Inhibitor-based Combination Therapy Research Articles

Conversion surgery intervention versus continued systemic therapy in patients with a response after PD-1/PD-L1 inhibitor-based combination therapy for initially unresectable biliary tract cancer: a retrospective cohort study.

The role of conversion surgery in patients with unresectable biliary tract cancer (BTC) who responded positively to PD-1/PD-L1 inhibitor-based therapy remains unclear. This study aimed to assess the outcomes in patients with or without conversion surgery. In this cohort study, patients with advanced BTC who received combination therapy with PD-1/PD-L1 inhibitors from July 2019 to January 2023 were retrospectively. Patients who exhibited positive responses and met the criteria for conversion surgery were enrolled, and their surgical and oncological outcomes were analyzed. Out of 475 patients, 34 who met the conversion resection criteria were enrolled. The median follow-up was 40.5 months post-initiation of systemic therapy. Ultimately, 13 patients underwent conversion surgery, while 21 received continuation of systemic treatment alone (non-surgical group). The median interval from the initial antitumor therapy to surgery was 6.7 (interquartile range [IQR] 4.9-9.2) months. Survival with conversion surgery was significantly longer than the non-surgical cohort, with a median progression-free survival (PFS) (unreached vs. 12.4mo; hazard ratio 0.17 [95% CI 0.06-0.48]; P=0.001) and overall survival (OS) (unreached vs. 22.4mo; hazard ratio 0.28 [95% CI 0.09-0.84]; P=0.02), respectively. After a median postoperative follow-up of 32.2 months in the surgical cohort, 8 patients survived without recurrence. The estimated 3-year OS, PFS and recurrence-free survival rate in the surgical cohort were 59.9%, 59.2% and 60.6%, respectively. The R0 resection rate reached 92.3%, with 2 achieving a pathological complete response. One patient experienced a Clavien-Dindo grade 3 complication without surgery-related mortality. No serious adverse events or surgical delays were observed. Multivariate analysis indicated that conversion surgery was independently associated with OS (P=0.03) and PFS survival (P=0.003). Conversion surgery appears safe and offers survival benefits to patients responding to immune checkpoint inhibitors (ICIs)-based combinations. However, further studies are required to validate this strategy in the era of immunotherapy.

Living with Metastatic Renal Cell Carcinoma: Survivorship Needs in the Combination Therapy Era

Prior to the development of new cancer technologies, metastatic Renal Cell Carcinoma (mRCC) had a poor prognosis. Fortunately, advances in treatment are allowing a growing population of patients to live with advanced or mRCC. While quality of life has been an area of investigation in this population as treatments advance, relatively little is known about the specific survivorship needs experienced by these patients in the modern treatment era. Using the five survivorship domains defined by the National Cancer Institute, this narrative review explores the literature addressing the survivorship needs of patients living with mRCC. Significant physical, mental, emotional, social and financial effects of mRCC are herein discussed. By comparing literature from the pre-combination treatment period to the modern era, this narrative review of the published literature highlights the significant gaps in our survivorship knowledge for this unique and expanding population. Specifically, this review identifies gaps in understanding of symptom burden, psychological impact, financial effects, and the particular impact of immune-checkpoint inhibitor based combination therapies. Here, we highlight these areas for further research with the hope of finding strategies to alleviate the effects of mRCC and improve the quality of life of patients living with metastatic disease.

Association Between Kidney Function and Outcomes Following Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Carcinoma

BackgroundIt remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)-based combination therapy for advanced renal cell carcinoma (RCC). MethodsWe retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 criteria. ResultsOf the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade ≥ 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade. ConclusionThere is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings.

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p=.014) and DCR (100.0% vs. 79.2%, p=.025) in the HPV+group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+group exhibited superior PFS (p=.005) and OS (p=.004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p>.050). HPV status remained an independent prognostic factor for predicting better ORR (p=.024), PFS (p=.002), and OS (p=.020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3months) and OS occurred at a relatively late stage (within 9months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+tissues. HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3months) whereas OS superiority occurs at a relatively late stage (within 9months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

P166 - Real-world outcomes of cabozantinib treatment after first-line checkpoint inhibitor-based combination therapy for patients with advanced renal cell carcinoma: CARINA study results

P166 - Real-world outcomes of cabozantinib treatment after first-line checkpoint inhibitor-based combination therapy for patients with advanced renal cell carcinoma: CARINA study results

Combination therapy with HSP90 inhibitors and piperlongumine promotes ROS-mediated ER stress in colon cancer cells

Colon cancer is a major cause of cancer-related death. Despite recent improvements in the treatment of colon cancer, new strategies to improve the overall survival of patients are urgently needed. Heat shock protein 90 (HSP90) is widely recognized as a promising target for treating various cancers, including colon cancer. However, no HSP90 inhibitor has been approved for clinical use due to limited efficacy. In this study, we evaluated the antitumor activities of HSP90 inhibitors in combination with piperlongumine in colon cancer cells. We show that combination treatment with HSP90 inhibitors and piperlongumine displayed strong synergistic interaction in colon cancer cells. These agents synergize by promoting ER stress, JNK activation, and DNA damage. This process is fueled by oxidative stress, which is caused by the accumulation of reactive oxygen species. These studies nominated piperlongumine as a promising agent for HSP90 inhibitor-based combination therapy against colon cancer.

Association of the CD4+/CD8+ ratio with response to PD-1 inhibitor-based combination therapy and dermatological toxicities in patients with advanced gastric and esophageal cancer

The host immune system affects the treatment response to immune checkpoint inhibitors and can be reflected by circulating immune cells. This study aimed to evaluate whether circulating T cell subtypes are correlated with clinical response and dermatological toxicities in patients with advanced gastric and esophageal cancer receiving PD-1 inhibitor-based combination therapy (n = 203). In the training cohort, Eastern Cooperative Oncology Group performance status (ECOG PS), PD-L1 expression, antibiotic use, and CD4+/CD8+ ratio were identified as independent prognostic factors in these patients, using a Cox regression model. A nomogram to predict the overall survival (OS) and survival probabilities was constructed using these factors. The nomogram showed good discrimination ability (C-index, 0.767) and was externally confirmed in the validation and test cohorts. Kaplan-Meier analysis showed that median OS in patients with a CD4+/CD8+ ratio ≥1.10 was 6.2 months, which was significantly shorter than that in patients with a CD4+/CD8+ ratio <1.10 (P < 0.001). Patients with a CD4+/CD8+ ratio <1.10 had a superior objective response (43.8% vs. 23.1%) and disease control (72.9% vs. 59.0%) rate, relative to those with ratio ≥ 1.10. In addition, PD-L1 expression, corticosteroid use, and CD4+/CD8+ ratio can independently predict dermatological toxicities. In conclusion, baseline CD4+/CD8+ ratio is a potential prognostic factor for patients with advanced gastric and esophageal cancer treated with PD-1 inhibitor-based combination therapy, and can independently predict dermatological toxicities. In addition, a nomogram incorporating CD4+/CD8+ ratio, ECOG PS, PD-L1 expression, and antibiotic use can predict OS with considerable accuracy.

Outcome differences between PD-1/PD-L1 inhibitors-based monotherapy and combination treatments in NSCLC with brain metastases

IntroductionWithout the clear immunophenotyping of brain metastases (BrMs), the optimal treatment strategy based on PD-1/PD-L1 inhibitor for patients with non-small-cell lung cancer (NSCLC) and BrMs remains unknown.Methods308 patients with NSCLC received PD-1/PD-L1 inhibitor-based monotherapy or combination therapy were retrospectively identified. Kaplan-Meier curves with log-rank tests were used to determine the treatment outcomes differences. Transcriptomic analysis of paired primary lung lesions and BrMs were performed to dissect the specific tumor immune microenvironment (TIME) of BrMs.ResultsThe presence of BrMs was associated with significantly inferior PFS (2.5 vs. 3.7 months; P = 0.0053) and OS (8.3 vs. 15.4 months; P = 0.0122) in monotherapy group, while it was only associated with poorer PFS (4.6 vs. 7.0 months; P = 0.0009) but similar OS (22.8 vs. 21.0 months; P = 0.9808) in combination treatment group. Of patients with BrMs, PD-1/PD-L1 inhibitor plus antiangiogenic therapy was associated with longest PFS (7.7 vs. 3.2 vs. 2.5 months; P = 0.0251) and OS (29.2 vs. 15.8 vs. 8.3 months; P = 0.0001) when compared with PD-1/PD-L1 inhibitor plus chemotherapy or anti-PD-1/PD-L1 monotherapy. Multivariate analyses suggested that combination treatment was independently correlated with significantly longer PFS (P = 0.028) and OS (P < 0.001) in patients with BrMs. Transcriptomic analysis showed a suppressive TIME in BrMs with decreased CD4+ T cells and M1 macrophages but increased M2 macrophages infiltration.ConclusionNSCLC with BrMs obtained barely satisfactory overall benefit from anti-PD-1/PD-L1 monotherapy, partly due to its immunosuppressive TIME. PD-1/PD-L1 inhibitor-based combination treatment, especially anti-PD-1/PD-L1 plus anti-angiogenic treatment, could significantly improve the clinical outcomes of patients with NSCLC and BrMs.

Sequencing checkpoint inhibitor therapy in renal cell carcinoma

Initial therapy in patients with advanced renal cell carcinoma includes drugs that inhibit immune checkpoints, thereby blocking the negative regulators of an antitumour immune response. Currently, this therapy includes a combination of a PD-1 inhibitor and either a second checkpoint inhibitor, an antibody against CTLA4, or one of several small molecule inhibitors of the VEGF receptor. These PD-1-based combination therapies have improved clinical outcomes including overall survival. 1 Motzer RJ McDermott DF Escudier B et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022; 128: 2085-2097 Crossref PubMed Scopus (47) Google Scholar , 2 Rini BI Plimack ER Stus V et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019; 380: 1116-1127 Crossref PubMed Scopus (1841) Google Scholar , 3 Choueiri TK Powles T Burotto M et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021; 384: 829-841 Crossref PubMed Scopus (618) Google Scholar , 4 Motzer R Alekseev B Rha S-Y et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021; 384: 1289-1300 Crossref PubMed Scopus (614) Google Scholar Although use of checkpoint inhibitor-based combination therapy has led to a subset of patients who have a durable response and disease control without the need for further systemic therapy, the majority of patients will progress and require additional treatment. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trialThe addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials. Full-Text PDF

Real-world treatment sequencing and outcomes for patients with advanced renal cell carcinoma treated with cabozantinib after first-line checkpoint inhibitor-based combination therapy: Results from the CARINA study.

e16512 Background: Real-world data are required to guide the optimal sequencing of therapies for advanced renal cell carcinoma (aRCC) when first-line (1L) checkpoint inhibitor (CPI)-based combinations are used. CARINA is a retrospective, non-interventional study of treatment sequencing and outcomes in patients with aRCC who progressed to second-line (2L) treatment after 1L CPI-based combination therapy. Methods: Electronic prescribing records and hospital medical records from nine participating UK specialist centers were reviewed to identify patients (aged ≥ 18 years) with a diagnosis of aRCC who received 2L therapy after 1L CPI-based combination therapy in line with UK National Health Service funding policy. The primary objective was to describe the treatment pathways of patients with aRCC who received 1L CPI-based combination and subsequent therapy. Secondary objectives included descriptive analysis of: duration of treatment (DoT), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Here we report a descriptive analysis of outcomes for subgroups who received 2L cabozantinib or other 2L therapies. Results: Between April 2015 and June 2022, data were collected from 281 patients (163 patients received 2L cabozantinib and 118 received other 2L therapies after 1L CPI-based therapy). Overall, mean (standard deviation [SD]) age at aRCC diagnosis was 59.4 (10.1) years, 76.5% were male and 87.5% had clear-cell aRCC (including those with a clear-cell component). In the 2L cabozantinib and other 2L therapies subgroups, the most common 1L regimens were ipilimumab + nivolumab (79.1% and 60.2%, respectively), axitinib + avelumab (9.8% and 22.0%) and pembrolizumab + axitinib (9.8% and 9.3%). Outcomes of 2L treatment for the 2L cabozantinib and other 2L therapies subgroups are shown in the Table. Conclusions: Among patients with aRCC who progressed to 2L treatment after 1L CPI-based therapy, the most common 1L therapies were ipilimumab + nivolumab followed by axitinib + avelumab. DoT and ORR were numerically better with 2L cabozantinib than with other 2L therapies, demonstrating the antitumor effect of 2L cabozantinib after 1L CPI-based therapy. Clinical trial information: NCT04957160 . [Table: see text]

Prospective cardiovascular surveillance of immune checkpoint inhibitor-based combination therapy in patients with early-stage, triple-negative breast cancer.

2607 Background: Both pembrolizumab and anthracyclines (AC) can cause adverse cardiovascular events; combination therapy is approved for high-risk, early-stage, triple-negative breast cancer (TNBC) and may further increase real-world cardiovascular risk. Cardiac surveillance with serial troponin measurements has been advocated in this population, though evidence supporting this approach is lacking. Methods: High-sensitivity troponin I (hs-TnI) was prospectively measured at baseline and with each treatment cycle in cancer patients receiving immune checkpoint inhibitors (ICI) at a single center as part of an institutional surveillance protocol for ICI-related adverse events from 2020-2022. Acute cardiac injury was defined as ≥1 abnormal hs-TnI value (&gt;17ng/dL in women and &gt;35ng/dL in men) with normal baseline hs-TnI, or at least 20% increase in hs-TnI from abnormal baseline. The incidence of acute cardiac injury and all-cause mortality were compared between patients receiving ICI in combination with AC versus ICI without AC. Results: Among 215 patients treated with ICI with baseline and ≥1 follow-up hs-TnI value, 28 patients (13%) received ICI with AC, all of whom were women with early-stage TNBC receiving pembrolizumab and AC-containing chemotherapy. 187 patients (87%) received ICI without AC for other oncological indications. Patients receiving ICI with AC were younger and more likely to be female than patients receiving ICI without AC (p&lt;0.001) with lower rates of smoking, hypertension, and diabetes (p&lt;0.04). Acute cardiac injury was observed in 33 patients, 21% of those receiving ICI with AC (N=6) and 14% of those receiving ICI without AC (N=27; p=0.34). Among these 33 patients, 2 patients were treated for ICI-associated myocarditis (1 receiving ICI with AC, 1 receiving ICI without AC); 67% of those receiving ICI with AC (N=4) were continued on ICI while only 30% of those receiving ICI without AC (N=8) were continued on ICI (p=0.16). The rate of all-cause mortality was significantly lower in patients receiving ICI with AC (0%) as compared to patients receiving ICI without AC (40%, p&lt;0.001). Conclusions: Among women with early stage TNBC receiving pembrolizumab with AC, the rate of acute cardiac injury by surveillance troponin measurements was numerically but not statistically higher than for patients receiving ICI without AC for other oncological indications, though the rate of all-cause mortality was significantly lower. These findings suggest that surveillance troponin monitoring may have less clinical utility among women with early-stage TNBC receiving ICI-based combination therapy as compared to other patient populations receiving ICI. Further study is needed to understand the mechanistic and prognostic significance of acute cardiac injury in patients with TNBC receiving ICI-based combination chemotherapy.

Metastatic sites and lesion numbers cooperated to predict efficacy of PD-1 inhibitor-based combination therapy for patients with metastatic colorectal cancer.

Limited data have been used to evaluate the efficacy of immunotherapy in metastatic colorectal cancer (mCRC). Furthermore, potential markers that can be used to identify responding patients and to further improve efficacy have not been fully explored. In our study, we included a total of 97 patients with mCRC, who each received programmed death-1 (PD-1) inhibitor-based combination therapy at our center. All 12 hypermutated patients benefited from immunotherapy, with median progression-free survival (mPFS) reaching 28.3 months, regardless of liver metastasis. The objective response rate (ORR) of non-hypermutated patients was 16.5% (14/85), with an mPFS of 4.0 months. For non-hypermutated patients, multivariate analysis revealed that the combination of liver metastasis and baseline lesion number significantly stratified response and survival. The lesion-based analysis indicated that the lymph node was the most responsive, followed by the peritoneum and lung, with liver metastasis being the least responsive. None of the patients (0/7) with negative programmed ligand-1 (PD-L1) expression responded, and positive PD-L1 expression may serve as a biomarker (mPFS 5.7 vs. 2.2 months, p = 0.002) that can be used to further guide treatment in non-hypermutated mCRC with liver metastasis (CRLMs). Patients with hypermutated mCRC benefited significantly from immunotherapy, whereas the non-hypermutated cohort with liver metastasis and numerous lesions showed less benefit. The lesion sites reflected varying levels of efficacy, among which PD-L1 potentially cooperated to guide the immunotherapy of CRLMs.

Immune Checkpoint Inhibitor-Based Combination Therapy for Colorectal Cancer: An Overview.

Colorectal cancer (CRC) is one of the most common diseases in the world. Tumor immunotherapy is an innovative cancer treatment that acts by activating the human body's autoimmune system. Immune checkpoint block has been shown to be effective in DNA deficient mismatch repair/microsatellite instability-high CRC. However, the therapeutic effect for proficient mismatch repair/microsatellite stability patients still requires further study and optimization. At present, the main CRC strategy is to combine other therapeutic methods, such as chemotherapy, targeted therapy, and radiotherapy. Here, we review the current status and the latest progress of immune checkpoint inhibitors in the treatment of CRC. At the same time, we consider therapeutic opportunities for transforming cold to hot, as well as perspectives on possible future therapies, which may be in great demand for drug-resistant patients.

CARINA interim analysis: A non-interventional study of real-world treatment sequencing and outcomes in patients with advanced renal cell carcinoma initiated on first-line checkpoint inhibitor-based combination therapy.

626 Background: First-line (1L) checkpoint inhibitor (CPI)-based combinations have become standard of care for patients with advanced renal cell carcinoma (aRCC). Data are required to inform optimal sequencing of aRCC therapies. CARINA is a non-interventional study of treatment sequencing and outcomes in patients with aRCC initiated on 1L CPI-based combination therapy. We report the results of a pre-planned interim analysis. Methods: We reviewed electronic prescribing records from participating UK specialist centers to identify patients (aged ≥ 18 years) with aRCC who received 2L therapy after 1L CPI-based combination therapy. The primary objective was to determine the treatment pathway for patients with aRCC who initiated treatment with a CPI-based combination and received subsequent therapy. Secondary objectives included treatment duration and objective response rate (ORR). Outcomes were evaluated for all patients (enrolled population [EP]) and for the patient subgroup who received 2L cabozantinib. Results: In total, 129 patients were eligible for inclusion in this interim analysis of the EP (mean [SD] age at diagnosis, 60.0 [9.9] years; 75.2% male; 77.3% clear-cell aRCC). Of these patients, 82.9% received 1L ipilimumab + nivolumab (Ipi + Nivo, n = 107) and 17.1% received axitinib + avelumab (Axi + Ave, n = 22); median (95% CI) duration of 1L treatment was 10.2 (9.1–17.1) weeks, ORR was 18.4%. The most commonly prescribed 2L therapies after Ipi + Nivo were cabozantinib (74.8%) and sunitinib (13.1%); the most commonly prescribed 2L therapies after Axi + Ave were lenvatinib + everolimus (45.5%) and cabozantinib (31.8%). Median (95% CI) duration of all 2L therapies was 23.6 (14.0–28.3) weeks, and median duration of 2L cabozantinib was 28.1 (20.1–37.1) weeks. ORR to 2L therapy was 30.4% for the EP, and 38.8% for the subgroup of patients who received 2L cabozantinib. Conclusions: In this interim analysis, the most commonly prescribed 2L therapies were cabozantinib and sunitinib after Ipi + Nivo, and lenvatinib + everolimus and cabozantinib after Axi + Ave. Antitumor response with 2L cabozantinib was observed after prior CPI-based therapy. Clinical trial information: NCT04957160 .

