Immunoterapia A cura di Emilio Bria Neoadjuvant nivolumab

Immunoterapia A cura di Emilio Bria

Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers Jamie E. Chaft

Background: Anti-PD-1 therapy produces objective and often durable responses in ~20% of unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). However, the role of PD-1 blockade in treating resectable NSCLC is unknown. This is the first study to test nivolumab in the neoadjuvant setting. This trial design provides an opportunity to examine anti-PD-1 mechanism of action and immunologic correlates of outcomes. Methods: Patients with Stage IB - IIIA NSCLC received 2 doses of nivolumab 3 mg/kg over 4 weeks before surgery. The primary endpoint was safety in 20 patients with resected NSCLC. Efficacy was explored using objective pathologic response criteria. Correlative studies of the tumor immune microenvironment, tumor mutation and predicted neoantigen loads, and changes in T cell receptor (TCR) clonality in tumor and blood pre and post treatment were conducted. Results: 22 pts were treated. Nivolumab was well-tolerated and no surgeries were delayed. 1 pt withdrew from study preop without progression or toxicity. Among the 21 attempted resections, 1 tumor was unresectable. 9/21 (43%, 95% CI 24 -63%) had a major pathologic response ( < 10% viable tumor cells in resection specimen). With a median postop follow-up of 9 months, 18 pts (86%) remain alive and recurrence free. Pre-treatment tumor exome sequencing showed a correlation between both tumor mutation and predicted neoantigen loads with pathologic response. Multiplex immunohistochemistry of pre- and post-treatment tumors showed an influx of PD-1+CD 8+ T cells into responding tumors. TCR sequencing demonstrated that expanded peripheral T cell clones after treatment match clones found in the tumor. Conclusions: Neoadjuvant nivolumab in resectable NSCLC did not delay surgery. Major pathologic response rate was encouraging and compares favorably to outcomes with cisplatin-based neoadjuvant chemotherapy. Genomic analyses suggest that higher mutational and neoantigen burden could result in deeper pathologic response. Immunologic analyses support the detection of intra-tumoral T cell clones in the blood after treatment with nivolumab and may provide further insight into the molecular and immunologic features of response and non-response to PD-1 blockade. Clinical trial information: NCT 02259621

Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from Check. Mate 032 Matthew David Hellmann

Background: Patients (pts) with advanced SCLC after first-line platinum-based chemotherapy (PLT-CT) have a poor prognosis and limited treatment options. Check. Mate 032 is a phase I/II trial evaluating multiple regimens of nivo ± ipi in solid tumors, including advanced SCLC. Tolerability and efficacy of nivo ± ipi were demonstrated in early results from the initial treatment arms (Antonia, Lancet Oncol 2016), prompting long-term follow-up and the addition of a randomized expansion cohort to further evaluate nivo ± ipi in advanced SCLC. Methods: In the initial treatment arms, pts with advanced SCLC and disease progression after prior PLT-CT were assigned to nivo (3 mg/kg Q 2 W; n = 98) or nivo 1 + ipi 3 (1 mg/kg and 3 mg/kg Q 3 W x 4, then nivo 3 Q 2 W; n = 61); safety/efficacy was assessed with a follow-up of ~18 mo. In the subsequent SCLC expansion cohort, pts were randomized 3: 2 to nivo vs nivo 1 + ipi 3 and stratified by number of prior therapies. The primary endpoint was objective response rate (ORR). Results: Updated efficacy/safety results from the initial (non-randomized) nivo and nivo 1 + ipi 3 arms are summarized in the table. Responses were durable and occurred regardless of PD-L 1 expression or PLT-sensitivity; safety was consistent with prior nivo ± ipi studies. In the expansion cohort, 247 pts were randomized to nivo or nivo 1 + ipi 3. The presentation will contain the first report of efficacy/safety results and subgroup analyses from this randomized expansion cohort. Conclusions: Durable responses are observed with nivo and nivo + ipi in pts with previously treated SCLC. The expansion cohort represents the first randomized evaluation of combined immune checkpoint blockade in SCLC. Clinical trial information: NCT 01928394

Prevalence and clinical correlation of programmed cell death 1 ligand (PD-L 1) expression in patients with resected non-small cell lung cancer (NSCLC): Results from the European Thoracic Oncology Platform (ETOP) Lungscape cohort Keith Kerr

Background: Conflicting data exists on the potential prognostic impact of PD-L 1 expression in NSCLC. The Lungscape project, a fully annotated large biobank of resected stage I-III NSCLC, allows detailed analysis of this issue. Methods: Prevalence of PD-L 1 positivity and its association with clinicopathological characteristics and patient outcome - Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS) - was explored in the ETOP Lungscape cohort. PD-L 1 expression was assessed on tissue microarrays (TMAs) using the DAKO 28 -8 immunohistochemistry assay. Positivity cut-off points of ≥ 1%, 5% and 50% for neoplastic cell membrane staining were considered. Results: PD -L 1 data were available for 2182 patients, from 15 ETOP centers, with median follow-up 4. 8 years; 1191 patients still alive; median age 66 years; 64% male, 32/54/11% for current/former/never smokers; 49/29/22% for stages I/II/III; 51/42/4/3% adenocarcinomas (AC)/squamous cell (SCC) /large cell and sarcomatoid (LCS)/other. Median RFS/TTR/OS were 53/99/69 months (AC: 52/84/72, SCC: 54/not reached/64; and LSC 52/103/74). PD-L 1 prevalence with 1% cut-off was, overall: 43%, 95% confidence interval (95%CI): 41 -46; (AC: 42%, 95%CI: 39 -46; SCC: 44%, 95%CI: 40 -47; and LCS: 53%, 95%CI: 42 -65), while for 5% threshold, prevalence was 34%, 95%CI: 32 -36. PD-L 1 1% positivity was a significant predictor only for AC: HRRFS: + vs - = 0. 82; 95%CI: 0. 69 -0. 97, HRTTR: + vs - = 0. 83; 95%CI: 0. 681. 01, HROS: + vs -= 0. 83; 95%CI: 0. 69 -1. 01 (adjusted p = 0. 024, 0. 063 respectively). This effect is found also for the 5% cut-off, and preserved in the overall model including all histologies. Using the 50% cut-off, PD-L 1 positivity was detected in 17% of patients; 95%CI: 15 -18, but was no longer a significant predictor of outcome, overall and by histology type. Conclusions: PD-L 1 positivity (1% and 5% cut-offs) was present in more than one third of resected NSCLC and was associated with a better prognosis for AC patients

Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers Jamie E. Chaft

Background: Anti-PD-1 therapy produces objective and often durable responses in ~20% of unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). However, the role of PD-1 blockade in treating resectable NSCLC is unknown. This is the first study to test nivolumab in the neoadjuvant setting. This trial design provides an opportunity to examine anti-PD-1 mechanism of action and immunologic correlates of outcomes. Methods: Patients with Stage IB - IIIA NSCLC received 2 doses of nivolumab 3 mg/kg over 4 weeks before surgery. The primary endpoint was safety in 20 patients with resected NSCLC. Efficacy was explored using objective pathologic response criteria. Correlative studies of the tumor immune microenvironment, tumor mutation and predicted neoantigen loads, and changes in T cell receptor (TCR) clonality in tumor and blood pre and post treatment were conducted. Results: 22 pts were treated. Nivolumab was well-tolerated and no surgeries were delayed. 1 pt withdrew from study preop without progression or toxicity. Among the 21 attempted resections, 1 tumor was unresectable. 9/21 (43%, 95% CI 24 -63%) had a major pathologic response ( < 10% viable tumor cells in resection specimen). With a median postop follow-up of 9 months, 18 pts (86%) remain alive and recurrence free. Pre-treatment tumor exome sequencing showed a correlation between both tumor mutation and predicted neoantigen loads with pathologic response. Multiplex immunohistochemistry of pre- and post-treatment tumors showed an influx of PD-1+CD 8+ T cells into responding tumors. TCR sequencing demonstrated that expanded peripheral T cell clones after treatment match clones found in the tumor. Conclusions: Neoadjuvant nivolumab in resectable NSCLC did not delay surgery. Major pathologic response rate was encouraging and compares favorably to outcomes with cisplatin-based neoadjuvant chemotherapy. Genomic analyses suggest that higher mutational and neoantigen burden could result in deeper pathologic response. Immunologic analyses support the detection of intra-tumoral T cell clones in the blood after treatment with nivolumab and may provide further insight into the molecular and immunologic features of response and non-response to PD-1 blockade. Clinical trial information: NCT 02259621

