Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumabin patients with SCLC who progressed after one or more previous regimens.
Methods
The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394.
Findings
Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0–464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0–470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0–288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis.
Interpretation
Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC.
Funding
Bristol-Myers Squibb.
Introduction
Small-cell lung cancer (SCLC), which accounts for roughly 14% of all lung cancers, is strongly associated with tobacco use and has high mutation rates without known oncogenic drivers.1, 2 Most patients present with extensive-stage disease characterised by widespread metastases and poor survival.2 Although 35–86% of patients respond to first-line chemotherapy, disease progresses rapidly, and outcomes with second-line treatment are poor.3, 4, 5, 6
Research in context
Evidence before this study
We searched the scientific literature for outcomes following failure of first-line treatment in patients with small-cell lung cancer (SCLC) and available subsequent treatment options. The search terms “SCLC”, “recurrent”, “relapsed”, “second-line”, “third-line”, “phase 1”, “phase 2” and/or “phase 3” were used in PubMed focusing on reports and meta-analyses during the 10-year period before the start of the trial from Jan 1, 2003, to Jan 1, 2013. To investigate the potential for immunotherapy in SCLC, the terms “SCLC” and “immune response”, “immunotherapy”, “PD-1”, “CTLA-4”, “NSCLC”, “PD-L1”, “nivolumab”, “ipilimumab”, “MK3475”, “lambrolizumab”, “MPDL3280A”, “MEDI4736”, and “tremelimumab” were used to search PubMed, congress abstracts from the annual meetings of the American Association of Cancer Research, American Society of Clinical Oncology, European Cancer Congress, and World Conference on Lung Cancer, and for ongoing trials in ClinicalTrials.gov.
The searches revealed poor survival outcomes for patients with recurrent or relapsed SCLC and no treatment options beyond second line. The following pieces of evidence underscored the rationale for investigating nivolumab and nivolumab plus ipilimumab in SCLC: SCLC is immunogenic, ipilimumab in combination with chemotherapy was active in extensive-disease SCLC, and nivolumab and nivolumab plus ipilimumab showed encouraging activity in non-small-cell lung cancer in phase 1/2 trials.
Added value of this study
Nivolumab alone and in combination with ipilimumab demonstrated durable objective responses, encouraging overall survival, and manageable safety in patients with advanced SCLC who had progressed after one or more previous regimens. To our knowledge, this is the first trial showing activity of nivolumab and nivolumab plus ipilimumab in SCLC, in a hard-to-treat population of patients with limited treatment options.
Implications of all the available evidence
Based on the notable objective responses, the duration of the responses, and the median overall survival seen with nivolumab plus ipilimumab treatment in this patient population, phase 3 studies for nivolumab and nivolumab plus ipilimumab as maintenance therapy (in non-progressing patients) after first-line chemotherapy (CheckMate 451, NCT02538666), and for nivolumab versus chemotherapy as second-line therapy (CheckMate 331, NCT02481830) in SCLC are ongoing.
Standard first-line chemotherapy for SCLC is a platinum–etoposide doublet, with topotecan as second-line therapy in the USA and European Union1 and amrubicin as second-line therapy in Japan.7 Although response with topotecan is achieved in 23% of platinum-sensitive patients and 9% of platinum-resistant or refractory patients, these responses are not durable.8
Nivolumab, a fully human IgG4 PD-1 immune-checkpoint inhibitor antibody, significantly improved overall survival and had a favourable safety profile compared with docetaxel in two phase 3 studies of patients with non-small-cell lung cancer (NSCLC) who progressed after first-line platinum-based doublet chemotherapy,9, 10 leading to its approval in the USA and the European Union for treatment of patients with locally advanced or metastatic NSCLC.11 Ipilimumab, a fully human IgG1 CTLA-4 immune-checkpoint inhibitor antibody, significantly improved overall survival compared with glycoprotein peptide 100 vaccine in patients with metastatic melanoma,12 and ipilimumab plus dacarbazine improved survival over dacarbazine alone in patients with metastatic melanoma.13 Ipilimumab is approved in the USA and the European Union for this indication.
Preclinical data suggest that the combination of PD-1 and CTLA-4 receptor blockade might improve antitumour activity,14 and the combination of nivolumab plus ipilimumab has demonstrated deep and durable responses in several tumour types.15, 16, 17 The combination of nivolumab plus ipilimumab is approved in the USA and the European Union for treatment of advanced melanoma. On the basis of efficacy of combination treatment in melanoma, CheckMate 032 was designed as a phase 1/2 trial to investigate the activity and safety of nivolumab as monotherapy or in combination with ipilimumab in several advanced or metastatic solid tumour types. The evaluation of nivolumab monotherapy and the combination of nivolumab and ipilimumab in patients with advanced or metastatic tumours for which no standard of care in advanced lines of treatment exists will potentially generate evidence of antitumour activity as a basis for further clinical development in these tumour types. Here, we report activity, safety, and biomarker analyses for the SCLC cohort.
