Dataset Information

Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients.

ABSTRACT:

Background

The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events.

Methods

To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non-small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up.

Results

Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2-15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response.

Conclusions

Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment.

Trial registration

University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623.

Funding

This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).

SUBMITTER: Osa A

PROVIDER: S-EPMC6237460 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients.

Osa Akio A Uenami Takeshi T Koyama Shohei S Fujimoto Kosuke K Okuzaki Daisuke D Takimoto Takayuki T Hirata Haruhiko H Yano Yukihiro Y Yokota Soichiro S Kinehara Yuhei Y Naito Yujiro Y Otsuka Tomoyuki T Kanazu Masaki M Kuroyama Muneyoshi M Hamaguchi Masanari M Koba Taro T Futami Yu Y Ishijima Mikako M Suga Yasuhiko Y Akazawa Yuki Y Machiyama Hirotomo H Iwahori Kota K Takamatsu Hyota H Nagatomo Izumi I Takeda Yoshito Y Kida Hiroshi H Akbay Esra A EA Hammerman Peter S PS Wong Kwok-Kin KK Dranoff Glenn G Mori Masahide M Kijima Takashi T Kumanogoh Atsushi A

JCI insight 20181004 19

<h4>Background</h4>The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events.<h4>Methods</h4>To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used i ...[more]

PMID: 30282824

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Project description:BackgroundSurgical outcomes for non-small cell lung cancer after neoadjuvant immune checkpoint inhibitors continue to be debated. We assessed perioperative outcomes of patients treated with Nivolumab or Nivolumab plus Ipilimumab (NEOSTAR) and compared them with patients treated with chemotherapy or previously untreated patients with stage I-IIIA non-small cell lung cancer.MethodsForty-four patients with stage I to IIIA non-small cell lung cancer (American Joint Committee on Cancer Staging Manual, seventh edition) were randomized to nivolumab (N; 3 mg/kg intravenously on days 1, 15, and 29; n = 23) or nivolumab with ipilimumab (NI; I, 1 mg/kg intravenously on day 1; n = 21). Curative-intent operations were planned between 3 and 6 weeks after the last dose of neoadjuvant N. Patients who completed resection upfront or after chemotherapy from the same time period were used as comparison.ResultsIn the N arm, 21 (91%) were resected on-trial, 1 underwent surgery off-trial, and one was not resected (toxicity-related). In the NI arm, 16 (76%) resections were performed on-trial, one off-trial, and 4 were not resected (none toxicity-related). Median time to operation was 31 days, and consisted of 2 (5%) pneumonectomies, 33 (89%) lobectomies, and 1 (3%) each of segmentectomy and wedge resection. The approach was 27 (73%) thoracotomy, 7 (19%) thoracoscopy, and 3 (8%) robotic-assisted. Conversion occurred in 17% (n = 2/12) of minimally invasive cases. All 37 achieved R0 resection. Pulmonary, cardiac, enteric, neurologic, and wound complications occurred in 9 (24%), 4 (11%), 2 (5%), 1 (3%), and 1 (3%) patient, respectively. The 30- and 90-day mortality rate was 0% and 2.7% (n = 1), respectively. Postoperative complication rates were comparable with lung resection upfront or after chemotherapy.ConclusionsOperating after neoadjuvant N or NI is overall safe and effective and yields perioperative outcomes similar to those achieved after chemotherapy or upfront resection.

Project description:Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.In this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non-small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.Overall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (?1%, ?5%, and ?10%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov number, NCT01673867.).

Project description:We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab. Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint. While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations. Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Project description:Importance:Nivolumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now the standard-of-care therapies in non-small cell lung cancer (NSCLC). Although EGFR-TKIs are well understood and have well-defined safety profiles, our experience with immune checkpoint inhibitors is still growing, particularly regarding the use of combinations of different classes of antitumor agents, including both the concomitant and sequential use of such agents. Objective:To determine whether nivolumab increases EGFR-TKI-associated interstitial pneumonitis (IP). Design, Setting, and Participants:A database study of 20 516 participants with NSCLC in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, performed between April 2015 and March 2017. Main Outcomes and Measures:We compared the incidence of EGFR-TKI-associated IP in patients receiving and not receiving nivolumab treatment. Results:The mean (SD) age of participants treated with EGFR-TKI, with and without nivolumab, was 64.4 (15.5) and 68.9 (11.8) years, respectively, and the proportion of men was 40.0% and 53.8%, respectively. Of the 20 516 participants with NSCLC, 985 cases (4.80%; 95% CI, 4.51-5.10) developed IP. Of 5777 patients treated with EGFR-TKI, 265 developed IP (4.59%; 95% CI, 4.06-5.16). Of 70 patients treated with both EGFR-TKI and nivolumab, 18 developed IP (25.7%; 95% CI, 16.0-37.6). The adjusted odds ratio for an interaction between EGFR-TKI and nivolumab was 4.31 (95% CI, 2.37-7.86; P < .001), suggesting the existence of an interaction. When we further stratified the patients by treatment with and without nivolumab, the odds ratio of EGFR-TKI-associated IP in cases with and without nivolumab treatment was 5.09 (95% CI, 2.87-9.03) and 1.22 (95% CI, 1.00-1.47), respectively. Conclusions and Relevance:We found a higher proportion of reports of IP for nivolumab in combination with EGFR-TKI vs treatment with either drug alone. Owing to the limitations of this study, the results warrant further confirmation. However, careful consideration should be given to the possibility of an increased risk of IP when EGFR-TKI is administered in combination with nivolumab, including concomitant and sequential use, and careful monitoring for IP is recommended.

Dataset Information

Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients.

Background

Methods

Results

Conclusions

Trial registration

Funding

Publications

Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients.

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