2024
EP.07C.10 Real-World Outcomes of Patients Treated with Neoadjuvant Immunotherapy for Resectable Non-Small Cell Lung Cancer
Ermer T, Kim S, Goldberg S, Zolfaghari E, Blasberg J, Boffa D, Herbst R, Politi K, Schalper K, Dacic S, Woodard G. EP.07C.10 Real-World Outcomes of Patients Treated with Neoadjuvant Immunotherapy for Resectable Non-Small Cell Lung Cancer. Journal Of Thoracic Oncology 2024, 19: s543-s544. DOI: 10.1016/j.jtho.2024.09.1007.Peer-Reviewed Original Research1309P A genomic scar based signature (HRDsig) and biallelic BRCA alterations identify a homologous recombination deficiency (HRD) phenotype of non-small cell lung cancer (NSCLC) potentially actionable to the PARP inhibitor rucaparib: Post-hoc analysis of lung-MAP substudy S1900A
Riess J, Miao J, Wheatley-Price P, Reckamp K, Kozono D, Redman M, Edelman M, Faller B, Villaruz L, Corum L, Gowda A, Srkalovic G, Osarogiagbon R, Baumgart M, Gandara D, Sokol E, Borghaei H, Gray J, Herbst R, Kelly K. 1309P A genomic scar based signature (HRDsig) and biallelic BRCA alterations identify a homologous recombination deficiency (HRD) phenotype of non-small cell lung cancer (NSCLC) potentially actionable to the PARP inhibitor rucaparib: Post-hoc analysis of lung-MAP substudy S1900A. Annals Of Oncology 2024, 35: s832-s833. DOI: 10.1016/j.annonc.2024.08.1366.Peer-Reviewed Original ResearchChitinase 3-like-1 (CHI3L1) in the pathogenesis of epidermal growth factor receptor mutant non-small cell lung cancer
Kamle S, Ma B, Schor G, Bailey M, Pham B, Cho I, Khan H, Azzoli C, Hofstetter M, Sadanaga T, Herbst R, Politi K, Lee C, Elias J. Chitinase 3-like-1 (CHI3L1) in the pathogenesis of epidermal growth factor receptor mutant non-small cell lung cancer. Translational Oncology 2024, 49: 102108. PMID: 39178575, PMCID: PMC11388375, DOI: 10.1016/j.tranon.2024.102108.Peer-Reviewed Original ResearchNon-small cell lung cancerEpidermal growth factor receptorTyrosine kinase inhibitorsEpidermal growth factor receptor mutant non-small cell lung cancerMutant non-small cell lung cancerEpidermal growth factor receptor axisCell lung cancerLung cancerTherapeutic resistanceDownstream targets of EGFRResistance to TKI therapyEpithelial cellsStimulated epidermal growth factor receptorWild type epidermal growth factor receptorTargeting of epidermal growth factor receptorActivating EGFR mutationsChitinase 3-like 1Progression free survivalInduce tumor cell deathEpidermal growth factor receptor activationEffects of EGFR activationInhibited pulmonary metastasisTumor cell deathResponse to treatmentGrowth factor receptorQuantitative Measurement of HER2 Expression in Non–Small Cell Lung Cancer With a High-Sensitivity Assay
Liu M, Vathiotis I, Robbins C, Chan N, Moutafi M, Burela S, Xirou V, Schalper K, Herbst R, Syrigos K, Rimm D. Quantitative Measurement of HER2 Expression in Non–Small Cell Lung Cancer With a High-Sensitivity Assay. Modern Pathology 2024, 37: 100556. PMID: 38964502, PMCID: PMC11416319, DOI: 10.1016/j.modpat.2024.100556.Peer-Reviewed Original ResearchNon-small cell lung cancerCases of non-small cell lung cancerNon-small cell lung cancer casesT-DXdCell lung cancerHER2 expressionBreast cancerRare case of non-small cell lung cancerQuantitative immunofluorescenceAntibody-drug conjugate trastuzumab deruxtecanLung cancerHER2 antibody-drug conjugatesNon-small cell lung cancer patientsDetecting HER2 expressionHER2-targeted therapyMetastatic breast cancerHER2 protein expressionBreast cancer casesHER2 protein levelsAntibody-drug conjugatesProportion of casesTrastuzumab deruxtecanNSCLC casesFrequency of casesImmunohistochemistry scoreSWOG S2302, PRAGMATICA-LUNG: A prospective randomized study of ramucirumab plus pembrolizumab (PR) versus standard of care (SOC) for participants previously treated with immunotherapy for stage IV or recurrent non-small cell lung cancer.