Section snippets
Study design and participants
This was a multicentre, open-label, two-stage, multi-arm phase 1/2 trial. Patients with SCLC were enrolled at 23 sites (academic centres and hospitals) in six countries (Finland, Germany, Italy, Spain, UK, and USA; appendix p 19). Eligible patients had histologically or cytologically confirmed, limited-stage or extensive-stage SCLC, with progressive disease after at least one platinum-based chemotherapy regimen. Patients with platinum-sensitive (relapse ≥90 days after chemotherapy) or
Results
We enrolled and treated 216 patients with SCLC between Nov 18, 2013, and July 28, 2015: 98 patients in the nivolumab 3 mg/kg cohort, three patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort, 61 patients in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and 54 in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort (figure 1). Three patients in the nivolumab 3 mg/kg group, two patients in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four patients in the nivolumab
Discussion
Our findings show that nivolumab monotherapy and nivolumab plus ipilimumab provide clinically meaningful activity and an acceptable safety profile for patients with limited-stage or extensive-stage SCLC and disease progression after at least one previous platinum-containing regimen. The prognosis for patients with progression after previous treatment with platinum-based chemotherapy is poor. Patients with advanced SCLC frequently respond to first-line therapy; however, recurrence is inevitable,
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Expanded cohort results from CheckMate 016: a phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC)
Renal cell carcinoma (RCC) is a frequent urological malignancy characterized by a high rate of metastasis and lethality. The treatment strategy for advanced RCC has moved through multiple iterations over the past three decades. Initially, cytokine treatment was the only systemic treatment option for patients with RCC. With the development of medicine, antiangiogenic agents targeting vascular endothelial growth factor and mammalian target of rapamycin and immunotherapy, immune checkpoint inhibitors (ICIs) have emerged and received several achievements in the therapeutics of advanced RCC. However, ICIs have still not brought completely satisfactory results due to drug resistance and undesirable side effects. For the past years, the interests form researchers have been attracted by the combination of ICIs and targeted therapy for advanced RCC and the angiogenesis and immunogenic tumor microenvironmental variations in RCC. Therefore, we emphasize the potential principle and the clinical progress of ICIs combined with targeted treatment of advanced RCC, and summarize the future direction.
Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here.
Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion).
Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year.
With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.
Lung cancer is a leading cause of cancer-related deaths globally, includes small cell lung cancer (SCLC), characterized by its aggressive nature and advanced disease at diagnosis. However, the identification of reliable biomarkers for SCLC has proven challenging, as no consistent predictive biomarker has been established. Nonetheless, certain tumor-associated antigens, including programmed death-ligand 1 (PDL1) and Delta-Like Ligand 3 (DLL3), show promise for targeted antibody-based immunotherapy. To ensure optimal patient selection, it remains crucial to comprehend the relationship between PDL1 and DLL3 expression and clinicopathological characteristics in SCLC. In this study, we investigated the expression patterns of PDL1 and DLL3 biomarkers in endobronchial samples from 44 SCLC patients, examining their association with clinical characteristics and survival. High PDL1 expression (>1%) was observed in 14% of patients, while the majority the SCLC patients (73%) exhibited high DLL3 expression (>75%). Notably, we found a positive correlation between high PDL1 expression (>1%) and overall survival. However, we did not observe any significant differences in the biomarkers expression concerning age, sex, disease status, smoking status, or distant metastases. Further subgroup analysis revealed that a high co-expression of both PDL1 (>1%) and DLL3 (100%) antigens was associated with improved overall survival. This suggests that SCLC expressing PDL1 and DLL3 antigens may exhibit increased sensitivity to therapy, indicating their potential as therapeutic targets. Thus, our findings provide novel insights into the simultaneous evaluation of PDL1 and DLL3 biomarkers in SCLC patients. These insights have significant clinical implications for therapeutic strategies, survival prediction, and development of combination immunotherapies.
Immunotherapy has shown promise in treating various cancers; however, its efficacy in endometrial cancer (EC) remains suboptimal owing to the complex dynamics of the tumour immune microenvironment. This study focuses on exploring the potential of targeting the programmed cell death protein 1 gene (PD-1) and the T cell Immunoreceptor with Ig and ITIM domains gene (TIGIT) coexpressing tissue-resident memory cells in EC.
A comprehensive approach, utilizing RNA sequencing, single-cell RNA sequencing, mass cytometry, and flow cytometry, was employed to analyse the expression patterns of PD-1 and TIGIT in the EC tumor environment and to characterize the phenotypic properties of tumor-infiltrating lymphocytes (TILs), particularly tissue-resident memory (TRM) cells. Additionally, in vitro cell experiments were conducted to assess the functional impact of PD-1 and TIGIT blockade on T-cell activity.
Our analysis identified a significant co-expression of PD-1 and TIGIT in TRM cells within the EC tumor microenvironment. These TRM cells displayed an exhausted phenotype with impaired cytotoxicity, enhanced proliferative capacity, and diminished cytotoxic activity. In vitro T-cell assays showed that a dual blockade of PD-1 and TIGIT more effectively restored T-cell functionality compared to single blockade, suggesting enhanced therapeutic potential.
TRM cells co-expressing PD-1 and TIGIT represent potential targets for EC immunotherapy. Dual immune checkpoint blockade targeting PD-1 and TIGIT may offer an effective therapeutic strategy for EC, providing valuable insights for the development of immunotherapeutic approaches.
In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival.
Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS.
More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm.
These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen.