A Multicenter,Randomized Phase III Study Comparing Platinum Combination Chemotherapy Plus Pembrolizumab With Platinum Combination Chemotherapy Plus Nivolumab and Ipilimumab for Treatment-Naive Advanced Non–Small Cell Lung Cancer Without Driver Gene Alterations: JCOG2007 (NIPPON Study)

BackgroundFirst-line treatment of non–small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death–1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte–associated protein–4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC.Patients and MethodsChemotherapy-naïve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events.ConclusionIf the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.     

Ipilimumab,Vemurafenib, Dabrafenib,and Trametinib: Synergistic Competitors in the Clinical Management of BRAF Mutant Malignant Melanoma

There have been significant advances in the treatment of malignant melanoma with the U.S. Food and Drug Administration approval of two drugs in 2011, the first drugs approved in 13 years. The developments of immune checkpoint modulation via cytotoxic T‐lymphocyte antigen‐4 blockade, with ipilimumab, and targeting of BRAF^V600, with vemurafenib or dabrafenib, as well as MEK, with trametinib, have been paradigm changing both for melanoma clinical practice and for oncology therapeutic development. These advancements, however, reveal new clinical questions regarding combinations and optimal sequencing of these agents in patients with BRAF mutant disease. We review the development of these agents, putative biomarkers, and resistance mechanisms relevant to their use, and possibilities for sequencing and combining these agents.     

肺鳞癌的免疫治疗进展

近几年来,肺鳞癌在化疗及靶向治疗上的进展不够显著,但免疫治疗却在肺鳞癌的治疗上取得了突破性的进展。免疫治疗通过免疫系统来清除肿瘤细胞,主要分为免疫检查点抑制剂及治疗性疫苗。免疫检查点抑制剂,包括抗细胞毒性T淋巴细胞抗原4（cytotoxic T-lymphocyte associated antigen 4, CTLA-4）抗体与抗程序性死亡受体-1（programmed death receptor 1, PD-1）抗体等多种药物已进行了肺鳞癌的II期、III期临床试验,并取得了一定成果。免疫治疗将成为肺鳞癌治疗的一种重要手段。     

Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out

Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small cell lung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-based chemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamous and non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition has shown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, the presence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has little benefit from immunotherapy combinations and for whom the best treatment option may still be platinum-based chemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity in EGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns in both EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumab in combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment option upon progression to first line tyrosine kinase inhibitors.     

Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications

Available medical treatments have limited impact on the survival of patients with advanced cancer; therefore, new therapeutic strategies able to generate more effective host's immune responses against neoplastic cells are being actively pursued. Among these, a recent approach involves targeting of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a key immune checkpoint molecule, by monoclonal antibodies (mAbs). Ipilimumab and tremelimumab represent the prototypes of this new class of immunomodulating mAb and have been extensively tested in metastatic melanoma with highly promising results. The clinical activity observed in melanoma has served as a model to exploit the therapeutic potential of CTLA-4 blockade in a variety of human malignancies. Along this line, early-phase trials with anti-CTLA-4 mAbs have been completed or are ongoing in tumors of different histotype. Results are demonstrating the feasibility, safety, and activity of these agents, thus suggesting a promising therapeutic role to be further investigated in phase II/III trials in a wide range of tumors. This review summarizes the main trials with ipilimumab and tremelimumab in tumors of different histotypes, excluding cutaneous melanoma, which is extensively described in other chapters of this issue of Seminars in Oncology.     

Safety and Clinical Activity of Atezolizumab Plus Ipilimumab in Locally Advanced or Metastatic Non–Small Cell Lung Cancer: Results From a Phase 1b Trial

BackgroundThis phase 1b study investigated safety and activity of combined checkpoint inhibition (CPI) with programmed death-ligand 1 (PD-L1) antibody atezolizumab plus cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab in NSCLC.Patients and MethodsEligible patients had previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) or melanoma. A standard 3+3 dose escalation investigated atezolizumab (600-1200 mg IV every 3 weeks) plus ipilimumab starting at 1 mg/kg, administered as a single dose or 4 doses, administered every 3 weeks. The expansion stage included a cohort previously treated with atezolizumab. Patients were monitored for safety and tolerability; response was evaluated every 6 weeks.ResultsTwenty-seven patients were enrolled, 4 with melanoma and 23 with NSCLC; here, we focus on data for the NSCLC population. Three of 23 patients (13.0%) received prior CPI. No dose-limiting toxicities were reported during dose escalation; dose expansion occurred with atezolizumab 1200 mg plus 1 cycle of ipilimumab 1 mg/kg. Most common treatment-emergent adverse events were dyspnea (39%) and cough (35%); treatment-related Grade ≥3 adverse events occurred in 11 patients (48%), most frequently pneumonitis (17%) and amylase or lipase elevation (9% each). Six of 23 NSCLC patients (26%) achieved confirmed responses, 5 of whom (25%) were CPI naive. Median duration of response was 23.0 (95% CI, 3.2-36.9) months overall and 36.9 (95% CI, 2.9-36.9) months in CPI-naive patients.ConclusionPreliminary efficacy of atezolizumab plus ipilimumab was observed in metastatic NSCLC. The combination had manageable toxicity, with a safety profile consistent with those of the individual agents.     

Recent advances in squamous non-small cell lung cancer: evidence beyond predictive biomarkers

Squamous non-small cell lung cancer (NSCLC) has always been characterized by a limited number of therapeutic options and by the lack of actionable biomarkers compared to its non-squamous counterpart. Recent clinical trials have led to the approval of new anti-neoplastic drugs available to both non-squamous and squamous NSCLC, consisting in a vascular-disrupting agent and two immune check-point inhibitors; additionally, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) is currently under evaluation by the Food and Drug Administration (FDA). While predictive molecular biomarkers have not been identified with consistency and are still highly demanded, these agents proved themselves noteworthy and can be considered a powerful addition to the available treatments for squamous NSCLC.     

Immunotherapy in NSCLC patients with brain metastases. Understanding brain tumor microenvironment and dissecting outcomes from immune checkpoint blockade in the clinic

BackgroundBrain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC.MethodsWe reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models.ResultsAlthough limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8⁺ infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion.ConclusionsDiscordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases.     

Next steps in immuno-oncology: enhancing antitumor effects through appropriate patient selection and rationally designed combination strategies

BackgroundCancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well-characterized at preclinical and clinical levels.Patients and methodsWe used PubMed and Google Scholar searches to identify key articles published reporting preclinical and clinical studies investigating CTLA-4 and PD-1/PD-L1, frequently cited review articles, and clinical studies of CTLA-4 and PD-1/PD-L1 pathway inhibitors, including combination therapy strategies. We also searched recent oncology congress presentations and clinicaltrials.gov to cover the most up-to-date clinical trial data and ongoing clinical trials of immune checkpoint inhibitor (ICI) combinations.ResultsInhibiting CTLA-4 and PD-1 using monoclonal antibody therapies administered as single agents has been associated with clinical benefit in distinct patient subgroups across several malignancies. Concurrent blockade of CTLA-4 and components of the PD-1/PD-L1 system using various schedules has shown synergy and even higher incidence of durable antitumor responses at the expense of increased rates of immune-mediated adverse events, which can be life-threatening, but are rarely fatal and are reversible in most cases using established treatment guidelines.ConclusionsDual immune checkpoint blockade has demonstrated promising clinical benefit in numerous solid tumor types. This example of concurrent modulation of multiple components of the immune system is currently being investigated in other cancers using various immunomodulatory strategies.     

Immune modulation for cancer therapy

Background:

Immune modulation in cancer refers to a range of treatments aimed at harnessing a patient''s immune system to achieve tumour control, stabilisation, and potential eradication of disease. A novel therapeutic drug class called immune checkpoint-blocking antibodies modulate T-cell pathways that regulate T cells and have the potential to reinvigorate an antitumour immune response. Ipilimumab was the first FDA-approved immune checkpoint antibody licensed for the treatment of metastatic melanoma (MM) and blocks a checkpoint molecule called cytotoxic T-lymphocyte antigen 4 (CTLA-4).

Methods:

Herein we review the preclinical and clinical development of ipilimumab. We outline the mode of action of these agents and other immune checkpoint inhibitors, the management of their toxicities, and how to adequately assess response to treatment.

Results:

As a result of these data, a number of other antibodies that block novel checkpoint molecules including programmed death-1 (PD-1), and corresponding ligands such as programmed death ligand-1 (PD-L1) are under preclinical and clinical development, and have demonstrated activity in multiple tumour types.

Conclusions:

This review will summarise the mechanism of action and clinical development of immune checkpoint antibodies, as well as lessons learned in the management and assessment of patients receiving these agents.     

A Phase IB Trial of Autologous Cytokine‐Induced Killer Cells in Combination with Sintilimab,Monoclonal Antibody Against Programmed Cell Death‐1, plus Chemotherapy in Patients with Advanced Non‐Small‐Cell Lung Cancer

IntroductionCan the Cytokine-induced killer (CIK) cells in combination with immune checkpoint inhibitor further improve the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients? What are the adverse reactions of this combination therapy? But these problems are not clear. Therefore, we conducted a phase 1b trial to evaluate the safety and efficacy of autologous CIK cells therapy combined with Sintilimab, antibody against programmed cell death-1, plus chemotherapy in untreated, advanced NSCLC patients.Patients and MethodsPatients with stage IIIB/IIIC/IV NSCLC received Sintilimab, platinum-based doublet chemotherapy, and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or 2 years. The primary endpoints were safety and objective response rate (ORR).ResultsThirty-four patients received the treatment. 94.1% of patients experienced treatment-related adverse events (TRAEs). Grade 3 or greater TRAEs occurred in 64.7% of patients. One (2.9%) patient died of grade 5 immune-related pneumonia. The ORR and DCR were 82.4% (95% CI, 65.5%-93.2%) and 100.0% (95% CI, 89.7%-100.0%), respectively. Objective responses were evaluated in 14 of 15 non-squamous patients (93.3%; 95% CI, 68.1%-99.8%) and in 14 of 19 squamous patients (73.7%; 95% CI, 48.8%-90.9%). Median PFS was 19.3 months (95% CI, 8.3 months to not available).ConclusionAutologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy was well tolerable and showed encouraging efficacy in patients with previously untreated, advanced NSCLC (ClinicalTrials.gov number, NCT03987867).     

Health-related quality of life results from the phase III CheckMate 067 study

BackgroundNivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067.Patients and methodsHRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated.ResultsNivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause.ConclusionThese results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.Study numberNCT01844505.     

Nivolumab for the treatment of hepatocellular carcinoma

Introduction: T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab.

Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin’s lymphoma, squamous head and neck cancer, and urothelial carcinoma. In September 2017, nivolumab was approved by the FDA for liver cancer as a second line treatment after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial CheckMate-040. This article reviews the concept of immunotherapy in liver cancer with focus on nivolumab.

Expert commentary: Immunotherapy in hepatocellular carcinoma is safe and is a new treatment option for patients with advanced stage disease besides sorafenib and regorafenib in the US. Randomized phase III trials of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono- or combination-therapy are ongoing.     

Epidermal Growth Factor Receptor Inhibition in the Management of Squamous Cell Carcinoma of the Lung

Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined.

Implications for Practice:

Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.     

Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients

BackgroundSurrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients.Patients and methodsMetastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2–4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann–Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves.ResultsTwenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2–4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression.ConclusionsChanges in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.     

A Phase 1 Trial of Concurrent or Sequential Ipilimumab,Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study

IntroductionPrevious studies have evaluated stereotactic body radiotherapy (SBRT) in oligometastatic patients with NSCLC, including multimodality treatment with anti–programmed cell death protein-1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to evaluate safety and obtain preliminary activity data.MethodsTreatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immunotherapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab and ipilimumab were continued until clinical progression, development of toxicity, or after 2 years. Dose-limiting toxicity was defined as greater than or equal to grade 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy occuring within 3 months.ResultsA total of 37 patients were assessable. No dose-limiting toxicity occurred in the concurrent cohort (n = 18). The sequential cohort required a dose reduction in the central lung group owing to two grade 4 pneumonitis events (2 of 19). Overall best response was as follows: 5.4% (2 of 37) complete response, 40.5% (15 of 37) partial response, 16.2% (6 of 37) stable disease, and 37.8% (14 of 37) progressive disease. Median progression-free survival was 5.8 months (95% confidence interval: 3.6–11.4 mo), with median follow-up of 17.0 months. Median overall survival was not reached.ConclusionsConcurrent nivolumab, ipilimumab, and SBRT were not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastasis control and encouraging early overall survival.     

