/14, 5/26/17 Alectinib 12/11/15, 11/6/17 Brigatinib 4/28/17

ROS1: Frequency: 2%(1.7%), Source: https://www.ncbi.nlm.nih.gov/pubmed/22215748 Best Overall Response Rate 2016‐2018: 66%, Crizotinib, from FDA drug label Drugs Approval Dates Crizotinib 3/11/16

BRAF: Frequency: 2%(1‐3%), Source: https://www.ncbi.nlm.nih.gov/pubmed/29057232 Best Overall Response Rate 2017‐2018: 63%, Dabrafenib and Trametinib, from FDA drug label Drugs Approval Dates Dabrafenib and 6/22/17 Trametinib

Breast Cancer: ‐Yearly Statistics from Cancer Statistics section, 2018 Breast Cancer deaths = 41,400

Mutations: HER2: Frequency: 17%(15‐20%), Source: https://www.ncbi.nlm.nih.gov/pubmed/25332249 Best Overall Response Rate: 2006‐2012: 16% Trastuzumab, FDA drug label 2013‐2018: 43.6%, Ado‐Trastuzumab emtansine, from FDA drug label Drugs Approval Dates Trastuzumab 11/16/06(originally in 1998) Lapatinib 3/13/07, 1/29/10 Pertuzumab 6/8/12, 9/30/13 Ado‐Trastuzumab 2/22/13 Emtannsine

BRCA: Frequency: 2%, Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408797/pdf/83‐6691407a.pdf Best Overall Response Rate 2018: 59.9%, Olaparib, from FDA drug label Drugs Approval Dates Olaparib 1/12/18

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Melanoma: ‐Yearly Statistics from Cancer Statistics section, 2018 Melanoma deaths = 9320

Mutations: BRAF V600E and V600K: Frequency: 50%, Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600117/ Best Overall Response Rate: 2011‐2012: 48.4%, Vemurafenib, FDA drug label 2013‐2014: 57% Dabrafenib+Trametinib, FDA drug label 2015‐2018: 70%, Cobimetinib, FDA drug label Drugs Approval Dates Vemurafenib 8/17/11 Dabrafenib 5/29/13 Trametinib 5/29/13 Trametinib w/ 1/10/14, 11/20/15 Dabrafenib Cobimetinib 11/10/15

Colorectal Cancer: ‐Yearly Statistics from Cancer Statistics section, 2018 Colorectal Cancer deaths = 50,630

Mutations: KRAS Wild Type: Frequency: 57%, Source: https://www.ncbi.nlm.nih.gov/pubmed?term=18316791 Best Overall Response Rate: 2006‐2011: 10.8% Cetuximab, FDA drug Label 2012‐2018: 18%, Cetuximab, FDA drug label Drugs Approval Dates Panitumumab 9/27/06 Cetuximab 10/2/07, 7/6/12(originally approved in 2004)

Ovarian Cancer: ‐Yearly Statistics from Cancer Statistics section, 2018 Ovarian Cancer deaths = 14,070

Mutations: BRCA: Frequency: 15%, Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524247/ Best Overall Response Rate:

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2014‐2015: 34%, Olaparib, FDA drug label 2016‐2018: 54%, Rucaparib, FDA drug label Drugs Approval Dates Olaparib 12/19/14 Rucaparib 12/19/16

Gastroesophageal Cancer(including GIST): ‐Yearly Statistics from Cancer Statistics section, 2018 Gastric+Esophageal Cancer deaths = 26,650

Mutations: HER2: Frequency: 17.9%, Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870069/ Best Overall Response Rate 2010‐2018: 12%, Trastuzumab, from FDA drug label Drugs Approval Dates Trastuzumab 10/20/10

Frequency of GIST: GIST involves multiple organ systems but with over 60% gastric (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880518/pdf/nihms771882.pdf) and being overall less than 1% of all gastrointestinal malignanices(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487456/) it is a small percentage. With the low overall prevalence, the vast majority of GIST being non‐metastatic (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039646/), and 85% mutation rate for KIT (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487456/) we felt that using 1% of gastric for an overall number was a reasonable and generous estimate of the small percentage KIT mutation positive metastatic GIST that contributes to total genomic cancer therapy. Frequency: 1%(per above) Best Overall Response Rate 2006‐2018: 67.3%, Imatinib, FDA drug label from 2006 Drugs Approval Dates Imatinib 12/19/08, 1/31/12(originally approved in 2001)

