Durvalumab and Chemotherapy Induction Followed by Durvalumab and Radiotherapy in Large Volume Stage III NSCLC

Overview

Standard treatment for stage III Non-Small Cells Lung Cancer (NSCLC) not eligibile for surgery is concomitant chemoradiotherapy. However median progression free survival and overall survival is still poor with only 15% of patients alive at 5 years. The addition of maintenance therapy with durvalumab after chemoradiation showed a significant benefit in PFS and OS, with good tolerability and no concerns in terms of safety. However, about 30% of patients with stage III are not eligible to concurrent chemoradiotherapy because of large volumes of the tumor. To date, these patients are initially treated with chemotherapy with the aim of reducing tumor volumes and allowing sequential radiotherapy. Response rate ranges between 25-30% and majority of patients will not become suitable for radiotherapy. The combination of immunotherapy plus standard chemotherapy in advanced stages doubles response rates and provides major tumor shrinkage compared to standard chemotherapy alone. For these reasons, the investigators want to exploit the synergistic effect of immunotherapy combined with chemotherapy in the induction phase, in order to render suitable for radiotherapy a larger number of patients, and in a second phase the synergistic effect with radiotherapy. Based on these premises the investigators designed a single arm, phase 2 trial to determine the efficacy and safety of combining immunotherapy with the drug durvalumab in association with standard chemotherapy and subsequently with standard radiotherapy, followed by a treatment of maintenance with only durvalumab. The study population includes patients with NSCLC not eligible for surgery or concurrent chemoradiation at diagnosis because of large tumor volumes. BRIDGE trial aims to evaluate and increase the proportion of patients eligible for immunotherapy plus radiotherapy (response) after induction with durvalumab and chemotherapy and to increase this proportion in comparison to historical controls. This study will last approximately 48 months and will include approximately 65 eligible patients in 3 international cancer centres of excellence.

Full Title of Study: “BRIDGE Trial: Phase II Trial of durvalumaB and chemotheRapy Induction Followed by Durvalumab and Radiotherapy in larGe volumE Stage III NSCLC”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2025

Detailed Description

Standard treatment for stage III Non-Small Cells Lung Cancer (NSCLC) not eligibile for surgery is concomitant chemoradiotherapy. However median progression free survival and overall survival is still poor with only 15% of patients alive at 5 years. The addition of maintenance therapy with durvalumab after chemoradiation showed a significant benefit in PFS and OS, with good tolerability and no concerns in terms of safety. However, about 30% of patients with stage III are not eligible to concurrent chemoradiotherapy because of large volumes of the tumor. To date, these patients are initially treated with chemotherapy with the aim of reducing tumor volumes and allowing sequential radiotherapy. Response rate ranges between 25-30% and majority of patients will not become suitable for radiotherapy. The combination of immunotherapy plus standard chemotherapy in advanced stages doubles response rates and provides major tumor shrinkage compared to standard chemotherapy alone. For these reasons, the investigators want to exploit the synergistic effect of immunotherapy combined with chemotherapy in the induction phase, in order to render suitable for radiotherapy a larger number of patients, and in a second phase the synergistic effect with radiotherapy. Based on these premises the investigators designed a single arm, phase 2 trial to determine the efficacy and safety of combining immunotherapy with the drug durvalumab in association with standard chemotherapy and subsequently with standard radiotherapy, followed by a treatment of maintenance with only durvalumab. The study population includes patients with NSCLC not eligible for surgery or concurrent chemoradiation at diagnosis because of large tumor volumes. The study consists of 3 parts: – Part 1: induction with durvalumab plus chemotherapy. – Part 2: patients responding or stable and eligible for radiotherapy after induction will be treated concomitantly with durvalumab and radiotherapy. – Part 3: patients responding or stable after part 2 will be eligible for durvalumab maintenance, for up to 2 years or until disease progression or unacceptable toxicity. BRIDGE trial aims to evaluate and increase the proportion of patients eligible for immunotherapy plus radiotherapy (response) after induction with durvalumab and chemotherapy and to increase this proportion in comparison to historical controls. This study will last approximately 48 months and will include approximately 65 eligible patients in 3 international cancer centres of excellence.

Interventions

  • Combination Product: durvalumab plus platinum-based chemotherapy (cisplatin or carboplatin plus vinorelbine or pemetrexed)
    • Induction therapy: durvalumab plus histology-based chemotherapy regimen (cisplatin or carboplatin plus vinorelbine for squamous histology and pemetrexed for non-squamous histology).
  • Combination Product: Durvalumab plus radiotherapy
    • Concomitant durvalumab and radiotherapy
  • Biological: durvalumab
    • Consolidation treatment with durvalumab

Arms, Groups and Cohorts

  • Experimental: BRIDGE single arm
    • Treatment plan: Part 1: induction with durvalumab plus histology-based chemotherapy regimen. Part 2: patients responding or stable after part a and eligible for radiotherapy after induction will be treated concomitantly with durvalumab and radiotherapy. Part 3: patients responding or stable after part 2 will be eligible for durvalumab maintenance

Clinical Trial Outcome Measures

Primary Measures

  • Proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy.
    • Time Frame: At the end of part 1 of induction chemo-immunotherapy/before part 2 (assessed up to 48 months)
    • To increase the proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy, in comparison to historical controls.

Secondary Measures

  • Progression-Free Survival (PFS) of patients receiving durvalumab and chemotherapy induction followed by immuno-radiotherapy and durvalumab consolidation.
    • Time Frame: From the date of start of induction chemo-immunotherapy until the date of first documented progression or death from any cause, whichever came first (assessed up to 48 months)
    • PFS is defined as the time from the date of start of induction treatment until the date of objective disease progression or death to any cause whichever comes first. PFS will be evaluated using RECIST 1.1 criteria according to investigators and blinded central review (BCR).
  • Proportion of patients with complete response or partial response (as best response)
    • Time Frame: Assessed up to 48 months
    • To evaluate Objective Response Rate (ORR) of each phase of treatment and the overall response rate. ORR is defined as the proportion of patients with complete or partial response (as best response) according to RECIST 1.1 as assessed by Investigators and BCR.
  • Overall Survival (OS) of patients receiving durvalumab and chemotherapy induction followed by immuno-radiotherapy and durvalumab consolidation.
    • Time Frame: Assessed up to 48 months
    • OS is defined as the time from the date of start of induction treatment until death due to any cause. Patients alive at the time of statistical analysis will be censored at their last information on vital status.
  • Frequency and nature of adverse reactions (ARs) and Serious Adverse Events (SAEs) (toxicity and safety).
    • Time Frame: Assessed up to 48 months
    • The assessment of safety will be mainly based on adverse reactions (ARs) and the frequency and nature of SAEs. Toxicity and safety will be evaluated during each part of the program, throughout study duration.

Participating in This Clinical Trial

Inclusion Criteria FOR PART 1 (INDUCTION CHEMOTHERAPY IN ASSOCIATION WITH DURVALUMAB): 1. Capable of giving signed informed consentwhich includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (eg, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 2. Age > 18 years at time of study entry 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Life expectancy of > 12 weeks 5. Histologically- or cytologically-documented NSCLC, in locally advanced (Stage III-v.8 IASLC) 6. Eligible for platinum-based chemotherapy (platinum – pemetrexed for non-squamous and platinum-vinorelbine for squamous histology) 7. Patients not eligible for surgery and chemoradiation (each patient will be discussed in a web multidisciplinary team among all the three involved Cancer Core Europe [CCE] centers). Main criteria for avoiding concurrent chemoradiation from the beginning are:

  • Bilateral supraclavicular involvement – Contralateral mediastinal and/or hilar involvement – Primary tumor > 7 cm or several nodules in different lobes of the same lung 8. Tumor sample requirements: availability of an archived tumour tissue block (or unstained slides to perform local PDL1 assessment following protocol procedure) 9. Patient's willingness to undergo blood draws to provide plasma and blood samples for analysis according to study objectives 10. Body weight > 30 Kg 11. Adequate normal organ and marrow function as defined below: – Haemoglobin ≥9.0 g/dL – Absolute neutrophil count (ANC) 1.5 x 109/L (> 1500/mm3) – Platelet count ≥100 x 109/L – Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. – AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal – Adequate renal function defined as normal serum creatinine levels or calculated creatinine clearance (according to Cockroft-Gault or by 24 hour-urine collection): ≥60 ml/min for patient receiving cisplatin ≥45 ml/min for patient receiving carboplatin. Cockcroft-Gault formula (Cockcroft and Gault 1976): Males: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) x 0.85 72 x serum creatinine (mg/dL) 12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: – Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). – Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 13. Patient willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. 14. Absence of a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents and/or to durvalumab and/or to any of their excipients. FOR PART 2 (RADIOTHERAPY CONCURRENTLY WITH DURVALUMAB): 1. Evidence of partial response or stable disease at the evaluation conducted at the end of Part 1 (each patient will be discussed in a web multidisciplinary team among the involved CCE centers to discuss eligibility for part 2) 2. ECOG Performance Status of 0 – 1 3. Absence of dyspnea of minimal exertion or oxygen requirement after CT+D 4. Sufficient PFTs performed after the last cycle of CT+D: – FEV1 > 1L or ≥ 30% – DLCO > 30% 5. The patient's dosimetry must meet the following constraints to organs at risk (Kong 2011, Marks 2010, De Ruysscher 2017, Marks 2010, Gagliardi 2010, Wang 2017, Kirkpatrick 2010): – Spinal cord maximum dose < 50 Gy – Total mean lung dose (Right Lung+Left Lung-GTV) ≤ 23 Gy [De Ruysscher] and/or – Lung V20 defined as percentage of normal parenchyma receiving 20 Gy or more (Right Lung+Left Lung-PTV) ≤ 37% – Heart V45 <30% and Mean Heart Dose ≤26 Gy if possible, Heart V45 <30% or Mean Heart Dose ≤26 Gy FOR PART 3 (MAINTENANCE WITH DURVALUMAB): 1. Evidence of partial response or stable disease at the evaluation conducted at the end of Part 2 2. Absence of grade 2-3 pneumonitis Exclusion Criteria:

1. Patient amenable to curative intent surgery or concurrent chemoradiation 2. Mixed small cell and non-small cell lung cancer histology 3. Patients who already received therapy for locally advanced NSCLC 4. Stage IV NSCLC 5. Dyspnea of minimal exertion or oxygen requirement 6. Recent medical history of cardiac events during the last 6 months (ischemic or congestive heart failure) 7. Pancoast tumors 8. Previous radiotherapy to the thorax (prior to inclusion), including radiotherapy for breast cancer 9. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody, including durvalumab 10. Participation in another clinical study with an investigational product during the last 4 weeks 11. Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. 12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any patient known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. 13. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study 14. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria a. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician. 15. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. 16. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational product. 17. History of allogenic organ transplantation. 18. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: 1. Patients with vitiligo or alopecia 2. Patients with Grave's disease not requiring systemic treatment within the past 2 years 3. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement 4. Any chronic skin condition that does not require systemic therapy 5. Patients without active disease in the last 2 years may be included but only after consultation with the study physician 6. Patients with celiac disease controlled by diet alone 19. History of another primary malignancy except for 1. Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study drug and of low potential risk for recurrence 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 3. Adequately treated carcinoma in situ without evidence of disease, e.g. cervical cancer in situ 4. Superficial bladder cancer without evidence of disease 20. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms 21. History of active primary immunodeficiency 22. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 23. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: 1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) 2. Systemic corticosteroids at physiologic doses not to exceed 10 mg daily of prednisone or its equivalent 3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) Systemic steroid administration required as prophylaxis against or to manage toxicities arising from chemotherapy and/or radiotherapy delivered as part of therapy for locally advanced NSCLC is allowed 24. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. 25. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy. 26. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 27. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Mario Negri Institute for Pharmacological Research
  • Collaborator
    • AstraZeneca
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Valter Torri, Study Chair, Istituto di Ricerche Farmacologiche Mario Negri IRCCS
    • Roberto Ferrara, Principal Investigator, Fondazione IRCCS Istituto Nazionale Tumori
  • Overall Contact(s)
    • Irene De Simone, +390239014661, irene.desimone@marionegri.it

References

Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR. Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500(7463):415-21. doi: 10.1038/nature12477. Epub 2013 Aug 14. Erratum in: Nature. 2013 Oct 10;502(7470):258. Imielinsk, Marcin [corrected to Imielinski, Marcin].

Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8.

Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350. doi: 10.1056/NEJMoa1809697. Epub 2018 Sep 25.

Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, Belderbos J, Clamon G, Ulutin HC, Paulus R, Yamanaka T, Bozonnat MC, Uitterhoeve A, Wang X, Stewart L, Arriagada R, Burdett S, Pignon JP. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010 May 1;28(13):2181-90. doi: 10.1200/JCO.2009.26.2543. Epub 2010 Mar 29. Review.

Bayman N, Blackhall F, McCloskey P, Taylor P, Faivre-Finn C. How can we optimise concurrent chemoradiotherapy for inoperable stage III non-small cell lung cancer? Lung Cancer. 2014 Feb;83(2):117-25. doi: 10.1016/j.lungcan.2013.11.017. Epub 2013 Dec 1. Review.

Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014 Jan;21(1):15-25. doi: 10.1038/cdd.2013.67. Epub 2013 Jun 21. Review.

Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. doi: 10.1016/S1470-2045(14)71207-0. Epub 2015 Jan 16.

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2.

Brahmer JR, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): Survival and clinical activity by subgroup analysis [ASCO abstract 8112]. J Clin Oncol 2014;32(Suppl)

Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 1982, 38, 29-41. doi:10.2307/2530286

Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007 Jul;27(1):111-22. Epub 2007 Jul 12.

De Ruysscher D, Reynders K, Van Limbergen E, Lambrecht M. Radiotherapy in combination with immune checkpoint inhibitors. Curr Opin Oncol. 2017 Mar;29(2):105-111. doi: 10.1097/CCO.0000000000000352. Review.

De Ruysscher D, Faivre-Finn C, Moeller D, Nestle U, Hurkmans CW, Le Péchoux C, Belderbos J, Guckenberger M, Senan S; Lung Group and the Radiation Oncology Group of the European Organization for Research and Treatment of Cancer (EORTC). European Organization for Research and Treatment of Cancer (EORTC) recommendations for planning and delivery of high-dose, high precision radiotherapy for lung cancer. Radiother Oncol. 2017 Jul;124(1):1-10. doi: 10.1016/j.radonc.2017.06.003. Epub 2017 Jun 27.

Drake CG, McDermott DF, Sznol M, Choueiri TK, Kluger HM, Powderly JD et al. Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term patient follow-up [abstract 4514]. J Clin Oncol 2013;31(Suppl)

Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329-60. Review.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. Contemp Clin Trials. 2008 Jul;29(4):456-65. doi: 10.1016/j.cct.2007.10.008. Epub 2007 Nov 12.

Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics of durvalumab, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid tumours. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts;32(5s): (suppl; abstr 2602)

Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008 Aug;224:166-82. doi: 10.1111/j.1600-065X.2008.00662.x. Review.

Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, Zahurak M, Yang SC, Jones DR, Broderick S, Battafarano RJ, Velez MJ, Rekhtman N, Olah Z, Naidoo J, Marrone KA, Verde F, Guo H, Zhang J, Caushi JX, Chan HY, Sidhom JW, Scharpf RB, White J, Gabrielson E, Wang H, Rosner GL, Rusch V, Wolchok JD, Merghoub T, Taube JM, Velculescu VE, Topalian SL, Brahmer JR, Pardoll DM. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018 May 24;378(21):1976-1986. doi: 10.1056/NEJMoa1716078. Epub 2018 Apr 16. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185.

Gagliardi G, Constine LS, Moiseenko V, Correa C, Pierce LJ, Allen AM, Marks LB. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S77-85. doi: 10.1016/j.ijrobp.2009.04.093. Review.

Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. doi: 10.1056/NEJMoa1801005. Epub 2018 Apr 16.

Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumours [abstract 3000]. J Clin Oncol 2013;31(Suppl 15)

Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, Tamada K, Chen L. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005 Feb 1;65(3):1089-96.

Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a Phase I trial [ASCO abstract 9002]. J Clin Oncol 2014; 32(Suppl)

Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7. Epub 2002 Sep 6.

Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331. Review.

Kong FM, Ritter T, Quint DJ, Senan S, Gaspar LE, Komaki RU, Hurkmans CW, Timmerman R, Bezjak A, Bradley JD, Movsas B, Marsh L, Okunieff P, Choy H, Curran WJ Jr. Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1442-57. doi: 10.1016/j.ijrobp.2010.07.1977. Epub 2010 Oct 8.

Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-63

Lesterhuis WJ, Punt CJ, Hato SV, Eleveld-Trancikova D, Jansen BJ, Nierkens S, Schreibelt G, de Boer A, Van Herpen CM, Kaanders JH, van Krieken JH, Adema GJ, Figdor CG, de Vries IJ. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest. 2011 Aug;121(8):3100-8. doi: 10.1172/JCI43656. Epub 2011 Jul 18.

Lin SH, Lin Y, Price J, Parker M, et al. DETERRED: PD-L1 blockade to evaluate the safety of lung cancer therapy using carboplatin, paclitaxel, and radiation combined with MPDL3280A (atezolizumab). Journal of Clinical Oncology 2017 35:15_suppl, 3064-3064

Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, Bentzen SM, Nam J, Deasy JO. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S10-9. doi: 10.1016/j.ijrobp.2009.07.1754.

Marks LB, Bentzen SM, Deasy JO, Kong FM, Bradley JD, Vogelius IS, El Naqa I, Hubbs JL, Lebesque JV, Timmerman RD, Martel MK, Jackson A. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S70-6. doi: 10.1016/j.ijrobp.2009.06.091. Review.

Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an investigational anti-interferon-α monoclonal antibody, in systemic lupus erythematosus. Clin Pharmacokinet. 2013 Nov;52(11):1017-27. doi: 10.1007/s40262-013-0085-2.

Nestle U, De Ruysscher D, Ricardi U, Geets X, Belderbos J, Pöttgen C, Dziadiuszko R, Peeters S, Lievens Y, Hurkmans C, Slotman B, Ramella S, Faivre-Finn C, McDonald F, Manapov F, Putora PM, LePéchoux C, Van Houtte P. ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung cancer. Radiother Oncol. 2018 Apr;127(1):1-5. doi: 10.1016/j.radonc.2018.02.023. Epub 2018 Mar 28.

Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm Res. 2006 Jun;23(6):1275-84. Epub 2006 May 26.

Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, Kurihara C, Kawaguchi A, Nagao S, Azuma M, Yagita H, Miura S. Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol. 2009 Oct;35(4):741-9.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. doi: 10.1038/nrc3239. Review.

Paterson AM, Brown KE, Keir ME, Vanguri VK, Riella LV, Chandraker A, Sayegh MH, Blazar BR, Freeman GJ, Sharpe AH. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J Immunol. 2011 Aug 1;187(3):1097-105. doi: 10.4049/jimmunol.1003496. Epub 2011 Jun 22.

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. doi: 10.1056/NEJMoa1810865. Epub 2018 Sep 25.

Peters S, De Ruysscher D, Dafni U, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-RT regimen in unresectable locally advanced NSCLC: The ETOP NICOLAS phase II trial. J Clin Oncol 36, 2018 (suppl; abstr 8510)

Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. doi: 10.1038/nature13904.

Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with nonsmall cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032

Roselli M, Cereda V, di Bari MG, Formica V, Spila A, Jochems C, Farsaci B, Donahue R, Gulley JL, Schlom J, Guadagni F. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Oncoimmunology. 2013 Oct 1;2(10):e27025.

Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma [abstract 24]. Presented at European Cancer Congress 2013 (ECCO-ESMO-ESTRO); 27 September to 01 October 2013; Amsterdam, The Netherlands

Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. J Clin Oncol 2015;33:Abstract 3011

Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. doi: 10.1200/JCO.2015.64.8824. Epub 2016 Jan 25.

Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10.

Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. doi: 10.1056/NEJMoa1716948. Epub 2018 Jun 4.

Steuer CE, Behera M, Ernani V, Higgins KA, Saba NF, Shin DM, Pakkala S, Pillai RN, Owonikoko TK, Curran WJ, Belani CP, Khuri FR, Ramalingam SS. Comparison of Concurrent Use of Thoracic Radiation With Either Carboplatin-Paclitaxel or Cisplatin-Etoposide for Patients With Stage III Non-Small-Cell Lung Cancer: A Systematic Review. JAMA Oncol. 2017 Aug 1;3(8):1120-1129. doi: 10.1001/jamaoncol.2016.4280. Review.

Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, Watkins A, Mullins S, Chodorge M, Andrews J, Bannister D, Dick E, Crawford N, Parmentier J, Alimzhanov M, Babcook JS, Foltz IN, Buchanan A, Bedian V, Wilkinson RW, McCourt M. Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody. Cancer Immunol Res. 2015 Sep;3(9):1052-62. doi: 10.1158/2326-6066.CIR-14-0191. Epub 2015 May 5.

Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with advanced cancers. Expert Opin Biol Ther. 2008 Oct;8(10):1583-93. doi: 10.1517/14712598.8.10.1583 .

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2.

Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014 Apr 1;32(10):1020-30. doi: 10.1200/JCO.2013.53.0105. Epub 2014 Mar 3.

Tsujino K, Kurata T, Yamamoto S, Kawaguchi T, Kubo A, Isa S, Hasegawa Y, Ou SH, Takada M, Ando M. Is consolidation chemotherapy after concurrent chemo-radiotherapy beneficial for patients with locally advanced non-small-cell lung cancer? A pooled analysis of the literature. J Thorac Oncol. 2013 Sep;8(9):1181-9. doi: 10.1097/JTO.0b013e3182988348.

Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009 Sep;49(9):1012-24. doi: 10.1177/0091270009337512. Epub 2009 Jul 20.

Wang E, Kang D, Bae KS, Marshall MA, Pavlov D, Parivar K. Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma. J Clin Pharmacol. 2014 Oct;54(10):1108-16. doi: 10.1002/jcph.309. Epub 2014 Apr 23.

Wang Z, Till B, Gao Q. Chemotherapeutic agent-mediated elimination of myeloid-derived suppressor cells. Oncoimmunology. 2017 Jun 16;6(7):e1331807. doi: 10.1080/2162402X.2017.1331807. eCollection 2017. Review.

Wang K, Eblan MJ, Deal AM, Lipner M, Zagar TM, Wang Y, Mavroidis P, Lee CB, Jensen BC, Rosenman JG, Socinski MA, Stinchcombe TE, Marks LB. Cardiac Toxicity After Radiotherapy for Stage III Non-Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy. J Clin Oncol. 2017 May 1;35(13):1387-1394. doi: 10.1200/JCO.2016.70.0229. Epub 2017 Jan 23.

Wiens BL. A fixed sequence Bonferroni procedure for testing multiple endpoints Pharmaceut. Statist. 2003; 2: 211-215

Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 Jun 2. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185.

Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, Xu Y, Pogoriler E, Terzulli SL, Kuk D, Panageas KS, Ritter G, Sznol M, Halaban R, Jungbluth AA, Allison JP, Old LJ, Wolchok JD, Gnjatic S. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16723-8. doi: 10.1073/pnas.1110814108. Epub 2011 Sep 20.

Zhang C, Wu S, Xue X, Li M, Qin X, Li W, Han W, Zhang Y. Anti-tumor immunotherapy by blockade of the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy. 2008;10(7):711-9. doi: 10.1080/14653240802320237.

Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of therapeutic peptides and proteins in adults. J Clin Pharmacol. 2012 Jan;52(1):18-28. doi: 10.1177/0091270010388648. Epub 2011 Jan 13.

Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008 Jun;8(6):467-77. doi: 10.1038/nri2326. Review.

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