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Lung Cancer Highlights : Best of ASTRO 2018 - Turkey

Lung Cancer Highlights : Best of ASTRO 2018 - Turkey. Banu Atalar, MD Acibadem University Maslak Hospital , Radiation Oncology Department Istanbul , Turkey. Outline 1. Practice-changing studies

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Lung Cancer Highlights : Best of ASTRO 2018 - Turkey

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  1. Lung Cancer Highlights:Best of ASTRO 2018- Turkey Banu Atalar, MD Acibadem University Maslak Hospital, RadiationOncologyDepartment Istanbul, Turkey

  2. Outline 1 • Practice-changing studies • PACIFIC survival results confirm the use of consolidation durvalumab for non-progressing favorable patients with Stage III NSCLC after concurrent chemo-RT (Raben D, abstr #LBA10) • Studies justifying future Phase III trials with survival as endpoint • Two prospective Phase IIR randomized trials of local consolidative radiotherapy after systemic treatment in patients with oligometastatic NSCLC • Phase IIR SABR COMET (Palma D, abstr #5) • Phase IIR multiinstitutionallong term follow-up (Gomez D, abstr #LBA3) • Retrospective analysis of local ablative therapy in patients with synchronous oligometastaticNSCLC harboring EGFR mutation (Xu C, abstr #189)

  3. Outline 2 • Adding to the cautionary SBRT data for ultracentral lung cancers • Toxicity and local control in “ultra-central” lung tumors treated with SBRT or high-dose hypofractionatedRT (Wang C, abstr# 18) • Long term FU SBRT results for Stage I operable patients • Nagata Y (abstr# 15) • Adding insight to cardiac toxicity of thoracic RT • Cardiac events after radiation therapy for Stage II-III NSCLC: Analysis of 748 Patients (Atkins K, abstr# 184)

  4. PACIFIC: Overall Survival with Durvalumab Versus Placebo After Chemoradiotherapy in Stage III NSCLC David Raben1, Corinne Faivre-Finn2, David R. Spigel3,  Davey Daniel4, Augusto Villegas5, David Vicente6, Rina Hui7, Javier de Castro Carpeño8, Shuji Murakami9, Luis Paz-Ares10, Mustafa Özgüroğlu11, Takayasu Kurata12, Alberto Chiappori13, Ki Hyeong Lee14, Maike de Wit15, Lynne Poole16, Catherine Wadsworth,17 Phillip A. Dennis18, Scott J. Antonia13 1University of Colorado Cancer Center, Aurora, Colorado; 2The University of Manchester and The Christie NHS Foundation Trust, Manchester, UK; 3Sarah Cannon Research Institute, Nashville, TN, USA; 4Tennessee Oncology, Chattanooga, TN, and Sarah Cannon Research Institute, Nashville, TN, USA; 5Cancer Specialists of North Florida, Jacksonville, FL, USA; 6Hospital Universitario Virgen Macarena, Seville, Spain; 7Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; 8Hospital Universitario La Paz, Madrid, Spain; 9Kanagawa Cancer Center, Yokohama, Japan; 10Hospital Universitario 12 de Octubre, CiberOnc, Universidad Complutense and CNIO, Madrid, Spain; 11Istanbul University − Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey; 12Kansai Medical University Hospital, Hirakata, Japan; 13H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 14Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea; 15Vivantes Klinikum Neukoelln, Berlin, Germany; 16AstraZeneca, Cambridge, UK; 17AstraZeneca, Alderley Park, UK; 18AstraZeneca, Gaithersburg, MD, USA

  5. Background • SoC for unresectable, Stage III NSCLC • Platinum-based CRT1 • Outcomes have been poor • 15–30% of patients alive at 5 years1,2 • PFS improvement of 11.2 months with durvalumab versus placebo3 Phase 3 PACIFIC Trial • Here, we report the second primary endpoint of OS • Plus PFS, updated secondary endpoints, and exploratory, post-hoc analyses of outcomes based on prior CRT features 1. Yoon SM, et al. World J Clin Oncol 2017;8:1–20; 2. Bradley JD, et al. Int J Radiat Oncol Biol Phys 2017;99(Suppl.):S105; 3. Antonia SJ, et al. N Engl J Med 2017;377:1919–29.

  6. PACIFIC: Study DesignPhase 3, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study1,2 • Unresectable, Stage III NSCLC without progression after definitive platinum-based cCRT (≥2 cycles) • 18 years or older • WHO PS score 0 or 1 • If available, archived pre-cCRT tumor tissue for PD-L1 testing • All-comers population (i.e. irrespective of PD-L1 status) • N=983 enrolled Durvalumab 10 mg/kg q2w forup to 12 months N=476 • Primary endpoints • PFS by BICR using RECIST v1.1 • OS 1–42 days post-cCRT N=713 randomized 2:1 randomization, stratified by age, sex, and smoking history R • Key secondary endpoints • ORR, DoR and TTDM by BICR • PFS2 by investigator • Safety • PROs Placebo q2w for up to 12 months N=237 Data cutoff (March 22, 2018) for the planned OS IA occurred after 299 events (61% of the target 491 events) OS sample size assumption: ≥85% power to detect an HR of 0.73 with 491 events, using a 2.5% 2-sided significance level 1. Antonia SJ, et al. N Engl J Med 2017;377:1919–29; 2. Antonia SJ, et al. N Engl J Med 2018; Epub Sep 25. ClinicalTrials.gov number: NCT02125461

  7. PACIFIC: Primary Endpoints (ITT)1,2 PFS (BICR) OS* 1.0 1.0 83.1% 0.9 0.9 0.8 0.8 66.3% 0.7 0.7 75.3% 55.9% 0.6 0.6 44.2% Probability of PFS 0.5 Probability of OS 0.5 55.6% 35.3% 0.4 0.4 27.0% 0.3 0.3 • PFS HR = 0.52 • 95% CI, 0.42–0.65 • P<0.001 • OS HR = 0.68 • 99.73% CI, 0.469–0.997† • P=0.0025 0.2 0.2 0.1 0.1 0.0 0.0 3 6 9 12 15 18 21 24 27 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time from randomization (months) Time from Randomization (months) No. at risk No. at Risk Durvalumab 44 21 4 1 377 301 264 159 86 476 476 464 431 415 385 364 343 319 274 210 115 57 23 2 0 0 Durvalumab 15 4 3 0 Placebo 237 163 106 87 52 28 237 220 198 178 170 155 141 130 117 78 42 21 9 3 1 0 Placebo 1. Antonia SJ, et al. N Engl J Med 2017;377:1919–29; 2. Antonia SJ, et al. N Engl J Med 2018; Epub Sep 25. *Median duration of follow-up was 25.2 months (range 0.2–43.1); †Adjusted for interim analysis; NR, not reached. Note: PFS data based on data cutoff of Feb 13, 2017, and OS data based on data cutoff of Mar 22, 2018.

  8. PFS and OS by Pre-specified Subgroup (ITT)1,2 NA* NA* NA* *Not calculated if subgroup has <20 events; NA, not available.Note: PFS data based on data cutoff of Feb 13, 2017, and OS data based on data cutoff of Mar 22, 2018 1. Antonia SJ, et al. N Engl J Med 2017;377:1919–29; 2. Antonia SJ, et al. N Engl J Med 2018; Epub Sep 25. 0.25 0.25 0.5 0.5 1.0 1.0 2.0 2.0 Durvalumab better Placebo better Placebo better Durvalumab better

  9. Updated Time to Death or Distant Metastasis (TTDM) by BICR (ITT)1 Updated Incidence of New Lesions by BICR (ITT)1 1.0 0.9 0.8 0.7 0.6 Probability of Death or Distant Metastasis 0.5 0.4 0.3 • TTDM HR = 0.53 • 95% CI, 0.41–0.68 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 *A patient may have had more than one new lesion site; †Monitoring for post-baseline CNS metastases was not specified in the protocol; brain scans were obtained at the investigator’s discretion upon suspicion of new lesions. Time from Randomization (months) No. at Risk Durvalumab 476 419 357 316 259 223 194 163 129 92 46 25 1 0 0 237 189 139 118 95 77 64 54 39 27 12 5 0 Placebo 1. Antonia SJ, et al. N Engl J Med 2018; Epub Sep 25.

  10. Updated Safety Summary1 AEs were graded according to CTCAE v4.03. Patients with multiple AEs are counted once at the maximum reported CTCAE grade. 1. Antonia SJ, et al. N Engl J Med 2018; Epub Sep 25.

  11. Impact of Prior CT and RT NA* 0.25 0.5 1 2 0.25 0.5 1 2 Durvalumab better Placebo better Durvalumab better Placebo better *Not calculated if subgroup has <20 events; NA, not availableNote: PFS data based on data cutoff of Feb 13, 2017, and OS data based on data cutoff of Mar 22, 2018 1. Antonia SJ, et al. N Engl J Med 2017;377:1919–29; 2. Antonia SJ, et al. N Engl J Med 2018; Epub Sep 25.

  12. Impact of Time from Prior RT to Randomization 0.25 0.5 1 2 0.25 0.5 1 2 Durvalumab better Placebo better Durvalumab better Placebo better *Not calculated if subgroup has <20 events; NA, not available.Note: PFS, TTDM, and ORR data based on data cutoff of Feb 13, 2017, and OS data based on data cutoff of Mar 22, 2018 1. Antonia SJ, et al. N Engl J Med 2017;377:1919–29; 2. Antonia SJ, et al. N Engl J Med 2018; Epub Sep 25.

  13. Conclusions • Durvalumab demonstrated significant and clinically meaningful improvements in PFS (HR = 0.52) and OS (HR = 0.68)1,2 • Improvements in TTDM and incidence of new lesions with durvalumab were maintained1,2 • PACIFIC is the first study to demonstrate an OS advantage for unresectable, Stage III NSCLC, supporting the PACIFIC regimen (CRT followed by durvalumab) as SoC • Subgroup analyses suggested that durvalumab improved PFS and OS regardless of type of CT or dose of RT used as prior cCRT, and regardless of time from RT to randomization • Durvalumab was well tolerated, with no new safety signals identified after longer follow-up1 1. Antonia SJ, et al. N Engl J Med 2018; Epub Sep 25; 2. Antonia SJ, et al. N Engl J Med 2017;377:1919–29.

  14. Öğrendiklerimiz… Evre 3 NSCLC tedavisindeşimdiyekadareldeedilen en uzun SK %66 @2 yıl PFS veuzakmetastasız SK 2 katınaçıkıyor, bunabeyinmetastazlarıdahil Toksisiteaynı! Başarıherşeydenbağımsız, hasta karakteristikleri, dozlar, PDL durumu

  15. Presented at: IASLC; ASTRO; ESMO PACIFIC represents a sea (or ocean?) change in therapy of Stage III NSCLC Published on-line Sept 25, 2018

  16. Post-PACIFIC: How Soon After Chemo-RT Should Durvalumab Be Started? • In PACIFIC trial, 0-6 weeks were allowed • A shorter interval may be associated with better outcome • Implications: since only those patients without progression should receive durvalumab, post-chemoRT imaging has to be ordered much sooner than the customary 6-12 weeks • One approach (Antonia SJ, personal communication): order CT/PET CT immediately after chemo-RT and start durvalumab at the 2 weeks mark

  17. PACIFIC 2 (NCT03519971) Phase III, randomized, double-blind, placebo-controlled, multicenter, global study1,2 Patients with Stage III, locally advanced, unresectable NSCLC 18 years or older ECOG PS score 0 or 1 Estimated life expectancy of ≥12 weeks At least 1 lesion, not previously irradiated, that qualifies as a Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 target lesion at baseline. All-comers population Durvalumab 1500mg q4w until disease progression • CRT + Durvalumab IV 1500mg q4w • Co-PRIMARY ENDPOINT • ORR and PFS using RECIST v1.1 • SECONDARY ENDPOINTS • OS • OS 24 • DoR • DCR • TDDM • Immunogenicity • Safety/tolerability Patients with SD, PR, CR 2:1 R Patients with SD, PR, CR • CRT + placebo • Placebo • 1. In House Data, AstraZeneca Pharmaceuticals LP. CSP D933KC00001 CR = complete response; CRT = chemoradiation therapy; DCR = disease control rate; DoR = duration of response; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; PS = performance status; q4w = every 4 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; TTDM = time to death or distant metastasis; WHO = World Health Organization.

  18. Post-PACIFIC Practical Considerations for Oncologists • Response to immunotherapy is decreased by concurrent use of: • Antibiotics (change in gut microbiota) • Corticosteroids (lymphopenic effect) • If such medications are necessary, preliminary evidence suggests: • Cortosteroids <10 mg prednisone • Antibiotics not longer than 6 days

  19. Antibiotics compromise the efficacy of PD-1 blockade in mouse tumor models and cancer patients • Patients with NSCLC (n=140) who received antibiotics within 2 mo before or 1 mo after the 1st administration • of PD-1/PD-L1 mAB, were more likely to be non-responders (NR) to therapy than responders (R). • Commensal bacteria from genus Ackermansia (A. municiphila) were overrepresented at diagnosis in the feces • of patients who later benefited from PD-1 inhibition. • Fecal transplants (in mice) from R patients restored anti-tumor activity of PD-1 blockade, unlike those from NR patients. Bertrand Routy et al. Science 2018;359:91-97