Chronic Myeloid Leukemia(CML): ‐Yearly Statistics from Cancer Statistics section, 2018 CML deaths = 1090

Mutations: Ph+: Frequency: 100%, Best Overall Response Rate 2006‐2018: 95.3%, Imatinib, from FDA drug label Drugs Approval Dates Imatinib 9/27/06, 1/25/13(originally approved in 2001) Dasatinib 6/28/06, 10/28/10, 11/9/17 Nilotinib 10/29/07, 6/17/10 5

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Ponatinib 12/14/12 Bosutinib 12/19/17

Chronic Lymphocytic Leukemia(CLL): ‐Yearly Statistics from Cancer Statistics section, 2018 CML deaths = 4510

Mutations: 17p Deletion: Frequency: 7%, Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116834/ Best Overall Response Rate: 2014‐2015: 47.6%, Ibrutinib, FDA drug label 2016‐2018: 80.2%, Venetoclax, FDA drug label Drugs Approval Dates Ibrutinib 7/28/14 Venetoclax 4/11/16

Acute Myeloid Leukemia(AML): ‐Yearly Statistics from Cancer Statistics section, 2018 AML deaths = 10670

Mutations: IDH2: Frequency: 11%, Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145345/ Best Overall Response Rate 2017‐2018: 40.3%, Enasidenib Source:http://www.bloodjournal.org/content/early/2017/06/05/blood201704779405?ssochecked=true Drugs Approval Dates Enasidenib 8/1/17

Mutations: FLT3: Frequency: 10.8%, Source: http://www.bloodjournal.org/content/118/20/5366 Best Overall Response Rate 2017‐2018: 5.4%, Midostaurin, Source: http://www.nejm.org/doi/full/10.1056/NEJMoa1614359 Drugs Approval Dates Midostaurin 4/28/17

Acute Lymphocytic Leukemia(ALL): ‐Yearly Statistics from Cancer Statistics section, 2018 AML deaths = 1470

Mutations: Ph+: 6

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Frequency: 25%(20‐30%), Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091825/ Best Overall Response Rate 2006‐2018: 19%, Imatinib, from FDA Drug Label Drugs Approval Dates Imatinib 10/19/06

Microsatellite Instability High(MSI): ‐Yearly Statistics from Cancer Statistics section, 2018 MSI Deaths Breast: 41,400 Colorectal: 50630 Endometrial: 11,350 Small Cell Lung: 23,107 Thyroid Cancer: 2,060 Adrenal Cortical: 1,020 Esophageal: 15,850 Cervical: 4,170 Glioblastoma: 8,751 Renal Cell Carcinoma(RCC): 14,970 Pancreatic: 44,330 Small Intestine: 1,450 Prostate Adenocarcinoma: 29,430 Cholangiocarcinoma: 3,790 Sarcoma: 4,990

Mutation Frequency: Malignancy Frequency Source Breast 1.70% https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467167/ Colorectal 4.00% https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594190/ Endometrial 28.3% https://www‐ncbi‐nlm‐nih‐gov/pmc/articles/PMC5467167/ Small Cell Lung 2.00% https://www.ncbi.nlm.nih.gov/pubmed/28596308 Thyroid 29.7% http://clincancerres.aacrjournals.org/content/7/11/3444 Adrenal Cortical 0.054% https://www‐ncbi‐nlm‐nih‐gov/pmc/articles/PMC5467167/ Esophageal 0.033% https://www‐ncbi‐nlm‐nih‐gov/pmc/articles/PMC5467167/ Cervical 0.023% https://www‐ncbi‐nlm‐nih‐gov/pmc/articles/PMC5467167/ Glioblastoma 0.013% https://www‐ncbi‐nlm‐nih‐gov/pmc/articles/PMC5467167/ RCC 0.011% https://www‐ncbi‐nlm‐nih‐gov/pmc/articles/PMC5467167/ Pancreatic 0.011% https://www‐ncbi‐nlm‐nih‐gov/pmc/articles/PMC5467167/ Small Intestine 18.00% https://www.ncbi.nlm.nih.gov/pubmed/12627520 Prostate 0.011% https://www‐ncbi‐nlm‐nih‐gov/pmc/articles/PMC5467167/ Cholangiocarcinoma 0.05% http://cco.amegroups.com/article/view/12260/12685 Sarcoma 0.03% https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/

