DOI: 10.1200/JCO.2017.77.0412 Journal of Clinical Oncology - published online before print March 23, 2018
Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non–Small-Cell Lung Cancer: Results From the CA209-003 Study
In two phase III studies, nivolumab, a programmed death-1 (PD-1) inhibitor antibody, improved overall survival (OS) versus docetaxel in pretreated advanced non–small-cell lung cancer (NSCLC). We report 5-year follow-up results from an early phase I study of nivolumab in this patient population and describe characteristics of 5-year survivors.
Patients with pretreated, advanced NSCLC received nivolumab 1, 3, or 10 mg/kg every 2 weeks in 8-week cycles for up to 96 weeks. OS from the time of first dose was estimated by the Kaplan-Meier method.
The estimated 5-year OS rate was 16% for all treated patients (N = 129); 5-year OS rates were similar for squamous (16%) and nonsquamous (15%) NSCLC. Of 16 5-year survivors, most (88%) were known current or former smokers. Of 10 5-year survivors with quantifiable PD-1 ligand 1 expression, 70% had ≥ 1% PD-1 ligand 1 expression at baseline. Twelve 5-year survivors (75%) achieved a partial response to nivolumab per Response Evaluation Criteria in Solid Tumors, version 1.0, and two each (12%) had stable disease and progressive disease as best response. Nine 5-year survivors (56%) completed the maximum 96 weeks of nivolumab; four (25%) discontinued owing to adverse events and three (19%) owing to disease progression. As of a November 2016 database lock, 12 5-year survivors (75%) received no subsequent therapy and were without evidence of progressive disease at last follow-up.
In two randomized, controlled phase III trials in patients with previously treated advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004)1 or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867)2 non−small-cell lung cancer (NSCLC), nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, significantly prolonged overall survival (OS), had a favorable safety profile, and was associated with lower symptom burden and better quality of life compared with docetaxel.1-5 The outcomes of these two trials resulted in the approval of nivolumab for the treatment of patients with previously treated squamous or nonsquamous advanced NSCLC.6,7 With similar results from phase III studies of other PD-1/PD-1 ligand 1 (PD-L1) inhibitors,8,9 immunotherapy has become the new standard of care for this patient population. However, there is limited information about long-term efficacy and safety of such therapies in patients with NSCLC, including a lack of published data on outcomes at 5 years, a clinical landmark in oncology.
CA209-003 (ClinicalTrials.gov identifier: NCT00730639) was an early, phase I, dose-escalation cohort expansion study that evaluated nivolumab treatment in 306 patients with a variety of solid tumors. Primary results of the study, as well as 3-year follow-up data from the cohort of patients (n = 129) with previously treated advanced NSCLC have been published.10,11 In this cohort, nivolumab was associated with an objective response rate of 17% (95% CI, 11% to 25%) with a median response duration of 17 months, and a 3-year survival rate of 18% (95% CI, 11% to 25%) across various doses.11 In addition, nivolumab was generally well tolerated, with mostly low-grade treatment-related adverse events including those of potential immunologic cause.11 Here, we report updated results from CA209-003 based on a minimum follow-up of 58.25 months, and describe the characteristics and treatment outcomes of long-term survivors.
Patient eligibility criteria have been previously described.11 Briefly, eligible patients were adults with pathologically confirmed advanced NSCLC who had received one to five prior systemic anticancer regimens, with progression after at least one platinum- or taxane-based regimen, and had at least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0.12 Patients with EGFR or ALK mutations were eligible. Patients with treated brain or meningeal metastases were eligible if they were without magnetic resonance imaging evidence of progression for at least 8 weeks before first study-drug administration. Patients with autoimmune disease, a condition requiring immunosuppressive medications, a history of HIV infection, or active hepatitis B or C infections were excluded.