  20. SABR-COMET: Stereotactic Radiation for the Comprehensive Treatment of Oligometastatic Cancers – Results of a Randomized Study D. Palma, R. Olson, S. Harrow, S. Gaede, A. Louie, C. Haasbeek, L. Mulroy, M. Lock, G. Rodrigues, B. Yaremko, D. Schellenberg, B. Ahmad, G. Griffioen, S. Senthi, A. Swaminath, N. Kopek, M. Liu, K. Moore, S. Currie, G. Bauman, A. Warner, S. Senan

  21. Limited Metastatic Disease Metastases are not always widely disseminated Metastases do not always progress in multiple sites Patients with limited sites of metastases may not progress or progress only in sites of initial disease 4. Therefore there may be a role for local therapy in selected patients

  22. SABR-COMET Schema • Primary endpoint: OS • Eligibility: • Controlled primary tumor • Max. 5 metastases • Maximum 3 lesions in any single organ system • All sites safely treatable • Results: • 18/99 pts had lung primary • 93% pts had <3 lesions

  23. SABR Details • Number of fractions dependent on tumor size and location • Lung: 54/3, 55/5, 60/8 • Bone: 35/5, 30/3, 16-20/1 • Brain: SRS (18-24/1) or SABR (40/5), WBRT optional • Liver: 45-60 Gy in 3-8 • Adrenal: 60/8 • Normal tissue tolerances not to be exceeded • PTV coverage compromised wherever needed

  24. Baseline Characteristics Between February 2012 and August 2016, 99 patients were randomized at centres in Canada, Scotland, Netherlands and Australia

  25. Overall Survival Median OS Control Arm: 28 months (95% CI: 19-33 months) SABR Arm: 41 months (95% CI: 26 months to ‘not reached’) 46% 24%

  26. Progression-Free Survival Median PFS Control Arm: 6 months (95% CI: 3.4-7.1 months) SABR Arm: 12 months (95% CI: 6.9-30 months) 16% 0% 8 patients on SABR Arm received salvage SABR after progression

  27. Adverse Events Related Events as determined by the treating investigator (Possibly, Probably, or Definitely Related)

  28. Is a Clear PFS Benefit Enough to Treat? • There is ample precedent in oncology • Aromatase Inhibitors for Breast Cancer • Crizotinib in ALK-rearranged NSCLC • Majority of FDA approvals for cancer drugs are not based on OS.1,2 Brooks et al, Drugs Context, 2017 Kim et Prasad, JAMA Internal Medicine 2015

  29. Conclusions • SABR was associated with an improvement in OS, meeting the primary endpoint of this trial, and PFS was doubled. Toxicities were more common with SABR, with a 4.5% risk of treatment-related death, and no decrease in QOL. • To our knowledge, these findings represent the strongest clinical evidence available in support of the oligometastaticstate across multiple tumor types • This is a higher level of evidence than exists for any surgical intervention for oligometastaticdisease

  30. Local Consolidative Therapy (LCT) Improves Overall Survival Compared to Maintenance Therapy/Observation in OligometastaticNSCLC: Final Results of a Multicenter, Randomized, Controlled Phase 2 Trial Daniel R. Gomez, MD, Chad Tang, MD, Jianjun Zhang, MD, PhD,George R. Blumenschein Jr, MD, Mike Hernandez, MS, J. Jack Lee, PhD, Rong Ye, MS, David A. Palma, MD, PhD , Alexander V. Louie, MD, PhD, D. Ross Camidge, MD, PhD, Robert C. Doebele, MD, PhD,FerdinandosSkoulidis, MD, Laurie E. Gaspar, MD, James W. Welsh, M.D., Don L. Gibbons, MD, PhD,Jose A. Karam, MD, Brian D. Kavanagh, MD, Anne S. Tsao, MD, Boris Sepesi, MD, Stephen G. Swisher, MD,* John V. Heymach, MD, PhD* *Dr. Swisher and Dr. Heymach contributed equally to this project

  31. Background • Biologic state of oligometastasis still being defined • Defining patients in-between locally advanced state and true metastases that could be “cured” • In 2012, initiated phase II randomized study in oligometastatic NSCLC • Key eligibility criteria: • Diagnosis of stage IV NSCLC • ≤3 metastases after standard front-line systemic therapy • Four cycles of platinum-doublet chemotherapy or 3 months of EGFR/ALK targeted therapy for appropriate molecular alterations • ECOG performance status 0-2 • Eligible for “local consolidative therapy” (surgery/radiation therapy=LCT) to all sites of disease • Treatment arms: • A) Standard = maintenance therapy/observation (MT/O) • B) Experimental = local consolidative therapy (LCT)

  32. Background (MT/O) Crossover allowed at time of progression (LCT) Primary Endpoint = Progression-free survival (powered for 4 months MT/O vs. 7 months LCT, n=94) Secondary Endpoints: Overall survival, safety/toxicity, time to appearance of new lesions Balanced randomization: 1) Number of metastases (0-1 vs. 2-3), 2) Response to first-line systemic therapy (stable disease vs. partial response), 3) N0-N1 vs. N2-N3, 4) CNS vs. no CNS metastases, 5) EGFR/ALK alteration vs. wild type Gomez et al., Lancet Oncol2016

  33. Background Gomez et al., Lancet Oncol2016 Iyengar et al., JAMA Oncol2017

  34. Aims of Presentation • Report final PFS data • Update secondary endpoints of safety, time to new lesion failure • Report OS data (immature in initial publication) • Exploratory analyses to assess effect of early vs. late LCT • Identify subgroups that may have improved OS in early LCT

  35. Update of PFS and (new) OS Results PFS OS MST 41.2 movs. 17.0 mo HR 0.40 P=0.017 No additional Grade 3 or higher adverse events in either arm

  36. Survival After Progression Median 37.6 months LCT [95% CI 9.0-not reached] vs. 9.4 months MT/O [95% CI 5.9–19.6, P=0.034]

  37. Effect of Complete LCT at Progression 32% (6/19) of patients eligible in LCT arm 45% (9/20) of patients eligible in MT/O arm

  38. Effect of Complete LCT at Progression by Treatment Arm LCT MT/O

  39. Subgroup Analysis of Prognostic Factors on OS

  40. Prospective Phase II Randomized Studies of Consolidative RT in Patients with Oligometastatic NSCLC

  41. Conclusions 1)With long-term follow-up, compared to MT/O, LCT in patients with oligometastatic disease who do not progress after front-line systemic therapy: • Improves PFS • Is associated with an improvement in OS • Trend towards improvement in time to appearance of new lesions 2) LCT with acceptable tolerance, long-term follow-up did not reveal further high-grade toxicity in either arm 3) Survival after progression improved in LCT arm • Trends towards improvement in survival with complete LCT, BUT… • Less than half of patients appear to be eligible for this treatment at progression 4) Patient subgroups that appeared to benefit from LCT include • 0-1 metastases after front-line systemic therapy • N0/N1 disease • The absence of CNS metastases

  42. Limitations 1) Trial stopped early; smaller number of patients complicated subgroup analysis • Imbalances in treatment arms limited through technique of balanced randomization 2) Heterogeneity of treatments on maintenance therapy arm, including observation • Trial designed to be pragmatic and assess overall treatment paradigm 3) Study performed prior to advent of immunotherapy and with small number of patients that had EGFR/ALK alterations • Unclear if same effects occur in these specific patient populations

  43. Future Directions 1) Expand with trials in oligometastatic NSCLC that contain large numbers of patients that use OS as an endpoint (phase III studies) 2) Current study provides strong evidence for LCT paradigm; assess PFS/OS endpoints in specific patient populations • Incorporate immunotherapy into systemic therapy paradigm (LONESTAR, NRG-LU002, MDACC EXTEND study) • Implement studies focused on patients eligible for targeted therapies (NORTHSTAR, HALT) 3) Utilize correlative analyses to determine predictive/prognostic biomarkers that can better select patients in true “oligometastatic” state

  44. Local Ablative Therapy Improves Survival in Patients with Synchronous Oligometastatic NSCLC Harboring EGFR Mutation Treated with First-Line EGFR-TKIs Qinghua Xu, Hui Liu, Yaping Xu, Caicun Zhou* ● Xu Q, Liu H,Xu Y. Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China ● Zhou C. Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China Shanghai Pulmonary Hospital Department of Radiation Oncology

  45. Background • Stage IV disease with oligometastases can represent an indolent phenotype that could benefit from LAT for consolidation. • Consolidative LAT for patients with stage IV EGFR-mutant NSCLC who have oligometastatic disease are sparse. • A retrospective study was from October 2011 to May 2016. • Advanced non-small cell lung cancer with EGFR mutation • — diagnosed within 2 months • — metastatic lesions ≤ 5 • — accepted first-line EGFR TKIs • local ablative therapy included radiotherapy, surgery and ablation.

  46. Retrospective analysis • Pts diagnosed within 2 mo • <5 metastases • First line EGFR TKIs

  47. Tab 1. Patients characteristics of three groups

  48. Fig 1. PFS in All-LAT, Part-LAT and Non-LAT group P ＜0.001

  49. Fig 2. OS in All-LAT, Part-LAT and Non-LAT group P ＜0.001 P ＜0.001

  50. Fig 3.OS by consolidative LAT sites brain metastases bone metastases primary tumor contralateral lung metastases adrenal metastases liver metastases

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