Ceritinib plus nivolumab (NIVO) in patients (pts) with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC) Enriqueta Felip

Background: Induction of PD-L 1 expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring EML 4–ALK rearrangements. Here we explore whether the combination of ALKi (ceritinib) and PD 1 -inhibitor (NIVO) will provide sustained clinical benefit to pts with ALK+ NSCLC. Methods: This phase 1 dose escalation study enrolled previously treated (ALK inhibitor [ALKi] or chemotherapy) or txnaive pts with stage IIIB/IV ALK+ NSCLC; who received NIVO 3 mg/kg IV Q 2 W + ceritinib with low-fat meal, at 450 mg/day (group 1) or 300 mg/day (group 2) until progression/unacceptable toxicity. Primary objective: MTD/recommended dose for expansion. Dose escalation was guided by Bayesian logistic regression model with overdose control. Results: Median follow-up: group 1 (n = 14) 13 mos (10 -15); group 2 (n = 22) 6 mos (2 -10). As of 9 Sep 2016, 16/36 (44%) pts discontinued tx: disease progression (11 [31%] pts), AE’s (3 [8%] pts), and death (2 [6%] pts). In group 1, 4 pts experienced DLT: pancreatitis (n = 2), lipase and transaminase increase (n = 1), and autoimmune hepatitis (n = 1). In group 2, 2 pts experienced DLT: G 3 ALT increase. Both dose levels met Bayesian criteria for dose expansion. Overall most frequent (≥ 40%) AEs (n = 36), were diarrhea (64%), ALT increase (56%), AST increase (44%) and vomiting (42%). Most frequent ( > 10%) grade ≥ 3 AEs were increases in ALT (22%), GGT (17%), amylase (11%), and lipase (11%), and maculopapular rash (11%). Incidence of rash (grouped term) was 61%; similar in both groups. Grade 3 rash was reported in 29% pts in group 1 and 14% pts in group 2. Preliminary ceritinib steady state PK (AUC 0 -24 and Cmax) suggested that 300 mg/day exposure was ~ 70 -75% of 450 mg/day. Confirmed (c)/unconfirmed (u) ORR: ALKi-pretreated pts (group 1 [n = 8], group 2 [n = 12]) was 63% (4 c. PR, 1 u. PR; 95% CI: 25%, 92%), and 33% (4 u. PR) 95% CI: 10%, 65%) respectively; ALKi-naïve pts, (group 1 [n = 6], group 2 [n = 10]) was 83% (5 c. PR; 95% CI: 36%, 100%), and 70% (1 c. CR, 3 c. PR 3 u. PR; 95% CI: 35%, 93%) respectively. Conclusions: Ceritinib + NIVO is an active combination in ALK+ NSCLC. However, the protocol will be amended to address observed toxicities. Data will be updated for presentation. Clinical trial information: NCT 02393625

First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G Vassiliki Papadimitrakopoulou

Background: Data from the randomized, phase 2 cohort G of KEYNOTE-021 (NCT 02039674) showed that adding pembro to first-line CP in patients (pts) with advanced nonsquamous NSCLC significantly improved the primary end point of ORR (55% vs 29%, P = 0. 0016) and the key secondary end point of PFS (HR 0. 53, P= 0. 0102) compared with CP alone and had a manageable safety profile (grade 3 -4 treatment-related AEs, 39% vs 26%; treatment-related AEs leading to discontinuation, 10% vs 13%). We present updated efficacy for cohort G based on 5 mo additional follow-up. Methods: 123 pts with stage IIIB/IV, chemotherapy-naive, nonsquamous NSCLC and no EGFR mutation or ALK translocation were randomized to 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m 2 Q 3 W ± 24 mo of pembro 200 mg Q 3 W; maintenance pemetrexed was permitted in both arms. Eligible pts in the CP arm who had radiologic progression could crossover to pembro monotherapy. Response was assessed per RECIST v 1. 1 by blinded, independent central review. All Pvalues are nominal. Results: As of Dec 31, 2016, median follow-up was 14. 5 mo (range, 0. 8 -24. 0). 36 of 48 pts (75. 0%) in the CP arm who discontinued CP received subsequent anti–PD-1 or PD-L 1 therapy. There was 1 additional response in each arm, and ORR was 56. 7% (95% CI 43. 2%-69. 4%) with pembro + CP vs 30. 2% (95% CI 19. 2%-43. 0%) with CP (P = 0. 0016). Median DOR was not reached for pembro + CP (range, 1. 4+ to 18. 6+ mo) and was 16. 2 mo (range, 2. 8 to 20. 7+) for CP alone. PFS remained longer with pembro + CP (HR 0. 49, 95% CI 0. 29 -0. 83, P = 0. 0035; median [95% CI] NR [9. 7 mo-NR] vs 8. 9 mo [6. 2 -10. 3]; 12 -mo estimate, 56% vs 34%). With 16 deaths in the pembro + CP arm and 23 deaths in the CP arm, HR for OS was 0. 69 (95% CI 0. 361. 31, P= 0. 13). Median OS was not reached in either arm; at 12 mo, estimated OS was 76% in the pembro + CP arm and 69% in the CP alone arm. Conclusions: With 5 mo additional follow-up, first-line pembro + CP continues to provide a substantial, clinically relevant improvement in efficacy over CP alone in pts with advanced nonquamous NSCLC, including an almost doubled ORR, halved risk of progression or death, and a trend toward improved OS despite a 75. 0% crossover rate in the CP arm. Clinical trial information: NCT 02039674

Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomized phase III OAK study David R. Gandara

Background: Cancer immunotherapy (CIT) can have a positive impact on OS that exceeds response rate or PFS effects, termed post progression prolongation of survival (PPPS). This effect can also result from unconventional CIT response due to tumor immune infiltration or delayed response, reducing reliability of RECIST v 1. 1 (RECIST) PD as an indicator of treatment failure. In the primary analysis (N = 850) of OAK, a study of atezo vs docetaxel (doc) in 2 L/3 L NSCLC, OS favored atezo (HR 0. 73; 95% CI: 0. 62, 0. 87), despite similar PFS between arms (HR 0. 95; 95% CI: 0. 82, 1. 10). Here we evaluate clinical benefit from TBP, defined by post PD tumor regression, OS and safety. Methods: Patients (pts) received atezo 1200 mg IV q 3 w until PD or loss of clinical benefit per investigator or doc 75 mg/m 2 IV q 3 w until PD per RECIST. No crossover was allowed. Primary outcome measure: OS. Atezo TBP pts were evaluated for post PD tumor change and for safety pre and post PD. OS from time of PD per RECIST was evaluated in both arms (data cutoff, July 7, 2016; minimum follow-up, 19 mo). Results: Among 332 atezo pts with PD, 51% (n = 168) continued atezo TBP; 7% (12/168) achieved subsequent response in target lesions (≥ 30% reduction from new baseline at PD); 49% (83/168) had stable target lesions (best change between +20% and − 30%). m. OS was 12. 7 mo (95% CI: 9. 3, 14. 9) post PD for pts on atezo TBP (Table). Atezo TBP was not associated with increased safety risk. Conclusions: This is the first report from a Phase III study of CIT in NSCLC to evaluate post PD OS in pts continuing treatment beyond RECIST PD. Atezo TBP was associated with high frequency of stable or decreased target lesions, m. OS > 1 year and a tolerable safety profile, all supporting prolonged treatment benefit consistent with PPPS. NCT 02008227 Clinical trial information: NCT 02008227