Best Overall Response Rate 2017‐2018: 39.6%, Pembrolizumab, from FDA drug label Drugs Approval Dates 7

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Pembrolizumab 5/23/17 Nivolumab 8/1/17

eAppendix 3. Pie Charts Estimating Patients Eligible for Genomically Targeted Therapy

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2006

Not Eligible 94.91%

Trastuzumab 1.25%

Imatinib 0.07% Imatinib, Dasatinib 0.11%

Gefitinib, Erlotinib 3.67%

2007

Not Eligible 94.92%

Trastuzumab, Lapatinib 1.28% Imatinib 0.06% Imatinib, Dasatinib 0.09%

Gefitinib, Erlotinib 3.65%

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2008

Not Eligible 94.94%

Trastuzumab, Lapatinib 1.27%

Imatinib 0.06%

Imatinib, Dasatinib 0.08% Gefitinib, Erlotinib 3.65%

2009

Not Eligible 94.96%

Trastuzumab, Lapatinib 1.26%

Imatinib, Dasatinib 0.08%

Imatinib 0.06%

Gefitinib, Erlotinib 3.63%

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2010

Not Eligible 94.31%

Trastuzumab 0.79%

Gefitinib, Erlotinib 3.52%

Trastuzumab, Lapatinib 1.24% Imatinib 0.06%

Imatinib, Dasatinib, Nilotinib 0.08%

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2011

Not Eligible 92.73% Crizotinib 1.05% Vemurafenib 0.61% Trastuzumab 0.78% Erlotinib, Gefitinib 3.50% Trastuzumab, Lapatinib 1.22% Imatinib 0.06% Imatinib, Dasatinib, Nilotinib 0.05%

2012

Not Eligible 92.59%

Crizotinib 1.06%

Vemurafenib 0.63% Trastuzumab 0.79% Erlotinib, Gefitinib 3.54% Trastuzumab, Lapatinib, Pertuzumab 1.21% Imatinib 0.06% Imatinib, Dasatinib, Nilotinib, Ponatinib 0.11%

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2013

Trametinib 0.10%

Crizotinib 1.05%

Not Eligible 92.52% Vemurafenib, Dabrafenib, Trametinib 0.65%

Trastuzumab 0.81%

Erlotinib, Gefitinib, Afatinib 3.50% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab Imatinib 1.21% 0.06% Imatinib, Dasatinib, Nilotinib, Ponatinib 0.11%

2014

Crizotinib, Ceritinib Not Eligible 1.04% 92.52% Vemurafenib, Dabrafenib, Trametinib 0.75%

Trastuzumab 0.81%

Erlotinib, Gefitinib, Afatinib 3.47% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab Imatinib 1.21% 0.06% Imatinib, Dasatinib, Nilotinib, Ponatinib 0.14% 14

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2015

Not Eligible Crizotinib, Ceritinib, 92.53% Alectinib 1.03% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.77% Trastuzumab 0.80% Erlotinib, Afatinib, Gefitinib, Osimertinib 3.42% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab 1.21% Imatinib 0.06% Imatinib, Dasatinib, Nilotinib, Ponatinib 0.19%

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2016

Crizotinib Not Eligible 0.45% 92.14% Crizotinib, Ceritinib, Alectinib 1.02% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.77% Trastuzumab 0.79% Erlotinib, Afatinib, Gefitinib, Osimertinib 3.38% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab 1.20% Imatinib, Dasatinib, Imatinib Nilotinib, Ponatinib 0.06% 0.18% 2017 Enasidenib 0.19%