Reckamp K, Redman M, Dragnev K, Iams W, Henick B, Miao J, LeBlanc M, Carrizosa D, Herbst R, Blanke C, Gray J. SWOG S2302, PRAGMATICA-LUNG: A prospective randomized study of ramucirumab plus pembrolizumab (PR) versus standard of care (SOC) for participants previously treated with immunotherapy for stage IV or recurrent non-small cell lung cancer. Journal Of Clinical Oncology 2024, 42: tps8657-tps8657. DOI: 10.1200/jco.2024.42.16_suppl.tps8657.Peer-Reviewed Original ResearchNon-small cell lung cancerAdvanced non-small cell lung cancerStandard of careCell lung cancerPD-(L)1Overall survivalAdverse eventsRecurrent non-small cell lung cancerLung cancerTreatment-related adverse eventsRandomized phase II trialStandard of care treatmentPlatinum-based therapyTreated with immunotherapyPhase II trialLog-rank testCompare OSInhibitor therapyII trialCombination therapyStatistically significant improvementTumor resistanceSafety profileTherapeutic optionsRandomized studyLung-MAP S1800D: A phase II/III study of N-803 (ALT-803) plus pembrolizumab versus standard of care in participants with stage IV or recurrent non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy.
Wrangle J, Redman M, Husain H, Reckamp K, Stinchcombe T, Edelman M, Leal T, Faller B, Minichiello K, Borghaei H, Kelly K, Herbst R, Gray J. Lung-MAP S1800D: A phase II/III study of N-803 (ALT-803) plus pembrolizumab versus standard of care in participants with stage IV or recurrent non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy. Journal Of Clinical Oncology 2024, 42: 2619-2619. DOI: 10.1200/jco.2024.42.16_suppl.2619.Peer-Reviewed Original ResearchNon-small cell lung cancerAdvanced non-small cell lung cancerProgression-free survivalPhase II/III studiesN-803Overall survivalIL-15Resistance cohortRecurrent non-small cell lung cancerTreated advanced non-small cell lung cancerLung cancerTreated with anti-PD-1Anti-PD-L1 therapyIL-15 receptor alphaAnti-PD-1Anti-PD-L1Performance of immunotherapiesAnti-PD-(L)1Cell lung cancerCancer related deathGamma-chain familyClinical unmet needStandard of careALT-803Secondary endpointsSummary of Research: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC
Tsuboi M, Herbst R, John T, Kato T, Majem M, Grohé C, Wang J, Goldman J, Lu S, de Marinis F, Shepherd F, Lee K, Le N, Dechaphunkul A, Kowalski D, Bonanno L, Dómine M, Poole L, Bolanos A, Rukazenkov Y, Wu Y. Summary of Research: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. Targeted Oncology 2024, 19: 131-134. PMID: 38466534, PMCID: PMC10963460, DOI: 10.1007/s11523-024-01034-3.Peer-Reviewed Original ResearchNon-small cell lung cancerEGFR-mutant non-small cell lung cancerResected EGFR-mutant non-small cell lung cancerEpidermal growth factor receptorOverall survivalEGFR-mutantStage IB-IIIA non-small cell lung cancerPatients treated with osimertinibDisease-free survivalStage II-IIIAEffects of osimertinibCell lung cancerGrowth factor receptorCancer cell deathRisk of deathADAURA studyLength of time patientsOsimertinib groupTumor shrinkagePlacebo groupCancer-freeOsimertinibLung cancerFactor receptorCancer cells
2023
Effect of a Personalized Tobacco Treatment Intervention on Smoking Abstinence in Individuals Eligible for Lung Cancer Screening
Cartmel B, Fucito L, Bold K, Neveu S, Li F, Rojewski A, Gueorguieva R, O'Malley S, Herbst R, Toll B. Effect of a Personalized Tobacco Treatment Intervention on Smoking Abstinence in Individuals Eligible for Lung Cancer Screening. Journal Of Thoracic Oncology 2023, 19: 643-649. PMID: 37977486, PMCID: PMC10999350, DOI: 10.1016/j.jtho.2023.11.012.Peer-Reviewed Original ResearchStandard of careLung cancer screeningCancer screeningQuit ratesGain-framed messagingPack-year smoking historySmoking cessation ratesSmoking quit ratesNumber of cigarettesTobacco treatment interventionsYears of ageCessation/reductionChi-square testSelf-reported numberSmoking historyStandard careCessation ratesRandomized trialsTobacco treatmentTobacco cessationBiomarker feedbackLung cancerSmoking abstinencePost randomizationSmoking behaviorUnderstanding health-related quality of life measures used in early-stage non-small cell lung cancer clinical trials: A review
Majem M, Basch E, Cella D, Garon E, Herbst R, Leighl N. Understanding health-related quality of life measures used in early-stage non-small cell lung cancer clinical trials: A review. Lung Cancer 2023, 187: 107419. PMID: 38070301, DOI: 10.1016/j.lungcan.2023.107419.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerEarly-stage diseaseHealth-related qualityClinical trialsEarly-stage non-small cell lung cancerTreatment-related adverse effectsAppropriate HRQoL instrumentNSCLC clinical trialsCell lung cancerLong-term treatmentLung cancer clinical trialsCancer clinical researchCancer clinical trialsAdjuvant treatmentAdvanced diseaseHRQOL assessmentTreatment landscapeDisease recurrenceHRQoL instrumentsLung cancerDisease progressionLife measuresHRQoLNarrative reviewHealthcare professionals606 IMpower110: Tertiary lymphoid structures (TLS) and clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with first-line atezolizumab or chemotherapy
Srivastava M, Gayevskiy V, Ma V, Estay I, Rodas M, Rajendran B, Hoang T, Ballinger M, Amin R, Herbst R, Marinis F, Giaccone G, Jassem J, Spigel D, Schalper K, Koeppen H, Shames D, Johnston R, Giltnane J, Nabet B. 606 IMpower110: Tertiary lymphoid structures (TLS) and clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with first-line atezolizumab or chemotherapy. 2023, a690-a690. DOI: 10.1136/jitc-2023-sitc2023.0606.Peer-Reviewed Original Research1103 Spatial mapping and clinical significance of the CD39/CD73 adenosinergic pathway as a candidate immunotherapy target in non-small cell lung cancer
Ashley K, Iyer K, Kumar R, Cooper Z, Herbst R, Goldberg S, Schalper K. 1103 Spatial mapping and clinical significance of the CD39/CD73 adenosinergic pathway as a candidate immunotherapy target in non-small cell lung cancer. 2023, a1214-a1214. DOI: 10.1136/jitc-2023-sitc2023.1103.Peer-Reviewed Original ResearchSAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
Borghaei H, de Marinis F, Dumoulin D, Reynolds C, Theelen W, Percent I, Calderon V, Johnson M, Madroszyk-Flandin A, Garon E, He K, Planchard D, Reck M, Popat S, Herbst R, Leal T, Shazer R, Yan X, Harrigan R, Peters S, Investigators S, Abdel-Karim I, Abdelsalam M, Addeo A, Aguado C, Alexander P, Alt J, Azzi G, Balaraman R, Biesma B, Blackhall F, Bohnet S, Boleti E, Borghaei H, Bradbury P, Brighenti M, Campbell N, Campbell T, Canon J, Cappuzzo F, Costa E, Cavanna L, Cetnar J, Chella A, Chouaid C, Christoph D, Castán J, Dakhil S, de Castro Carpeño F, de Marinis F, Delmonte A, Demedts I, Demey W, Dits J, del Pilar Diz Taín M, Gómez M, Dorius T, Dumoulin D, Duruisseaux M, Eaton K, González E, Evans D, Faehling M, Farrell N, Feinstein T, Font E, Campelo M, Garon E, López M, Germonpré P, Gersten T, Cao M, Gopaluni S, Greillier L, Grossi F, Guisier F, Gurubhagavatula S, Calderón V, Hakimian D, Hall R, Hao D, Harris R, Hashemi S, He K, Hendriks L, Huang C, Ibrahim E, Jain S, Johnson M, Jones B, Jones M, Vidal Ó, Juergens R, Kaderbhai C, Kastelijn E, Keresztes R, Kio E, Kokowski K, Konduri K, Kulkarni S, Kuon J, Kurkjian C, Labbé C, Lerner R, Lim F, Madroszyk-Flandin A, Marathe O, Martincic D, McClay E, McIntyre K, Mekhail T, Misino A, Molinier O, Morabito A, Morócz É, Müller V, Nagy T, Nguyen A, Nidhiry E, Okazaki I, Ortega-Granados A, Ostoros G, Oubre D, Owen S, Pachipala K, Park D, Patel P, Percent I, Pérol M, Peters S, Piet B, Planchard D, Polychronis A, Aix S, Pons-Tostivint E, Popat S, Pulla M, Quantin X, Quéré G, Rafique N, Ramaekers R, Reck M, Reiman A, Reinmuth N, Reynolds C, Rodríguez-Abreu D, Romano G, Roque T, Salzberg M, Sanborn R, Sandiego S, Schaefer E, Schreeder M, Seetharamu N, Seneviratne L, Shah P, Shunyakov L, Slater D, Parra H, Stigt J, Stilwill J, Su J, Surmont V, Swink A, Szalai Z, Talbot T, Garcia A, Theelen W, Thompson J, Tiseo M, Uprety D, Uyeki J, van der Leest K, Van Ho A, van Putten J, Estévez S, Veatch A, Vergnenègre A, Ward P, Weise A, Weiss M, Whitehurst M, Zai S, Zalcman G, Zuniga R. SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Annals Of Oncology 2023, 35: 66-76. PMID: 37866811, DOI: 10.1016/j.annonc.2023.10.004.Peer-Reviewed Original ResearchClinical benefit rateObjective response rateProgression-free survivalCell lung cancerOverall survivalNonsquamous NSCLCPrimary endpointLung cancerMedian progression-free survivalTreatment-related adverse eventsReceptor tyrosine kinase inhibitorsAdvanced nonsquamous NSCLCCheckpoint inhibitor therapyMedian overall survivalPlatinum-based chemotherapyDuration of responseImmunosuppressive tumor microenvironmentTyrosine kinase inhibitorsImmunostimulatory stateMedian DoRSecondary endpointsMost patientsAdverse eventsInhibitor therapySafety profileLBA63 SAPPHIRE: Phase III study of sitravatinib plus nivolumab versus docetaxel in patients with previously treated advanced non-squamous non-small cell lung cancer (NSCLC)
Borghaei H, Johnson M, Garon E, He K, Planchard D, Reck M, Popat S, Herbst R, Leal T, Dumoulin D, de Marinis F, Reynolds C, Theelen W, Percent I, Calderon V, Flandin A, Shazer R, Yan X, Harrigan R, Peters S. LBA63 SAPPHIRE: Phase III study of sitravatinib plus nivolumab versus docetaxel in patients with previously treated advanced non-squamous non-small cell lung cancer (NSCLC). Annals Of Oncology 2023, 34: s1308. DOI: 10.1016/j.annonc.2023.10.064.Peer-Reviewed Original ResearchBiomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results
Gutierrez M, Lam W, Hellmann M, Gubens M, Aggarwal C, Tan D, Felip E, Chiu J, Lee J, Yang J, Garon E, Finocchiaro G, Ahn M, Luft A, Landers G, Basso A, Ma H, Kobie J, Palcza J, Cristescu R, Fong L, Snyder A, Yuan J, Herbst R. Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results. Nature Medicine 2023, 29: 1718-1727. PMID: 37429923, DOI: 10.1038/s41591-023-02385-6.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerObjective response rateAdvanced non-small cell lung cancerCell lung cancerSafety profileCombination therapyLung cancerInvestigator-assessed objective response rateRandomized phase 2 studySolid Tumors version 1.1T-cell-inflamed gene expression profileGroup IIIBiomarker-defined subgroupsFirst-line pembrolizumabPhase 2 studyProgression-free survivalResponse Evaluation CriteriaSubset of patientsHeterogenous tumor microenvironmentData cutoffOverall survivalSecondary outcomesPrimary outcomeTreatment armsTMB assessmentECOG-ACRIN LUNG-MAP S1900E substudy: A phase II study of sotorasib in participants (Pts) with previously treated stage IV or recurrent KRAS G12C mutant non-squamous (Non-sq) non-small cell lung cancer (NSCLC).
Padda S, Redman M, Gerber D, Stinchcombe T, Waqar S, Leal T, Minichiello K, Reckamp K, Herbst R, Borghaei H, Brahmer J, Gray J, Kelly K, Ramalingam S, Neal J. ECOG-ACRIN LUNG-MAP S1900E substudy: A phase II study of sotorasib in participants (Pts) with previously treated stage IV or recurrent KRAS G12C mutant non-squamous (Non-sq) non-small cell lung cancer (NSCLC). Journal Of Clinical Oncology 2023, 41: tps9143-tps9143. DOI: 10.1200/jco.2023.41.16_suppl.tps9143.Peer-Reviewed Original ResearchNon-squamous non-small cell lung cancerTarget sample sizeKRAS G12C inhibitorsCohort 1Eligible ptsBrain metastasesG12C inhibitorsPhase 2 open-label studyNon-small cell lung cancerAsymptomatic brain metastasesOpen-label studyPhase II studyUntreated brain metastasesCell lung cancerDuration of responsePresence of TP53Wild-type TP53Oral dailySecondary endpointsII studySystemic treatmentAccrual targetLung cancerCohort 2Clinical activityRandomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer
Johnson D, Fehrenbacher L, Novotny W, Herbst R, Nemunaitis J, Jablons D, Langer C, DeVore R, Gaudreault J, Damico L, Holmgren E, Kabbinavar F. Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. Journal Of Clinical Oncology 2023, 41: 2305-2312. PMID: 37126944, DOI: 10.1200/jco.22.02543.Peer-Reviewed Original ResearchCell lung cancerSingle-agent bevacizumabLung cancerMajor hemoptysisCell histologyControl armResponse ratePrimary efficacy end pointNonsquamous cell histologyProminent adverse eventSafety of bevacizumabEfficacy end pointDistinct clinical patternsPhase II trialSquamous cell histologyLonger median timeHigh response rateMajor blood vesselsPreviously UntreatedStable diseaseII trialAdverse eventsControl patientsClinical patternMedian timeNovel Approaches for Dynamic Visualization of Adverse Event Data in Oncology Clinical Trials: A Case Study Using Immunotherapy Trial S1400-I (SWOG)
