Programmed Death-ligand 1 Monotherapy Research Articles

Efficacy of PD-1/PD-L1 inhibitors in advanced hepatocellular carcinoma: A systematic review and meta-analysis.

This study aimed to investigate the efficacy and safety of programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in patients with advanced hepatocellular carcinoma (HCC). PubMed, EMBASE, and the Cochrane Library were searched for articles published until November 2022. Studies reporting the efficacy of PD-1/PD-L1 inhibitors in patients with advanced HCC were eligible for inclusion. The outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and ≥ Grade 3 treatment-related adverse events (TrAEs). Fourteen trials with 4515 patients with HCC were included. Our results showed that treatment with PD-1/PD-L1 inhibitors was associated with better ORR and DCR than that with control (placebo or sorafenib or lenvatinib) (odds ratio [OR], 3.89; 95% confidence interval (CI), 2.55-5.95 and OR, 1.47; 95% CI, 1.11-1.95, respectively). The overall hazard ratio (HR) of PFS and OS were 0.66 (95% CI 0.56-0.78) and 0.65 (95% CI 0.55-0.77), respectively. In subgroup analysis, PD-1/PD-L1 inhibitor combination therapy had an advantage in terms of PFS (HR: 0.57 vs. 0.81) compared to that of PD-1/PD-L1 monotherapy. The incidence of grade 3-5 TrAEs was not significantly higher with PD-1/PD-L1 inhibitors than that with the control (OR, 1.12; 95% CI, 0.70-1.81). However, the combination of PD-1inhibitor with higher incidence of Grade 3-5 TrAEs (OR: 2.04, 95% CI 0.66-6.32) than the combination PD-L1 inhibitor (OR: 0.95, 95% CI 0.50-1.81). The combination of PD-1/PD-L1 inhibitors and targeted agents significantly improved the clinical outcomes in patients with advanced HCC. However, the incidence of Grade 3-5 TrAEs with PD-1 inhibitor combination therapy was higher than the combination PD-L1 inhibitor.

Incidence of Hyper Progressive Disease in Combination Immunotherapy and Anti-Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Monotherapy for Unresectable Hepatocellular Carcinoma

Introduction: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies. Methods: This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January 2015 to December 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40%, and tumor growth kinetics ratio ≥4. Results: The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (p = 0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% confidence interval [CI]: 0.05–3.83) when compared to the anti-PD-1/PD-L1 monotherapy group and 2.93 (95% CI: 0.25–33.79) when compared to the combined VEGF antibody group. Conclusion: The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.

The predictive value of PD-L1 expression in patients with advanced hepatocellular carcinoma treated with PD-1/PD-L1 inhibitors: A systematic review and meta-analysis.

Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have transformed the treatment landscape of advanced hepatocellular carcinoma (HCC), but consistent responses are not observed in all patients, and prognostic biomarkers to guide treatment decisions are lacking. We aimed to evaluate the predictive value of PD-L1 expression in advanced HCC patients treated with PD-1/PD-L1 inhibitors. A comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted. Studies comparing the objective response rate (ORR) and/or disease control rate (DCR) based on the tumor PD-L1 status of HCC were included. Eleven studies with 1,330 HCC patients treated with PD-1/PD-L1 inhibitors were included. Pooled odds ratio (OR) analysis demonstrated a significantly improved ORR in PD-L1-positive patients compared with PD-L1-negative patients (OR, 1.86, 95% CI, 1.35-2.55). Similar results were observed in the anti-PD-1 treatment (p < 0.001) and anti-PD-1/PD-L1 monotherapy (p < 0.001) subgroups. The pooled ORRs in the PD-L1-positive and PD-L1-negative groups were 26% (95% CI, 20%-32%) and 18% (95% CI, 13%-22%), respectively. For DCR, the pooled OR analysis showed no significant difference between PD-L1-positive patients and PD-L1-negative patients (66% [95% CI, 55%-76%] vs. 69% [95% CI, 62%-76%]; OR, 0.92, 95% CI, 0.59-1.44). The results were consistent across the drug target and combination treatment subgroups. Positive PD-L1 expression is associated with a better ORR in advanced HCC patients treated with anti-PD-1/PD-L1-based therapies. This feature can help to identify HCC patients who will benefit most from PD-1/PD-L1 inhibitors.