Dabrafenib and Trametinib 0.44% Midostaurin 0.19% Crizotinib Not Eligible 0.44% 91.47% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.99% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.74% Trastuzumab 0.79% Erlotinib, Afatinib, Gefitinib, Osimertinib 3.31% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Imatinib, Dasatinib, Imatinib Trastuzumab Nilotinib, Ponatinib, 0.06% 1.20% Bosutinib 0.18% 16

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2018 Enasidenib 0.19%

Dabrafenib and Trametinib 0.43% Midostaurin 0.19% Not Eligible Crizotinib 91.67% 0.43%

Crizotinib, Ceritinib, Alectinib, Brigatinib 0.97% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.70% Trastuzumab 0.78% Erlotinib, Afatinib, Imatinib Gefitinib, Osimertinib Imatinib, Dasatinib,0.06% Trastuzumab,3.22% Lapatinib, Nilotinib, Ponatinib, Pertuzumab, Ado‐ Bosutinib Trastuzumab 0.18% 1.19%

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eAppendix 4. Pie Charts Estimating Patients Who Could Benefit from Genomically Targeted Therapy

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2006

Do Not Benefit 99.30%

Trastuzumab 0.20% Imatinib 0.01% Imatinib, Dasatinib 0.10% Gefitinib, Erlotinib 0.39%

2007

Do Not Benefit 99.31% Trastuzumab, Lapatinib 0.20% Imatinib 0.01% Imatinib, Dasatinib 0.08% Erlotinib 0.39%

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2008

Do Not Benefit 99.32% Trastuzumab, Lapatinib 0.20% Imatinib 0.01%

Imatinib, Dasatinib 0.08% Erlotinib 0.39%

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2009

Do Not Benefit 99.32% Trastuzumab, Lapatinib 0.20%

Imatinib 0.01% Imatinib, Dasatinib 0.08% Erlotinib 0.39%

2010

Trastuzumab Do Not Benefit 0.09% 99.25% Erlotinib 0.37%

Imatinib 0.01%

Trastuzumab, Lapatinib 0.20%

Imatinib, Dasatinib, Nilotinib 0.07%

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2011

Crizotinib 0.59% Do Not Benefit 98.40% Vemurafenib 0.29% Trastuzumab 0.09%

Erlotinib 0.37%

Trastuzumab, Lapatinib 0.20%

Imatinib 0.01%

Imatinib, Dasatinib, Nilotinib 0.04%

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2012

Crizotinib 0.60% Do Not Benefit Vemurafenib 98.32% 0.30%

Trastuzumab 0.10%

[CATEGORY NAME], Gefitinib [PERCENTAGE] Imatinib 0.01%

Trastuzumab, Lapatinib, Pertuzumab Imatinib, Dasatinib, 0.19% Nilotinib, Ponatinib 0.10%

2013

Trametinib Do Not Benefit 0.02% 95.91% Crizotinib 0.68%

Vemurafenib, Dabrafenib 0.37% Trastuzumab 0.10% Erlotinib, Gefitinib, Afatinib 2.28% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab Imatinib0.53% 0.01% Imatinib, Dasatinib, Nilotinib, Ponatinib 0.10%

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2014

Crizotinib, Ceritinib Do Not Benefit 0.68% 95.87% Vemurafenib, Dabrafenib, Trametinib 0.43%

Trastuzumab 0.10% Erlotinib, Afatinib 2.25% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Imatinib Trastuzumab 0.01% 0.53% Imatinib, Dasatinib, Nilotinib, Ponatinib 0.13%

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2015

Crizotinib, Ceritinib, Alectinib 0.67% Do Not Benefit 95.76% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.54%

Trastuzumab 0.10%

Erlotinib, Afatinib, Gefitinib, Osimertinib 2.22% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab 0.53% Imatinib 0.01%

Imatinib, Dasatinib, Nilotinib, Ponatinib 0.18%

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2016

Crizotinib 0.30% Crizotinib, Ceritinib, Alectinib Do Not Benefit 0.57% 95.59% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.54%

Trastuzumab 0.10% Erlotinib, Afatinib, Gefitinib, Osimertinib 2.20%

Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab 0.52% Imatinib, Dasatinib, Imatinib Nilotinib, Ponatinib 0.01% 0.17%

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2017

Enasidenib 0.08%

Dabrafenib and Trametinib 0.28% Midostaurin 0.14% Crizotinib Do Not Benefit 0.29% 94.97% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.78% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.52% Trastuzumab 0.10% Erlotinib, Afatinib, Gefitinib, Osimertinib 2.15% Trastuzumab, Lapatinib, Imatinib, Dasatinib, Pertuzumab, Ado‐ Nilotinib, Ponatinib, Imatinib Trastuzumab Bosutinib 0.01% 0.52% 0.17%

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Enasidenib 2018 0.08%

Dabrafenib and Trametinib 0.27%

Midostaurin Crizotinib 0.13% 0.28%

Do Not Benefit 95.10% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.76%

Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.49% Trastuzumab 0.09% Erlotinib, Afatinib, Gefitinib, Osimertinib 2.09%

Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Imatinib, Dasatinib, Trastuzumab Imatinib Nilotinib, Ponatinib, 0.52% Bosutinib 0.01% 0.17%

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eAppendix 5. Pie Charts Estimating Patients Eligible for Genomically Informed Therapy 2006

Not Eligible 89.50% Imatinib 0.04%

Trastuzumab 1.25% Imatinib 0.07%

Imatinib, Dasatinib 0.11% Panitumumab, Cetuximab 5.37%

Gefitinib, Erlotinib 3.67%

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2007

Not Eligible 89.75% Imatinib 0.04%

Trastuzumab, Lapatinib 1.28% Imatinib 0.06%

Imatinib, Dasatinib 0.09%

Panitumumab, Cetuximab 5.13%

Gefitinib, Erlotinib 3.65%

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2008

Not Eligible 90.05%

Imatinib 0.04%

Trastuzumab, Lapatinib 1.27% Imatinib 0.06%

Imatinib, Dasatinib 0.08%

Panitumumab, Cetuximab 4.86%

Gefitinib, Erlotinib 3.65%

2009

Not Eligible Imatinib 90.04% 0.04%

Trastuzumab, Lapatinib 1.26%

Imatinib 0.06%

Imatinib, Dasatinib 0.08% Panitumumab, Cetuximab 4.88% Gefitinib, Erlotinib 3.63%

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2010

Not Eligible 89.32%

Trastuzumab 0.79%

Erlotinib, Gefitinib 3.52% Imatinib 0.04% Trastuzumab, Lapatinib Imatinib 1.24% 0.06%

Imatinib, Dasatinib, Nilotinib 0.08% Panitumumab, Cetuximab 4.96%

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2011

Not Eligible Crizotinib 87.94% 1.05% Vemurafenib 0.61% Trastuzumab 0.78% Erlotinib, Gefitinib 3.50%

Imatinib 0.04%

Trastuzumab, Lapatinib 1.22% Imatinib 0.06% Imatinib, Dasatinib, Panitumumab, Cetuximab Nilotinib 4.75% 0.05% 2012

Crizotinib Not Eligible 1.06% 87.63% Vemurafenib 0.63%

Trastuzumab 0.79%

Erlotinib, Gefitinib 3.54% Imatinib 0.04% Trastuzumab, Lapatinib, Pertuzumab Imatinib 1.21% 0.06%

Imatinib, Dasatinib, Nilotinib, Ponatinib Panitumumab, Cetuximab 0.11% 4.93% 33

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2013

Trametinib 0.10% Not Eligible Crizotinib 87.67% 1.05% Vemurafenib, Dabrafenib, Trametinib 0.65% Trastuzumab 0.81%

Erlotinib, Gefitinib, Afatinib 3.50%

Imatinib 0.04% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Imatinib Trastuzumab 0.06% 1.21% Imatinib, Dasatinib, Panitumumab, Cetuximab Nilotinib, Ponatinib 4.82% 0.11%

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2014 Olaparib 0.37%

Ibrutinib 0.05%

Crizotinib, Ceritinib Not Eligible 1.04% 87.34% Vemurafenib, Dabrafenib, Trametinib 0.75%

Trastuzumab 0.81%

Erlotinib, Geftinib, Afatinib 3.47% Imatinib 0.04%

Trastuzumab, Lapatinib, Imatinib Pertuzumab, Ado‐ 0.06% Trastuzumab 1.21% Imatinib, Dasatinib, Panitumumab, Cetuximab Nilotinib, Ponatinib 4.72% 0.14%

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2015

Olaparib 0.36% Not Eligible Ibrutinib 87.44% 0.06%

Crizotinib, Ceritinib, Alectinib 1.03% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.77% Trastuzumab 0.80% Erlotinib, Afatinib, Gefitinib, Osimertinib Imatinib 3.42% 0.04% Imatinib Trastuzumab, Lapatinib, 0.06% Pertuzumab, Ado‐ Trastuzumab Imatinib, Dasatinib, 1.21% Panitumumab, CetuximabNilotinib, Ponatinib 4.64% 0.19%

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2016

Crizotinib 0.45% Not Eligible 87.15% Olaparib, Rucaparib 0.36% Ibrutinib, Venetoclax 0.05% Crizotinib, Ceritinib, Alectinib 1.02% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib Trastuzumab 0.77% 0.79% Erlotinib, Afatinib, Imatinib Gefitinib, Osimertinib 0.04% 3.38% Imatinib Trastuzumab, Lapatinib, 0.06% Pertuzumab, Ado‐ Trastuzumab 1.20% Panitumumab, Cetuximab Imatinib, Dasatinib, 4.54% Nilotinib, Ponatinib 0.18%

Enasidenib 2017 0.19% Nivolumab, Pembrolizumab 0.33% Dabrafenib and Trametinib 0.44% Not Eligible Pembrolizumab Crizotinib 84.83% 1.26% 0.44% Midostaurin 0.19% Olaparib, Rucaparib 0.35% Ibrutinib, Venetoclax 0.05% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.99% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.74% Trastuzumab 0.79% Imatinib Erlotinib, Afatinib, 0.04% Gefitinib, Osimertinib 3.31% Panitumumab, Cetuximab Imatinib, Dasatinib, 4.60% Nilotinib, Ponatinib, Trastuzumab, Lapatinib, Bosutinib Pertuzumab, Ado‐ Imatinib 0.18% Trastuzumab 0.06% 1.20%

Downloaded From: https://jamanetwork.com/ on 09/27/2021 2018 Olaparib Nivolumab, Pembrolizumab 0.14% 0.33% Enasidenib 0.19% Dabrafenib and Trametinib Not Eligible 0.43% 84.56% Pembrolizumab Crizotinib 1.23% 0.43% Midostaurin 0.19% Olaparib, Rucaparib 0.35% Ibrutinib, Venetoclax 0.05% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.97% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.70% Trastuzumab 0.78% Imatinib Erlotinib, Afatinib, Imatinib 0.04% Gefitinib, Osimertinib 0.06% 3.22% Imatinib, Dasatinib, Trastuzumab, Lapatinib, Nilotinib, Ponatinib, Pertuzumab, Ado‐ Panitumumab, Cetuximab Bosutinib Trastuzumab 4.98% 0.18% 1.19%

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Imatinib Do Not Benefit 0.03% 98.69% Trastuzumab 0.20%

Imatinib 0.01% Imatinib, Dasatinib 0.10% Cetuximab 0.58%

Gefitinib, Erlotinib 0.39%

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2007

Imatinib 0.03%

Trastuzumab, Lapatinib Do Not Benefit 0.20% 98.73% Imatinib 0.01% Imatinib, Dasatinib 0.08% Panitumumab, Cetuximab 0.55%

Gefitinib, Erlotinib 0.39%

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2008

Do Not Benefit 98.77% Imatinib 0.03%

Trastuzumab, Lapatinib 0.20% Imatinib 0.01% Imatinib, Dasatinib 0.08% Panitumumab, Cetuximab 0.52% Gefitinib, Erlotinib 0.39%

2009

Imatinib Do Not Benefit 0.03% 98.77% Imatinib 0.01%

Trastuzumab, Lapatinib 0.20% Imatinib, Dasatinib 0.08% Panitumumab, Cetuximab 0.52% Gefitinib, Erlotinib 0.39%

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2010

Erlotinib, Gefitinib 0.37%

Do Not Benefit Trastuzumab 98.69% 0.09% Imatinib 0.02% Trastuzumab, Lapatinib 0.20% Imatinib 0.01%

Imatinib, Dasatinib, Nilotinib 0.07%

Panitumumab, Cetuximab 0.54%

2011

Crizotinib 0.59%

Vemurafenib 0.29% Do Not Benefit 97.86% Trastuzumab 0.09% Erlotinib, Gefitinib 0.37% Imatinib 0.02%

Trastuzumab, Lapatinib 0.20% Imatinib 0.01%

Imatinib, Dasatinib, Nilotinib 0.04% Panitumumab, Cetuximab 0.51%

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2012

Crizotinib Vemurafenib 0.60% 0.30%

Trastuzumab Do Not Benefit 0.10% 97.41% Erlotinib, Gefitinib 0.38%

Imatinib 0.02% Trastuzumab, Lapatinib, Pertuzumab 0.19%

Imatinib 0.01%

Imatinib, Dasatinib, Panitumumab, Cetuximab Nilotinib, Ponatinib 0.89% 0.10%

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2013 Trametinib 0.02% Crizotinib 0.68%

Vemurafenib, Dabrafenib 0.37% Trastuzumab Do Not Benefit 0.10% 95.02%

Erlotinib, Geftinib, Afatinib 2.28%

Imatinib 0.03% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab 0.53%

Imatinib, Dasatinib, Nilotinib, Ponatinib 0.10% Imatinib Panitumumab, Cetuximab 0.01% 0.87%

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2014

Ibruintib Olaparib 0.03% 0.12% Do Not Benefit Crizotinib, Ceritinib 94.85% 0.68% Vemurafenib, Dabrafenib, Trametinib 0.43% Trastuzumab 0.10% Erlotinib, Geftinib, Afatinib 2.25% Imatinib 0.03% Trastuzumab, Lapatinib, Imatinib Pertuzumab, Ado‐ 0.01% Trastuzumab 0.53% Imatinib, Dasatinib, Panitumumab, Cetuximab Nilotinib, Ponatinib 0.85% 0.13%

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Ibrutinib 0.03% 2015 Olaparib 0.12%

Crizotinib, Ceritinib, Alectinib 0.67%

Vemurafenib, Dabrafenib, Do Not Benefit Trametinib, Cobimetinib 94.75% 0.54% Trastuzumab 0.10%

Erlotinib, Afatinib, Gefitinib, Osimertinib 2.22%

Imatinib 0.02% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Trastuzumab 0.53% Imatinib 0.01% Imatinib, Dasatinib, Panitumumab, Cetuximab Nilotinib, Ponatinib 0.83% 0.18%

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Olaparib, rucaparib 2016 0.19% Ibrutinib 0.04% Crizotinib 0.30% Crizotinib, Ceritinib, Alectinib 0.66% Do Not Benefit Vemurafenib, Dabrafenib, 94.42% Trametinib, Cobimetinib 0.54% Trastuzumab 0.10% Erlotinib, Afatinib, Gefitinib, Osimertinib 2.20% Imatinib 0.02% Trastuzumab, Lapatinib, Pertuzumab, Ado‐ Imatinib Trastuzumab 0.01% 0.52% Imatinib, Dasatinib, Panitumumab, Cetuximab Nilotinib, Ponatinib 0.82% 0.17%

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Enasidenib 2017 0.08% Nivolumab, Pembrolizumab 0.13% Dabrafenib and Trametinib 0.28% Midostaurin Pembrolizumab 0.01% 0.50% Crizotinib 0.29% Do Not Benefit Olaparib, rucaparib 93.38% 0.19% Ibrutinib, Venetoclax 0.04% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.78% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.52% Trastuzumab 0.10% Erlotinib, Afatinib, Gefitinib, Osimertinib Imatinib 2.15% Imatinib 0.02% 0.01% Trastuzumab, Lapatinib, Imatinib, Dasatinib, Panitumumab, Cetuximab Pertuzumab, Ado‐ Nilotinib, Ponatinib, 0.83% Trastuzumab Bosutinib 0.52% 0.17%