Lee S, Fan W, Wang A, Vaidya R, Redman M, Gettinger S, Bazhenova L, Herbst R, Hershman D, Unger J. Novel Approaches for Dynamic Visualization of Adverse Event Data in Oncology Clinical Trials: A Case Study Using Immunotherapy Trial S1400-I (SWOG). JCO Clinical Cancer Informatics 2023, 7: e2200165. PMID: 37084329, PMCID: PMC10281446, DOI: 10.1200/cci.22.00165.Peer-Reviewed Original ResearchConceptsSystem organ classAdverse event dataRandomized phase III trialPhase III trialsCell lung cancerOncology clinical trialsOverall toxicity profileIII trialsNeurologic toxicityTreatment armsCardiac toxicityLung cancerClinical trialsGrade 3High prevalenceOrgan classToxicity profileNivolumabTreatment groupsStage IVEndocrine toxicityType of AEToxicity typesAE termsIpilimumabGenomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer
Ravi A, Hellmann M, Arniella M, Holton M, Freeman S, Naranbhai V, Stewart C, Leshchiner I, Kim J, Akiyama Y, Griffin A, Vokes N, Sakhi M, Kamesan V, Rizvi H, Ricciuti B, Forde P, Anagnostou V, Riess J, Gibbons D, Pennell N, Velcheti V, Digumarthy S, Mino-Kenudson M, Califano A, Heymach J, Herbst R, Brahmer J, Schalper K, Velculescu V, Henick B, Rizvi N, Jänne P, Awad M, Chow A, Greenbaum B, Luksza M, Shaw A, Wolchok J, Hacohen N, Getz G, Gainor J. Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer. Nature Genetics 2023, 55: 807-819. PMID: 37024582, PMCID: PMC10181943, DOI: 10.1038/s41588-023-01355-5.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerAdvanced non-small cell lung cancerCell lung cancerLung cancerAnti-PD-1/PD-L1 agentsCheckpoint blockade responsePD-L1 agentsTumor intrinsic subtypesCheckpoint inhibitorsCheckpoint blockadeTreatment landscapeImmunotherapy outcomesBlockade responseCohortBiological determinantsGenomic subgroupsEnhanced responseMolecular featuresWhole exomeCancerProminent associationOutcomesAssociationResponseNumber of associationsOA01.09 Adjuvant Osimertinib in Resected EGFR-Mutated Stage IB–IIIA Non-Small Cell Lung Cancer: Updated ADAURA Results
Herbst R, Wu Y, Grohe C, John T, Majem M, Wang J, Kato T, Goldman J, Kim S, Yu C, Vu H, Mukhametshina G, Akewanlop C, de Marinis F, Shepherd F, Urban D, Stachowiak M, Bolanos A, Huang X, Tsuboi M. OA01.09 Adjuvant Osimertinib in Resected EGFR-Mutated Stage IB–IIIA Non-Small Cell Lung Cancer: Updated ADAURA Results. Journal Of Thoracic Oncology 2023, 18: e4. DOI: 10.1016/j.jtho.2022.09.125.Peer-Reviewed Original ResearchAdjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non–Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial
Herbst R, Wu Y, John T, Grohe C, Majem M, Wang J, Kato T, Goldman J, Laktionov K, Kim S, Yu C, Vu H, Lu S, Lee K, Mukhametshina G, Akewanlop C, de Marinis F, Bonanno L, Domine M, Shepherd F, Urban D, Huang X, Bolanos A, Stachowiak M, Tsuboi M. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non–Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. Journal Of Clinical Oncology 2023, 41: 1830-1840. PMID: 36720083, PMCID: PMC10082285, DOI: 10.1200/jco.22.02186.Peer-Reviewed Original ResearchConceptsII-IIIA diseaseStage IB-IIIAAdjuvant osimertinibDFS HRDFS ratesDistant recurrenceEnd pointSafety profileLung cancerSignificant disease-free survival benefitPrimary analysisDisease-free survival benefitLong-term safety profileSmall cell lung cancerStratified log-rank testExploratory end pointsPrimary end pointSecondary end pointsConsistent safety profilePatterns of recurrenceCell lung cancerComplete tumor resectionLog-rank testADAURA trialData cutoff