Immunotherapy in combination with chemotherapy vs. immunotherapy alone for advanced non-small cell lung cancer and programmed death ligand 1 score

IntroductionLittle is known about the effectiveness of immunotherapy alone or with chemotherapy for patients with non-small cell lung cancer (NSCLC) and programmed death ligand 1 (PD-L1) expression <50 %. We examined the outcomes of PD-L1 therapy vs. PD-L1 therapy in combination with chemotherapy as first-line treatment among NSCLC patients with PD-L1 score <50 %. MethodsWe used administrative claims and prior authorization data of a national insurer from November 2015 to July 2021. We selected patients with Stage IIIb/IV NSCLC and PD-L1 expression <50 %. Each patient was required to have ≥1 claim of a PD-L1 or PD-1 inhibitor. Treatment groups were propensity-score matched 1:1 on baseline characteristics. We measured PD-L1 therapy duration, incident immune-related adverse events (irAEs), healthcare utilization, costs, and overall survival (OS). ResultsIn the matched sample totaling 176 patients, mean duration of PD-L1 therapy was similar (4.1 [SD 3.3] months combination vs. 4.0 [SD 4.9] months monotherapy, p = 0.800). IrAEs were similar, both for FDA-recognized irAEs (48.9 % combination, 48.9 % monotherapy, p = 0.710) and other types (34.1 % combination, 39.8 % monotherapy, p = 0.473). The combination group had more all-cause inpatient stays, ER visits, and outpatient visits (all p < 0.001). Total adjusted all-cause medical cost was $112,833 (95 % CI $5,548-$251,973) higher for combination therapy. We saw no difference in OS (adjusted hazard ratio 1.09 [95 % CI 0.72–1.65]). ConclusionThis study found no difference in adverse drug effects or survival between PD-L1 monotherapy compared to combination therapy for patients with Stage IIIb/IV NSCLC and PD-L1 expression <50 %, though the combination therapy cohort had higher healthcare utilization and costs. MicroAbstractUse of immunotherapy alone or combined with chemotherapy for patients with non-small cell lung cancer and programmed death ligand 1 expression <50 % is understudied. Our observational study using claims and authorization data from a matched sample of 176 patients found no difference in survival or the rate of adverse drug effects between groups, although the chemo-immunotherapy cohort generated higher overall healthcare costs.

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study.

Simple SummaryProgrammed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitor is the standard therapy for advanced microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers. However, the suitable therapy after the progression of anti-PD1/PD-L1 for MSI/dMMR gastrointestinal cancer patients was unknown, until now. Here, we conducted a retrospective study to evaluate the efficacy of anti-PD1/PD-L1 plus other drug therapy versus chemotherapy with or without targeted therapy for patients who had progressed on prior anti-PD1/PD-L1 monotherapy. Our study found that anti-PD1/PD-L1 plus other drug therapy had significantly improved the disease control rate, progression-free survival, and overall survival, along with a numerically higher objective response rate versus chemotherapy with or without targeted therapy. The promising findings of our retrospective study need to be further confirmed in prospective trials.Background: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with or without targeted therapy in MSI/dMMR gastrointestinal cancer patients after progression on anti-PD1/PD-L1 monotherapy. Methods: We retrospectively recruited MSI/dMMR gastrointestinal cancer patients who had progressed on anti-PD1/PD-L1 monotherapy. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr) were compared between patients who received anti-PD1/PD-L1 plus other therapy (ICI-plus group) and patients who received chemotherapy with or without targeted therapy (chemo-targeted group). Results: In total, 26 and 25 patients were recruited in the ICI-plus group and chemo-targeted group, respectively. Significantly better DCR (80.8% vs. 44.0%, p = 0.007), PFS (median PFS 6.9 months vs. 3.0 months, p = 0.001), OS (median OS NR vs. 14.1 months, p = 0.043), and PFSr (2.4 vs. 0.9, p = 0.021), along with a numerically higher ORR (23.1% vs. 12.0%, p = 0.503) were observed in the ICI-plus group compared with the chemo-targeted group. Multivariate analyses identified the therapy regimen as an important prognostic factor in gastrointestinal cancers. Conclusions: Compared to conventional chemotherapy with or without targeted therapy, continuing anti-PD1/PD-L1 in combination with other treatments showed better clinical outcomes in MSI/dMMR gastrointestinal cancer patients who progressed on PD1/PD-L1 blockade, which should be validated prospectively in clinical trials.

Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial

Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy. In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406. 50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B. First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma. Bristol Myers Squibb Rare Population Malignancy Program.

Clinical outcomes of PD-1/PD-L1 inhibitors in patients with advanced hepatocellular carcinoma: a systematic review and meta-analysis.

Programmed death ligand 1(PD-L1)/programmed cell death-1(PD-1) inhibitors have shown promising efficacy in unresectable patients with advanced hepatocellular carcinoma (HCC), but the results are not consistent. Our goal was to evaluate the safety and efficacy of PD-L1/PD-1 inhibitors or plus anti-CTLA-4 antibody or anti-VEGF agents for the treatment of unresectable HCC. Cochrane library, Embase, and PubMed were searched till August 2021. Data on progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and disease control rate (DCR) were pooled and analyzed by Stata14 software. Thirteen prospective trials with 2,386 HCC patients were included. Pooled analysis estimated an ORR of about 0.21 (95% CI = 0.18-0.25) and a DCR of 0.59 (95% CI = 0.52-0.65) for anti-PD-1/PD-L1 therapy. Summary PFS was 4.19 (95% CI = 3.31-5.18) months and summary OS was 13.23 (95% CI = 12.06-14.41) months. After using PD-L1/PD-1 inhibitors plus anti-VEGF agents, ORR was 0.26 (95% CI = 0.20-0.33), DCR was 0.75 (95% CI = 0.69-0.81) and PFS was 6.2 (95% CI = 4.61-7.78) months. PD-L1/PD-1 inhibitors plus anti-CTLA-4 antibody therapy achieved an ORR of 0.23 (95% CI = 0.14-0.33), an DCR of 0.44 (95% CI = 0.39-0.50) and a PFS of 1.88 (95% CI = 1.51-2.26). PD-L1/PD-1 inhibitors were effective and tolerable in patients with advanced HCC. Furthermore, compared with anti-PD-1/PD-L1 monotherapy, PD-L1/PD-1 inhibitors plus anti-VEGF agents resulted in more clinical improvements in ORR, DCR, and PFS.

The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3.

Simple SummaryMalignant pleural mesothelioma is an aggressive cancer most commonly associated with asbestos exposure. Its prognosis is very poor, and the current treatments have only a limited impact on survival. Therefore, there is an urgent need to develop new treatment strategies. We investigated combinations of different immune checkpoint blocking antibodies that have already shown promising results in several cancer types. We suggested that the effect of a combination treatment might even be better than one, single therapy. Based on our in vitro results about the secretion of several immune related molecules we selected promising treatments for further investigation in a mesothelioma mouse model. We found that monotherapy with an immune checkpoint blocking antibody against programmed death-1 (PD-1), and its combination with another blocking antibody against lymphocyte activation gene-3 (LAG-3), resulted in delayed tumor growth and survival benefit in our mice. Further research is warranted to optimize the treatment schedule of the combination therapy.Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9–12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit.

Higher Enhancement Intrahepatic Nodules on the Hepatobiliary Phase of Gd-EOB-DTPA-Enhanced MRI as a Poor Responsive Marker of Anti-PD-1/PD-L1 Monotherapy for Unresectable Hepatocellular Carcinoma

Introduction: Immune checkpoint inhibitors (ICIs) are promising agents for the treatment of hepatocellular carcinoma (HCC). However, the establishment of noninvasive measure that could predict the response to ICIs is challenging. This study aimed to evaluate tumor responses to ICIs using the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), which was shown to reflect Wnt/β-catenin activating mutation. Methods: A total of 68 intrahepatic HCC nodules from 18 patients with unresectable HCC and Child-Pugh class A liver function who received anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy were enrolled in this study. All patients had viable intrahepatic lesions evaluable using the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI within the 6 months prior to the treatment. The relative enhancement ratio was calculated, and the time to nodular progression (TTnP) defined as 20% or more increase in each nodule was compared between higher or hypo-enhancement HCC nodules. Then, the progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) were compared between patients with and without HCC nodules with higher enhancement on hepatobiliary phase images. Results: The median PFS was 2.7 (95% confidence interval [CI]: 1.4–4.0) months in patients with HCC nodules with higher enhancement (n = 8) and 5.8 (95% CI: 0.0–18.9) months in patients with hypointense HCC nodules (n = 10) (p = 0.007). The median TTnP of HCC nodules with higher enhancement (n = 23) was 1.97 (95% CI: 1.86–2.07) months and that of hypointense HCC nodules (n = 45) was not reached (p = 0.003). The ORR was 12.5% (1/8) versus 30.0% (3/10); the disease control rate was 37.5% (3/8) versus 70.0% (7/10), respectively, in patients with or without higher enhancement intrahepatic HCC nodules. Conclusion: The TTnP on HCC nodules with higher enhancement and the median PFS in patients who carried higher enhancement intrahepatic HCC nodules were significantly shorter than those in hypointense HCC nodules with anti-PD-1/PD-L1 monotherapy. The intensity of the nodule on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 monotherapy in patients with HCC.