CA209-003, a multicenter, phase I, dose-escalation cohort expansion trial in the United States, evaluated the safety and clinical activity of nivolumab in patients with advanced NSCLC, melanoma, or kidney, colorectal, or castration-resistant prostate cancer.10 Patients received a 1-hour intravenous infusion of nivolumab at a dose of 1, 3, or 10 mg/kg every 2 weeks in 8-week treatment cycles. During cohort expansion, patients with NSCLC were stratified by tumor histology (squamous or nonsquamous) and assigned to each dose. Treatment continued up to 96 weeks (12 cycles) or until unacceptable toxicity, confirmed complete response, confirmed progressive disease, or withdrawal of consent. Treatment beyond initial disease progression was permitted in the absence of clinical deterioration, to allow for patterns of response consistent with immune-related response criteria.13 Per protocol, patients were followed for survival approximately every 3 months by office visits or telephone calls. Post-study data other than OS were collected by the investigators independent of the sponsor, as allowed by each institution.
The study protocol was approved by local institutional review boards, and the study was conducted in accordance with international standards of good clinical practice. All patients or their legal representatives provided written informed consent before enrollment.
Radiographic tumor assessments were performed at screening and after each 8-week treatment cycle. After the last dose, patients who completed the 96-week treatment period or discontinued without disease progression continued to be assessed every 8 weeks for up to 1 year as long as they did not relapse or start a new therapy. Response was assessed per RECIST, version 1.0. OS from the time of the first dose of nivolumab was estimated using the Kaplan-Meier method. These analyses were post hoc and not powered for statistical comparison of OS rates across subgroups. Effect of PD-L1 expression on nivolumab activity was an exploratory end point. PD-L1 expression in archived pretreatment tumor samples was assessed using the 28-8 antibody.1,2
In the subgroup of patients who survived ≥ 5 years, information about patients’ clinical status after the protocol-specified follow-up period, including response and progression status and subsequent treatment received, was provided by the investigator.
Safety data were collected for all treated patients every 2 weeks during therapy and for ≤ 70 days after the last dose of nivolumab. The Medical Dictionary for Regulatory Activities (version 15.1; https://www.meddra.org/) was used to code adverse events, and the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) was used to grade the severity of adverse events.14 A sponsor-derived prespecified list of Medical Dictionary for Regulatory Activities terms in seven categories was used to identify select adverse events, which were defined as adverse events of potential immunologic etiology that require frequent monitoring or intervention with immune suppression or hormone replacement therapy.15
Baseline characteristics of the 129 patients with NSCLC treated with nivolumab have been described previously.11 Median age was 65 years, 61.2% of the patients were male, 19.4% had received only a single line of prior systemic therapy, and 57.4% had nonsquamous tumor histology. Of 69 patients (53.5%) with known EGFR mutation status, 13 (18.8%) were EGFR-mutation positive. Of 68 patients with quantifiable tumor PD-L1 expression, 38 (55.9%) had ≥ 1% and 13 (19.1%) had ≥ 50% PD-L1 expression.
The administered dose of nivolumab was 1 mg/kg, 3 mg/kg, and 10 mg/kg in 33 (25.6%), 37 (28.7%), and 59 (45.7%) patients, respectively. Ten patients (7.8%) completed the maximum 96 weeks of treatment per protocol. Seventy-six patients (58.9%) discontinued owing to progressive disease, 27 (20.9%) owing to adverse events, and four (3.1%) for other reasons. In addition, nine patients (7.0%) withdrew consent and three (2.3%) died during treatment.
The minimum follow-up for this analysis was 58.25 months, based on a database lock on November 15, 2016. Median OS was 9.9 months (95% CI, 7.8 to 12.4), and the estimated 5-year OS rate was 16% (Table 1; Fig 1A). OS was similar in patients with squamous and nonsquamous histology (Fig 1B). In patients who received nivolumab 1 mg/kg, 3 mg/kg, and 10 mg/kg, the 5-year OS rates were 13%, 26%, and 11%, respectively (Table 1; Fig 1C). Among patients with quantifiable PD-L1 tumor expression (n = 68), the estimated 5-year OS rate was similar for patients with < 1% versus ≥ 1% PD-L1 expression (20% v 23%) and numerically higher (43%) for those with ≥ 50% PD-L1 expression (Table 1; Fig 1D).
A total of 16 patients had an OS duration ≥ 5 years (up to 88.6 months) after starting nivolumab (Fig 2; Table 2). Of those, two died before database lock, one due to chronic obstructive pulmonary disease and one due to disease progression (Table 2).
The baseline characteristics of the 16 patients who survived ≥ 5 years were largely similar to those of all treated patients (Table 3). Fourteen of the 5-year survivors (87.5%) were known current or former smokers, and two of eight evaluable patients (25.0%) had EGFR mutations, including an exon 20 insertion mutation (patient 14 in Table 2) and an exon 18 missense mutation (G719A; patient 5 in Table 2). Of 10 patients with quantifiable PD-L1 expression, seven (70.0%) had ≥ 1% PD-L1 expression, including five patients (50.0%) with ≥ 50% PD-L1 expression, and three (30.0%) had < 1% PD-L1 expression.
The median time from diagnosis to initiation of nivolumab was 1.2 years (range, 0.4 to 6.1 years), with three of the 16 5-year survivors (18.8%) being diagnosed > 24 months before nivolumab initiation. Of the 16 patients, three (18.8%) had received one prior line of systemic therapy, three (18.8%) had received two prior lines, seven (43.8%) had received three prior lines, and three (18.8%) had received four prior lines (Fig 2). Of the two patients with EGFR mutations, one patient (patient 5) received no prior EGFR tyrosine kinase inhibitor therapy, and the other patient (patient 14) received erlotinib for approximately 3 months immediately before starting nivolumab (Table 2). Ten patients (62.5%) had received prior radiotherapy, either for palliation (n = 5; 31.3%) or as curative treatment (n = 5; 31.3%).
Four patients (25.0%) had prior lung surgery with curative intent for NSCLC (patients 1, 5, 7, and 14; Table 2). Of those, three patients had pathologic stage IIB disease at surgery, with subsequent disease-free intervals of 12 months (patient 14), 16 months (patient 7), and 24 months (patient 1). The remaining patient (patient 5) had pathologic stage IIIA disease at surgery and disease recurrence 6 months later.
Of the 16 5-year survivors, three (18.8%), seven (43.8%), and six (37.5%) received nivolumab at a dose of 1 mg/kg, 3 mg/kg, and 10 mg/kg, respectively (Table 2). Nine of the 16 5-year survivors (56.2%) completed the maximum number of nivolumab treatment cycles per protocol (in the overall population, 10 of 129 patients [7.8%] completed the maximum number of treatment cycles; Fig 2). Three 5-year survivors (18.8%) discontinued nivolumab because of disease progression, and four (25.0%) because of adverse events (Fig 2; Table 2).
Twelve 5-year survivors (75.0%) had a partial response, two (12.5%) had stable disease (SD), and two (12.5%) had progressive disease as best response during therapy (Fig 2; Table 2). Among patients who responded to nivolumab (n = 22), 12 had an OS duration ≥ 5 years. Baseline characteristics of responders who survived ≥ 5 years were generally similar to those of responders who survived < 5 years (Appendix Table A1, online only).
Rates of treatment-related select adverse events of any grade were 68.8% in 5-year survivors and 43.4% in all treated patients (Table 4). Of the four 5-year survivors who discontinued nivolumab owing to adverse events, three discontinued between 18 and 19 months after treatment initiation (owing to grade 2 arthritis, grade 2 hypersensitivity, and grade 3 hypersensitivity), and one patient discontinued approximately 8 months after starting nivolumab, because of grade 2 pneumonitis (Fig 2).
Twelve of the 5-year survivors (75%) received no further therapy after nivolumab and were without evidence of progressive disease at last follow-up before the database lock. Of the four patients who received subsequent therapy before the database lock, one had surgical resection of right lower-lobe lung nodules (and remains with no evidence of disease), another had a lung transplant followed by systemic therapies, and two received systemic therapies (Table 2).
Two of the 16 5-year survivors were treated with nivolumab beyond disease progression. One of the two patients (patient 2; Table 2) acquired new lesions after 1.8 months of nivolumab treatment, with a 45% reduction in target lesion tumor burden < 4 months after treatment initiation. The patient completed nivolumab treatment per protocol, at which point there was a 63% reduction in tumor burden. The patient received no further systemic therapy and was without recurrence until her death, which was the result of chronic obstructive pulmonary disease. The second patient (patient 14; Table 2) continued nivolumab after early disease progression, with subsequent tumor regression and stability lasting 8 months, when nivolumab was discontinued because of further disease progression.
Two of the 5-year survivors were retreated with a PD-1 inhibitor after disease progression. The first patient (patient 5) had an early response to nivolumab and received the maximum number of treatment cycles. However, the patient experienced disease progression 16 months after completing treatment. Retreatment with nivolumab (2 years after completion of the initial treatment) again resulted in a response within 3 months; however, the patient had a second progression 11 months after starting nivolumab retreatment and eventually died of the disease (Table 2). The second patient (patient 1) also had an early response to nivolumab, completed treatment per protocol, and was without evidence of disease at the November 2016 database lock, > 5 years after stopping treatment (OS, 88.5 months; Table 2). However, 5 months later, the patient had pathologically confirmed disease progression, including squamous cell carcinoma metastatic to the colon wall and a small, solitary brain metastasis. The patient joined a clinical trial with an experimental PD-1 inhibitor and, at last follow-up (2 months after initiating therapy) had achieved a response.
One 5-year survivor (patient 15) with SD as best response discontinued nivolumab after 14 months because of disease progression. The patient had isolated tumor progression that was treated with resection of right lower-lobe lung nodules. The patient received no further systemic anticancer therapy. The patient was alive and without evidence of further disease progression at database lock (Table 2).
Nivolumab is an established standard-of-care therapy for patients with previously treated advanced NSCLC. Here, we present the longest follow-up of previously treated patients with advanced NSCLC after initiation of PD-1 axis inhibitor therapy. Prior analysis of this cohort from CA209-003 demonstrated 3-year OS rates with nivolumab of 19% for squamous and 16% for nonsquamous NSCLC,11 consistent with the recently reported 3-year OS rates in the Checkmate 017 and 057 trials (16% and 18%, respectively),16 and similar to the 3-year OS rates observed with pembrolizumab (19%) and atezolizumab (19%) in patients with previously treated advanced NSCLC.17,18 With a minimum follow-up now of 58.25 months, we report an unprecedented 5-year OS rate of 16%. This number compares favorably with historic 5-year OS rates for stage IV NSCLC of 1% to 8%, depending on the extent of metastasis.19,20
Characteristics of 5-year survivors generally resembled those of the overall population, including tumor histology, Eastern Cooperative Oncology Group performance status, smoking status, and diversity of prior systemic therapies. Although five of the 10 5-year survivors with evaluable tumor tissue had ≥ 50% PD-L1 expression, three had no detectable PD-L1 expression. Overall, these findings are consistent with those from CheckMate 017 and 057, which showed a survival benefit with nivolumab across all levels of PD-L1 expression.1,2,21
As previously reported, 22 patients (17.1%) in the NSCLC cohort of CA209-003 had a response to nivolumab.11 Of those, 12 patients (54.5%) were among the 16 5-year survivors. The other four 5-year survivors had progressive disease or SD as best response; two did not receive additional systemic therapy. No clear differences in baseline characteristics were observed between the responders who did and did not achieve 5-year survival.