Ipilimumab: attenuation of an inhibitory immune checkpoint improves survival in metastatic melanoma

Evaluation of: Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).

Interference with the inhibitory immune regulatory checkpoints that act to constrain overly exuberant immune responses and help to maintain peripheral tolerance represents an exciting new paradigm in tumor immunotherapy. We review the study of Hodi and colleagues evaluating the role of blockade of one of these pathways (cytotoxic T-lymphocyte antigen-4) with a monoclonal antibody (ipilimumab, developed by Medarex, NJ, USA and Bristol-Myers Squibb, NY, USA) in patients with advanced melanoma who had failed prior treatments. The randomized Phase III study demonstrates superior overall survival in patients receiving ipilimumab, either alone or in combination with a gp100 peptide vaccine, compared with those receiving the vaccine alone. The results represent the first positive randomized clinical trial ever reported in patients with metastatic melanoma in terms of overall survival, the first showing a beneficial effect of a melanoma treatment in the second-line setting, and the first demonstration that blockade of an immune-inhibitory pathway can be an effective cancer therapeutic.     

Clinical Benefit From Immunotherapy in Patients With SCLC Is Associated With Tumor Capacity for Antigen Presentation

IntroductionA small percentage of patients with SCLC experience durable responses to immune checkpoint blockade (ICB). Defining determinants of immune response may nominate strategies to broaden the efficacy of immunotherapy in patients with SCLC. Prior studies have been limited by small numbers or concomitant chemotherapy administration.MethodsCheckMate 032, a multicenter, open-label, phase 1/2 trial evaluating nivolumab alone or with ipilimumab was the largest study of ICB alone in patients with SCLC. We performed comprehensive RNA sequencing of 286 pretreatment SCLC tumor samples, assessing outcome on the basis of defined SCLC subtypes (SCLC-A, -N, -P, and -Y), and expression signatures associated with durable benefit, defined as progression-free survival more than or equal to 6 months. Potential biomarkers were further explored by immunohistochemistry.ResultsNone of the subtypes were associated with survival. Antigen presentation machinery signature (p = 0.000032) and presence of more than or equal to 1% infiltrating CD8+ T cells by immunohistochemistry (hazard ratio = 0.51, 95% confidence interval: 0.27–0.95) both correlated with survival in patients treated with nivolumab. Pathway enrichment analysis revealed the association between durable benefit from immunotherapy and antigen processing and presentation. Analysis of epigenetic determinants of antigen presentation identified LSD1 gene expression as a correlate of worse survival outcomes for patients treated with either nivolumab or the combination of nivolumab and ipilimumab.ConclusionsTumor antigen processing and presentation is a key correlate of ICB efficacy in patients with SCLC. As antigen presentation machinery is frequently epigenetically suppressed in SCLC, this study defines a targetable mechanism by which we might improve clinical benefit of ICB for patients with SCLC.     

Immunotherapy for Head and Neck Squamous Cell Carcinoma

Purpose of Review

Discussion of current strategies targeting the immune system related to solid tumors with emphasis on head and neck squamous cell carcinoma (HNSCC).This review will outline the current challenges with immunotherapy and future goals for treatment using these agents.

Recent Findings

Agents targeting immune checkpoint receptors (IR) such as program death 1 (PD1) have been used in the clinical realm for melanoma and non-small cell lung cancer (NSCLC), and the use of these agents for these malignancies has provided crucial information about how and why patients respond or not to inhibitory checkpoint receptor blockade therapy (ICR). The anti PD1 agent, nivolumab, was recently approved by the FDA as a standard of care regimen for patients with platinum refractory recurrent/metastatic (R/M) HNSCC. Molecular pathways leading to resistance are starting to be identified, and work is underway to understand the most optimal treatment regimen with incorporation of immunotherapy.

Summary

ICR has renewed interest in the immunology of cancer, but resistance is not uncommon, and thus understanding of these mechanisms will allow the clinician to appropriately select patients that will benefit from this therapy.