Systemic Analysis and Review of Nivolumab-ipilimumab Combination as a Rescue Strategy for Renal Cell Carcinoma After Treatment With Anti-PD-1/PD-L1 Therapy.

Nivolumab-ipilimumab has become the standard of care in the frontline setting for intermediate-/poor-risk metastatic renal cell carcinoma (mRCC). This regimen is associated with survival improvement but significant toxicity. Anti-programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) monotherapy may provide response and offers a better safety profile. In this context, nivolumab-ipilimumab has been postulated as a rescue treatment after anti-PD-1/PD-L1 therapy. Recent retrospective data has shown positive results, and several nonrandomized clinical trials (NRCTs) have evaluated this strategy. Therefore, we performed a meta-analysis of available NRCTs to clarify the efficacy and safety of salvage nivolumab-ipilimumab in mRCC after prior anti-PD-1/PD-L1 monotherapy. We searched PubMed, Medline, Embase, and the Cochrane Central Register of Controlled Trials to identify clinical trials investigating the efficacy and safety of salvage nivolumab-ipilimumab after prior anti-PD-1/PD-L1 in patients with mRCC. Only phase II NRCTs were available for the analysis. The pooled effect of single proportions with a 95% confidence interval (CI) was used as the measure of effect (overall response rate [ORR] and incidence of grade≥ 3 adverse events). Four studies accounting for 237 patients were included. All patients received prior anti-PD-1/PD-L1 monotherapy. The pooled ORR of salvage nivolumab-ipilimumab after prior anti-PD-1/PD-L1 failure was 10.0% (95% CI, 6%-14%; I2= 41%; P= .17). The incidence of grade≥ 3 irAEs was 27.0% (95% CI, 20%-35%; I2= 0%; P= .56). The results of this analysis suggest that the use of salvage nivolumab-ipilimumab in mRCC after prior anti-PD-1/PD-L1 has limited activity with a 10% ORR, and a non-negligible toxicity with 1 of 4 patients developing grade≥ 3 immune-related adverse events.

Therapeutic efficacy analysis of immunotherapy in small cell lung cancer

Objective: Recently, increasing number of lung cancer patients benefit from immune-checkpoint inhibitors (ICIs). However, the data of Chinese small cell lung cancer (SCLC) patients is limited. This study aims to analyze the response and survival data of ICIs treatment in SCLC and to explore the predictive biomarkers. Methods: Forty-seven SCLC patients who received ICIs treatment from Peking University Cancer Hospital from May 2017 to September 2019 was recruited. Clinical characteristics including sex, age, smoking status, ICIs strategy, PD-L1 expression and therapeutic efficacy were collected to explore the clinical predictive biomarkers for SCLC ICIs treatment. Results: Among the 47 patients, 18 (38.3%) cases were partial repose (PR), 11 (23.4%) were stable disease (SD), 18 (38.3%) were progressive disease (PD), and the objective response rate (ORR) was 38.3%, disease control rate (DCR) was 61.7%, the median progression-free survival (PFS) was 5.3 months. ICIs monotherapy accounts for 27.7%, the ORR was 15.4%, DCR was 53.8%, median PFS was 2.7 months. Combined therapy accounts for 72.3%, the ORR was 47.1%, DCR was 64.7%, median PFS was 5.4 months. Fourteen (29.8%) patients received ICIs as the first line treatment, their ORR was 85.7%, DCR was 100%, median PFS was 9.1 month. The ORR was not related to the age, sex, body mass index (BMI), smoking status and programmed death-ligand 1 (PD-L1) expression (P>0.05). The ORRs were higher in patients underwent PD-L1 monotherapy (P=0.001), combined therapy (P=0.002) and received ICIs as the first line treatment (P<0.001). Log-rank analysis indicated that the PFS of female patients were 12.0 months, significantly longer than 4.4 months of male patients in ICIs treatment (P=0.038). Patients who received PD-L1 monotherapy, combined treatment, or ICIs as the first line treatment had longer PFS than their counterparts, though no statistical significant was observed (P>0.05). Cox multivariate analysis showed that, the gender was not an independent predictor for PFS in ICIs treatment (HR=3.777, 95%CI=0.974~30.891, P=0.054). Conclusions: Immunotherapy is an effective treatment strategy for SCLC. Patients who receive combined ICIs treatment, first line ICIs treatment and PD-L1 treatment may get greater benefits. PD-L1 expression cannot predict the response and PFS in SCLC ICIs treatment.

Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials.

Background:Inhibitors targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have unprecedented effects in cancer treatment. However, the objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS) of PD-1/PD-L1 blockade monotherapy have not been systematically evaluated.Methods:We searched Embase, PubMed, and Cochrane database from inception to July 2019 for prospective clinical trials on single-agent PD-1/PD-L1 antibodies (avelumab, atezolizumab, durvalumab, cemiplimab, pembrolizumab, and nivolumab) with information regarding ORR, PFS, and OS.Results:Totally, 28,304 patients from 160 perspective trials were included. Overall, 4747 responses occurred in 22,165 patients treated with PD-1/PD-L1 monotherapy [ORR, 20.21%; 95% confidence interval (CI), 18.34–22.15%]. Compared with conventional therapy, PD-1/PD-L1 blockade immunotherapy was associated with more tumor responses (odds ratio, 1.98; 95% CI, 1.52–2.57) and better OS [hazard ratio (HR), 0.75; 95% CI, 0.67–0.83]. The ORRs varied significantly across cancer types and PD-L1 expression status. Line of treatment, clinical phase and drug target also impacted the response rates in some tumors. A total of 2313 of 9494 PD-L1 positive patients (ORR, 24.39%; 95% CI, 22.29–26.54%) and 456 of 4215 PD-L1 negative patients (ORR, 10.34%; 95% CI, 8.67–12.14%) achieved responses. For PD-L1 negative patients, the ORR (odds ratio, 0.92; 95% CI, 0.70–1.20) and PFS (HR, 1.15; 95% CI, 0.87–1.51) associated with immunotherapy and conventional treatment were similar. However, PD-1/PD-L1 blockade monotherapy decreased the risk of death in both PD-L1 positive (HR, 0.66; 95% CI, 0.60–0.72) and PD-L1 negative (HR, 0.86; 95% CI, 0.74–0.99) patients compared with conventional therapy.Conclusion:The efficacies associated with PD-1/PD-L1 monotherapy vary significantly across cancer types and PD-L1 expression. This comprehensive summary of clinical benefit from immunotherapy in cancer patients provides an important guide for clinicians.

EP1.16-38 Pulmonary Infiltrates in Patients Treated with Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy

Interstitial lung disease (ILD) is one of the fatal toxicities of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Some possible risk factors are indicated like male, smoker, and previous history of interstitial pneumonia, but clinical, and radiologic features are not well known. Patients who received anti-PD-1/PD-L1 monotherapy were identified at our hospital from March 2016 to October 2018. We identified the patients who developed pulmonary infiltrates after PD-1/PD-L1 therapy, cases with confirmed malignant lung infiltration were excluded. We retrospectively analyzed their clinical and radiological features. Of 77 patients who received anti-PD-1/PD-L1 mAbs, pulmonary infiltrates developed in 10. The clinical and radiologic features are shown in Table1,2.Table.1Baseline characteristics of 10 patients with pulmonary infiltrates related to immune checkpoint inhibitors.PtSexAgeHistologySmoking statusSmoking (pack-years)StagePrimary sitePerformance statusPrior chemotherapyRadiation history to the ChestTPS (22c3)Agents1M73AdenoFormer45ⅣRight upper lobe0NoneNone100Pembrolizumab2M74AdenoFormer80ReccurentRight lower lobe1NoneNone95Pembrolizumab3M71SquamousCurrent85.5ⅣRight lower lobe1NoneNone70Pembrolizumab4M84AdenoCurrent48ⅢCLeft lower lobe1NoneNone65Pembrolizumab5M71SquamousFormer46ⅣRight upper lobe1Carboplatin/nab-PaclitaxelDocetaxelNone30Pembrolizumab6M70SquamousFormer80ⅣLeft upper lobe0Carboplatin/nab-PaclitaxelCarboplatin/S1NoneNANivolumab7M61AdenoFormer28ⅢBLeft upper lobe1Carboplatin/PaclitaxelDocetaxelCarboplatin/PemetrexedCarboplatin/nab-Paclitaxel60GyNANivolumab8M61AdenoFormer37ⅣRight pleural0Carboplatin/PaclitaxelCarboplatin/PemetrexedDocetaxelCarboplatin/S-1NoneNANivolumab9M58SquamousFormer54ⅣLeft upper lobe2Carboplatin/Paclitaxel70GyNANivolumab10M81SquamousFormer59ⅣRight upper lobe2DocetaxelCarboplatin/S-1 nab-PaclitaxelNoneNANivolumab Open table in a new tab Table.2Occurrence with pulmonary infiltrates related to immune checkpoint inhibitors.PtRadiographic pattermGradeDistributionTime to event onset, daysKL-6, U/mlCRP at onset, mg/dlTreatmentTime from treatment to resolution/ resolving, daysOutcomeat Baselineat Event onset1DAD4Bilateral/Diffuse151493434825.2Steroid pulse therapyAntibiotics64Resolving2OP5Bilateral/Diffuse936894825.2Steroid pulse therapyAntibioticsNot resolvedNot resolved3OP2Bilateral/Focal6334015911.1Oral steroidsAntibiotics9Resolved4NSIP2Bilateral/Diffuse7140748912.2Antibiotics→Oral steroids60Resolved5NSIP3Bilateral/Diffuse1772412669.9Steroid pulse therapy7Resolved6OP3Bilateral/Diffuse29125411820.3Steroid pulse therapyNot resolvedNot resolved7NSIP1Unilateral/Focal2512561890.2None24Resolved8OP2Unilateral/Diffuse70N/A3002.3Steroid pulse therapy69Resolved9NSIP3Bilateral/Diffuse402N/AN/A7.3Steroid pulse therapyOxygen therapyAntibiotics18Resolving10OP1Unilateral/Focal56107812571.0None31Resolved Open table in a new tab Pulmonary infiltrates associated with anti-PD-1/PD-L1 mAbs showed variable onset and clinical, and radiologic appearances. Sometimes it is difficult to identify whether it is ILD or infection. Most ILD cases were successfully treated with corticosteroids, but rarely, ILD worsened despite treatment. Thus, careful monitoring including imaging examinations is important to preventing the worsening of ILD.

Relationship Between Prior Radiotherapy and Checkpoint-Inhibitor Pneumonitis in Patients With Advanced Non–Small-Cell Lung Cancer

PurposeTo investigate the relationship between radiotherapy (RT), in particular chest RT, and development of immune-related (IR) pneumonitis in non–small-cell lung cancer (NSCLC) patients treated with anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1). Patients and MethodsBetween June 2011 and July 2017, NSCLC patients treated with anti–PD-1/PD-L1 at a tertiary-care academic cancer center were identified. Patient, treatment, prior RT (intent, technique, timing, courses), and IR pneumonitis details were collected. Treating investigators diagnosed IR pneumonitis clinically. Diagnostic IR pneumonitis scans were overlaid with available chest RT plans to describe IR pneumonitis in relation to prior chest RT. We evaluated associations between patient, treatment, RT details, and development of IR pneumonitis by Fisher exact and Wilcoxon rank-sum tests. ResultsOf the 188 NSCLC patients we identified, median follow-up was 6.78 (range, 0.30-79.3) months and median age 66 (range, 39-91) years; 54% (n = 102) were male; and 42% (n = 79) had stage I-III NSCLC at initial diagnosis. Patients received anti–PD-1/PD-L1 monotherapy (n = 127, 68%) or PD-1/PD-L1-based combinations (n = 61, 32%). In the entire cohort, 70% (132/188) received any RT, 53% (100/188) chest RT, and 37% (70/188) curative-intent chest RT. Any grade IR pneumonitis occurred in 19% (36/188; 95% confidence interval, 13.8-25.6). Of those who developed IR pneumonitis and received chest RT (n = 19), patients were more likely to have received curative-intent versus palliative-intent chest RT (17/19, 89%, vs. 2/19, 11%; P = .051). Predominant IR pneumonitis appearances were ground-glass opacities outside high-dose chest RT regions. ConclusionNo RT parameter was significantly associated with IR pneumonitis. On subset analysis of patients who developed IR pneumonitis and who had received prior chest RT, IR pneumonitis was more common in patients who received curative-intent chest RT. Attention should be paid to NSCLC patients receiving curative-intent RT followed by anti–PD-1/PD-L1 agents.

Hematologic Complications of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP (n = 68) and HA (n = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days, p = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.

Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy.

Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher's exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti-PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non-small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.