One of several remaining questions concerning treatment approaches involving immuno-oncology agents is the optimal treatment duration. The 5-year follow-up data from CA209-003 suggest patients may achieve long-term survival with nivolumab treatment of 2 years (per protocol for this study) or less. However, current indications for nivolumab and other approved PD-1 inhibitors require continuous dosing until unacceptable toxicity or disease progression, based on corresponding registrational studies. Recently, exploratory survival data based on a minimum follow-up of 10 months were reported from CheckMate 153 (ClinicalTrials.gov identifier: NCT02066636), a randomized study of nivolumab in patients with previously treated advanced NSCLC that compared continuous treatment with treatment of a fixed 1-year period (with the option to reinitiate treatment at the time of progression). The hazard ratios for progression-free survival and OS were 0.42 (95% CI, 0.25 to 0.71) and 0.63 (95% CI, 0.33, 1.20), respectively, in favor of continuous therapy.22 The findings from CA209-003 indicate some patients can derive long-term benefit from nivolumab treatment that is limited to 2 years; however, the question of optimal treatment duration remains to be formally addressed in a prospective controlled trial.
Another uncertainty related to immune checkpoint inhibitor therapy is the optimal management of recurrence on and off therapy. The present findings from CA209-003 suggest that rechallenge with nivolumab and/or local intervention (particularly for oligoprogressive disease) may have a positive effect on the long-term survival of patients with disease progression after initial response to nivolumab. Two 5-year survivors in our study were rechallenged with PD-1 inhibitor therapy after disease recurrence off therapy (one with nivolumab and the other with an experimental PD-1 inhibitor). Both patients achieved a second response. A 5-year survivor with RECIST progression due to the early development of new lung lesions in the setting of regressing target lesions continued nivolumab without subsequent progression of disease. Two additional 5-year survivors without RECIST response underwent resection of progressing sites of disease 15 and 24 months after starting nivolumab treatment. One of the two patients had no recurrence at the time of database lock, without having received any subsequent systemic therapy.
In conclusion, the results from this analysis of CA209-003 demonstrate that nivolumab treatment can enable long-term survival in a diverse population of patients with previously treated advanced NSCLC. Considering the historically low 5-year survival rate for patients with metastatic lung cancer, the estimated 5-year OS rate of 16% from the time of nivolumab treatment initiation observed in this cohort of heavily pretreated patients with advanced NSCLC constitutes a milestone in the advancement of lung cancer treatment.
Supported by Bristol-Myers Squibb and ONO Pharmaceutical.
Presented at American Association for Cancer Research Annual Meeting 2017, Washington, DC, April 1-5, 2017.
See accompanying Editorial on page 1647
Conception and design: Scott Gettinger, Dennis Yoon, Julie Brahmer
Provision of study materials or patients: Scott Gettinger, Leora Horn, David Jackman, David Spigel, Scott Antonia, Matthew Hellmann, John Powderly, Rebecca Heist, Lecia V. Sequist, David C. Smith, Philip Leming, Julie Brahmer
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Consulting or Advisory Role: Bristol-Myers Squibb, ARIAD, Alexion Pharmaceuticals, Pfizer
Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), ARIAD (Inst), Incyte (Inst), Pfizer (Inst)
Travel, Accommodations, Expenses: Merck
Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Xcovery, Genentech, Boehringer Ingelheim, Eli Lilly, AbbVie, AstraZeneca
Travel, Accommodations, Expenses: Boehringer Ingelheim, Bristol-Myers Squibb
Consulting or Advisory Role: Genentech, Eli Lilly, Celgene, Bayer, CVS Caremark, AstraZeneca
No relationship to disclose
