Integration of longitudinal deep-radiomics and clinical data improves the prediction of durable benefits to anti-PD-1/PD-L1 immunotherapy in advanced NSCLC patients.

BACKGROUND: Identifying predictive non-invasive biomarkers of immunotherapy response is crucial to avoid premature treatment interruptions or ineffective prolongation. Our aim was to develop a non-invasive biomarker for predicting immunotherapy clinical durable benefit, based on the integration of radiomics and clinical data monitored through early anti-PD-1/PD-L1 monoclonal antibodies treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: In this study, 264 patients with pathologically confirmed stage IV NSCLC treated with immunotherapy were retrospectively collected from two institutions. The cohort was randomly divided into a training (n = 221) and an independent test set (n = 43), ensuring the balanced availability of baseline and follow-up data for each patient. Clinical data corresponding to the start of treatment was retrieved from electronic patient records, and blood test variables after the first and third cycles of immunotherapy were also collected. Additionally, traditional radiomics and deep-radiomics features were extracted from the primary tumors of the computed tomography (CT) scans before treatment and during patient follow-up. Random Forest was used to implementing baseline and longitudinal models using clinical and radiomics data separately, and then an ensemble model was built integrating both sources of information. RESULTS: The integration of longitudinal clinical and deep-radiomics data significantly improved clinical durable benefit prediction at 6 and 9 months after treatment in the independent test set, achieving an area under the receiver operating characteristic curve of 0.824 (95% CI: [0.658,0.953]) and 0.753 (95% CI: [0.549,0.931]). The Kaplan-Meier survival analysis showed that, for both endpoints, the signatures significantly stratified high- and low-risk patients (p-value< 0.05) and were significantly correlated with progression-free survival (PFS6 model: C-index 0.723, p-value = 0.004; PFS9 model: C-index 0.685, p-value = 0.030) and overall survival (PFS6 models: C-index 0.768, p-value = 0.002; PFS9 model: C-index 0.736, p-value = 0.023). CONCLUSIONS: Integrating multidimensional and longitudinal data improved clinical durable benefit prediction to immunotherapy treatment of advanced non-small cell lung cancer patients. The selection of effective treatment and the appropriate evaluation of clinical benefit are important for better managing cancer patients with prolonged survival and preserving quality of life.

Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: The phase II ATLANTIC study.

INTRODUCTION: In the phase II ATLANTIC study, durvalumab provided durable responses with acceptable tolerability in heavily pretreated patients with advanced NSCLC, across three independent patient cohorts defined by EGFR/ALK status and tumour PD-L1 expression. Preliminary overall survival (OS) data were encouraging. We now report final OS and updated safety data. METHODS: Patients with advanced NSCLC with disease progression following ≥2 previous systemic regimens received durvalumab 10 mg/kg every 2 weeks. The primary endpoint was objective response rate among patients with increased PD-L1 expression (defined as ≥25 % or ≥90 % of tumour cells [TCs], cohort-dependent). Secondary endpoints included OS and safety. RESULTS: 444 patients received durvalumab: 111 in Cohort 1 (EGFR+/ALK+), 265 in Cohort 2 (EGFR-/ALK-), and 68 in Cohort 3 (EGFR-/ALK-; TC ≥ 90 %). Median (95 % CI) OS was 13.3 months (6.3-24.5) in patients with EGFR+/ALK+ NSCLC with TC ≥ 25 %, 10.9 months (8.6-13.6) in patients with EGFR-/ALK- NSCLC with TC ≥ 25 %, and 13.2 months (5.9-not reached) in patients with EGFR-/ALK- NSCLC with TC ≥ 90 %. Median (95 % CI) OS was slightly shorter in patients with TC < 25 % (9.9 months [4.2-13.3] in patients with EGFR+/ALK+ NSCLC and 9.3 months [5.9-10.8] in those with EGFR-/ALK- NSCLC). Treatment-related adverse events of special interest occurred with similar incidences as reported previously. CONCLUSIONS: After additional follow-up, final OS data remain encouraging across all cohorts, further supporting the clinical activity of durvalumab in patients with heavily pretreated advanced NSCLC, including those with EGFR+/ALK+ tumours. There were no new safety signals.

Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

Randomized, Double-Blind Phase Ib/III Study of Erlotinib With Ramucirumab or Placebo in Previously Untreated EGFR-Mutant Metastatic Non-Small-Cell Lung Cancer (RELAY): Phase Ib Results.

BACKGROUND: Despite the likelihood of an initial response to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), EGFR-mutant non-small-cell lung cancer (NSCLC) patients develop disease progression. Antiangiogenic agents in combination with an EGFR TKI might provide additional benefit in patients with EGFR-mutant NSCLC. In this article we report safety, exposure, and progression-free survival (PFS) results for part A (phase Ib) of RELAY, a randomized, double-blind, phase Ib/III study investigating safety and efficacy of erlotinib (EGFR TKI) with ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) or placebo in first-line EGFR-mutant stage IV NSCLC. PATIENTS AND METHODS: Eligible patients had untreated stage IV NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). Patients received ramucirumab 10 mg/kg on day 1 of a repeating 14-day cycle and erlotinib 150 mg/d. Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs), during the first 2 cycles. RESULTS: Fourteen patients were treated and 12 were evaluable for DLTs. One patient experienced a DLT of Grade 3 elevated alanine aminotransferase during the DLT assessment period. Adverse events were reported in all patients, but were generally mild and manageable. The most common Grade 3 adverse events were hypertension, rash, and diarrhea. No serious or Grade 4 to 5 events occurred. Median PFS was 17.1 months (95% confidence interval, 8.8-not reached). Five patients continue receiving study treatment. CONCLUSION: Ramucirumab with erlotinib showed no unexpected toxicities and encouraging clinical activity in part A. Phase III enrollment has been initiated, maintaining ramucirumab 10 mg/kg every 2 weeks with erlotinib 150 mg/d.

Treatment Rationale and Study Design for the RELAY Study: A Multicenter, Randomized, Double-Blind Study of Erlotinib With Ramucirumab or Placebo in Patients With Epidermal Growth Factor Receptor Mutation-Positive Metastatic Non-Small-Cell Lung Cancer.

INTRODUCTION: We present the treatment rationale and study design for the RELAY study (NCT02411448 ). This phase Ib/III study will assess safety, tolerability, and efficacy of the combination of ramucirumab with erlotinib in previously untreated stage IV non-small-cell lung cancer patients with an activating epidermal growth factor receptor (EGFR) mutation. PATIENTS AND METHODS: The study is being conducted in approximately 120 sites in North America, Europe, and Asia and is currently open for enrollment. In part A (phase Ib), approximately 12 patients will receive ramucirumab (10 mg/kg) every 2 weeks with erlotinib (150 mg) every day. Dose-limiting toxicity will be assessed during 2 cycles (4 weeks) of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every 2 weeks with erlotinib daily until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary end point is progression-free survival, on the basis of investigator assessment. Secondary end points include overall survival, objective response rate, disease control rate, duration of response, safety, and quality of life. CONCLUSION: Erlotinib with ramucirumab combination was chosen because the addition of an antiangiogenic agent, such as ramucirumab, would further improve the efficacy of erlotinib, which is a standard of care in the first-line treatment of patients with activating EGFR mutations.

Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase. DISCUSSION: Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment. TRIAL REGISTRY: Clinicaltrials.gov REGISTRATION NUMBER: NCT00789373 TRIAL ABBREVIATION: H3E-EW-S124.