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Enasidenib 2018 0.08% Olaparib 0.07% Nivolumab, Pembrolizumab 0.13% Dabrafenib and Trametinib 0.27% Do Not Benefit Pembrolizumab Crizotinib 93.38% 0.49% 0.28% Midostaurin 0.01% Olaparib, rucaparib 0.19% Ibrutinib, Venetoclax 0.04% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.76% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib 0.49% Trastuzumab 0.09% Erlotinib, Afatinib, Gefitinib, Osimertinib Imatinib Imatinib 2.09% 0.01% 0.02% Imatinib, Dasatinib, Trastuzumab, Lapatinib, Nilotinib, Ponatinib, Pertuzumab, Ado‐ Panitumumab, Cetuximab Bosutinib Trastuzumab 0.90% 0.52% 0.17%

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eAppendix 7. Pie Charts Estimating Patients Eligible for and who could Benefit from Adjuvant and Consolidative Therapy in 2018 2018 Adjuvant Therapy Eligible

Not Eligible 96.97% GIST 0.18% Breast 2.29%

CML 0.42% AML 0.07%

ALL 0.06%

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2018 Adjuvant Therapy Benefit

Do Not Benefit GIST 99.31% 0.03% Breast 0.19% CML 0.40%

AML 0.05% ALL 0.01%

eFigure 1. Percent of US Metastatic Cancer Patients Who May Be Eligible for and Benefit from Genomically Informed Treatment Nivolumab, Genomically Informed Eligible in 2018 Pembrolizumab Enasidenib Dabrafenib0.33% and 0.19% Trametinib Olaparib 0.43% Not Eligible 0.14% Pembrolizumab [84.56%] 1.23% Midostaurin 0.19% Crizotinib 0.43% Olaparib, Rucaparib 0.35% Ibrutinib, Venetoclax 0.05% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.97% Vemurafenib, Dabrafenib, Trametinib, Cobimetinib Trastuzumab 0.70% 0.78% Erlotinib, Afatinib, Imatinib Gefitinib, Osimertinib 0.04% 3.22% Imatinib, Dasatinib, Trastuzumab, Lapatinib, Total Eligible: 15.44% Nilotinib, Ponatinib, Imatinib Pertuzumab, Ado‐ 0.06% Panitumumab, Cetuximab Bosutinib Trastuzumab 4.98% 0.18% 1.19% 51

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Genomically Informed Benefit in 2018 Enasidenib 0.08%Nivolumab, Olaparib Pembrolizumab 0.07% Dabrafenib0.13% and Trametinib 0.27% Midostaurin Pembrolizumab Do Not Benefit 0.01% 0.49% [93.38%] Crizotinib 0.28% Olaparib, rucaparib 0.19% Ibrutinib, Venetoclax 0.04% Crizotinib, Ceritinib, Alectinib, Brigatinib 0.76% Trastuzumab Vemurafenib, Dabrafenib, 0.09% Trametinib, Cobimetinib 0.49% Erlotinib, Afatinib, Imatinib Imatinib Gefitinib, Osimertinib 0.01% 0.02% Imatinib, Dasatinib, Trastuzumab, Lapatinib,2.09% Nilotinib, Ponatinib, Pertuzumab, Ado‐ Total Benefit: Panitumumab, Cetuximab Bosutinib Trastuzumab 0.90% 0.17% 0.52%

eFigure 2. Growth of genome targeted and informed therapy over time with fitted linear regression.

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Genome Therapy Over time 20

18 y = 0.428x ‐ 849.17 R² = 0.855 16

14 TREATABLE

12 y = 0.324x ‐ 645.11 10

PATIENTS R² = 0.8845

OF y = 0.5406x ‐ 1084.2 8 R² = 0.9014 6 y = 0.4482x ‐ 899.21 4 R² = 0.8836 PERCENTAGE 2

0 2004 2006 2008 2010 2012 2014 2016 2018 2020 YEAR OF FDA APPROVAL

Genome Informed Eligible Patients Genome Informed Benefit Patients Genome Targeted Eligible Patients Genome Targeted Benefit Patients Linear (Genome Informed Eligible Patients) Linear (Genome Informed Benefit Patients) Linear (Genome Targeted Eligible Patients) Linear (Genome Targeted Benefit Patients)

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