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Honoraria: AstraZeneca, Bristol-Myers Squibb, Merck, Boehringer Ingelheim
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Travel, Accommodations, Expenses: Bristol-Myers Squibb, AstraZeneca, Merck, Boehringer Ingelheim
Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/MedImmune, Novartis, Janssen, Mirati Therapeutics, Shattuck Labs
Research Funding: Bristol-Myers Squibb
Employment: Carolina BioOncology Institute, BioCytics
Leadership: BioCytics, Carolina BioOncology Institute
Stock or Other Ownership: BioCytics, Lion Biotechnologies, Juno Therapeutics, Bluebird Bio, Kite Pharma, ZIOPHARM Oncology, Carolina BioOncology Institute
Consulting or Advisory Role: Bristol-Myers Squibb, Roche, AstraZeneca/MedImmune, Curis, TopAlliance BioSciences
Speakers' Bureau: Roche, Dendreon, Merck, Bristol-Myers Squibb
Research Funding: Bristol-Myers Squibb, Roche, AstraZeneca/MedImmune, EMD Serono, Eli Lilly/ImClone, Macrogenics, Incyte, Top Alliance BioScience, Seattle Genetics, AbbVie, Corvus Pharmaceuticals, Curis
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Research Funding: GlaxoSmithKline, Sanofi, AbbVie, Novartis, Roche, Incyte, Celgene, Mirati Therapeutics, Peregrine Pharmaceuticals, Exelixis, Millennium, Debiopharm Group
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Research Funding: Boehringer Ingelheim (Inst), Clovis Oncology (Inst), Genentech (Inst), Merrimack (Inst), Novartis (Inst), AstraZeneca (Inst), Johnson & Johnson (Inst), Merck (Inst), Pfizer (Inst)
Consulting or Advisory Role: Merck
Research Funding: Agensys (Inst), Atterocor (Inst), Bayer (Inst), Boston Biomedical (Inst), Exelixis (Inst), Incyte (Inst), Eli Lilly (Inst), MedImmune (Inst), Novartis (Inst), OncoMed (Inst), Seattle Genetics (Inst), Bristol-Myers Squibb/Medarex (Inst), ESSA (Inst), Genentech (Inst), Medivation/Astellas (Inst), Merck (Inst)
No relationship to disclose
Employment: Bristol-Myers Squibb
Stock or Other Ownership: Bristol-Myers Squibb
Employment: Bristol-Myers Squibb
Stock or Other Ownership: Bristol-Myers Squibb
Travel, Accommodations, Expenses: Bristol-Myers Squibb (I)
Employment: Bristol-Myers Squibb
Consulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, Celgene, Syndax, Janssen Oncology, Merck
Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Incyte (Inst), Five Prime Therapeutics (Inst), Janssen Oncology (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Merck
Other Relationship: Bristol-Myers Squibb, Merck
Julie Brahmer, MD, Drew Pardoll, MD, PhD, and Suzanne Topalian, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
John D Powderly, MD; Carolina BioOncology Institute, Huntersville, NC
Mario Sznol, MD, and Scott Gettinger, MD; Yale Cancer Center, New Haven, CT
David C Smith, MD; University of Michigan Health System Cancer Center, Ann Arbor, MI
F Stephen Hodi, MD, Leena Gandhi, MD, and David M Jackman, MD; Dana Farber Cancer Institute, Boston, MA
Rebecca S Heist, MD, MPH, and Lecia V Sequist, MD, MPH; Massachusetts General Hospital, Boston, MA
David McDermott, MD; Beth Israel Deaconess Medical Center, Boston, MA
Richard D Carvajal, MD, Mathew Hellmann, MD, and Naiyer Rizvi, MD; Memorial Sloan-Kettering Cancer Center, New York, NY
David P Carbone, MD, PhD, Leora Horn, MD, and Jeffrey Sosman, MD; Vanderbilt University Medical Center, Nashville, TN
Philip Leming, MD; Christ Hospital Cancer Center, Cincinnati, OH
David R Spigel, MD; Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN
Scott Antonia, MD, and Mary Pinder-Schenck, MD; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
David S Mendelson, MD; Oncology Research Associates d/b/a Pinnacle Oncology Hematology, Scottsdale, AZ
We thank the patients and their families. We thank Allyson Pollack for her contributions as protocol manager for this study and Dako for collaborative development of the PD-L1 IHC 28-8 pharmDx assay. Medical-writing and editorial assistance was provided by Roland Tacke of Evidence Scientific Solutions, with funding from Bristol-Myers Squibb.
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