Decreased monocyte-to-lymphocyte ratio was associated with satisfied outcomes of first-line PD-1 inhibitors plus chemotherapy in stage IIIB-IV non-small cell lung cancer.

Immune-checkpoint inhibitors (ICIs) combined with chemotherapy are more widely used than monotherapy and have shown better survival in patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver alterations. The monocyte-to-lymphocyte ratio (MLR) might predict the treatment outcomes of ICI therapy in advanced NSCLC patients but has not yet been investigated. In addition, the cutoff of MLR is controversial. Therefore, the present study aimed to explore the associations between changes in MLR at the initial stage of treatment and clinical outcomes in stage IIIB-IV NSCLC patients receiving first-line PD-1 inhibitor combined with chemotherapy. The present study included 139 stage IIIB-IV NSCLC patients treated with first-line PD-1 inhibitor combined with chemotherapy. The blood results were assessed 10 days before initiation of PD-1 inhibitor-based combination therapy (time point 1, baseline) and before the third cycle of combined therapy (time point 2). Compared to altered MLR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in baseline and in time point 2, patients were divided into decreased MLR/NLR/PLR and increased MLR/NLR/PLR groups. The objective response rate (ORR), progression-free survival (PFS), and the association with the changes in blood indicators were analyzed. A total of 48 patients were categorized in the decreased MLR group and 91 in the increased MLR group. Patients with decreased MLR had a significantly higher ORR in the univariate (P<0.001) and multivariate (P<0.001) Cox proportional hazards models. On the other hand, decreased MLR was significantly associated with prolonged PFS in the univariate (P=0.007) and multivariate (P=0.016) analyses. Next, 91 patients comprised the decreased NLR group and 48 as the increased NLR group. Patients with decreased NLR exhibited high ORR (P=0.001) and prolonged PFS in univariate analysis (P=0.033). Then, 64 patients comprised the decreased PLR group and 75 the increased PLR group. Decreased PLR was significantly associated with high ORR in univariate (P<0.001) and multivariate (P=0.017) analyses. The subgroup analyses showed that decreased MLR was significantly associated with satisfactory outcomes in patients with all PD-L1 expressions. Decreased MLR was associated with high ORR and long PFS and might have a potential predictive value in patients with stage IIIB-IV NSCLC treated with first-line PD-1 inhibitor combined with chemotherapy. In addition, changes in MLR might have predictive value in all PD-L1-expressing populations. Decreased NLR and PLR also showed improved survival, suggesting that changes in NLR and PLR may be complementary to predicting prognosis.

Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies

BackgroundsPapillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed.MethodsSurgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively.ResultsWe established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone.ConclusionsThese data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.

Biomarkers for predicting tumor response to PD-1 inhibitors in patients with advanced pancreatic cancer

ABSTRACT Pancreatic cancer is among the most lethal malignant neoplasms, and few patients with pancreatic cancer benefit from immunotherapy. We retrospectively analyzed advanced pancreatic cancer patients who received PD-1 inhibitor-based combination therapies during 2019–2021 in our institution. The clinical characteristics and peripheral blood inflammatory markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], and lactate dehydrogenase [LDH]) were collected at baseline. Chi-squared and Fisher’s exact tests were used to evaluate relationships between the above parameters and tumor response. Cox regression analyses were employed to assess the effects of baseline factors on patients’ survival and immune-related adverse events (irAEs). Overall, 67 patients who received at least two cycles of PD-1 inhibitor were considered evaluable. A lower NLR was independent predictor for objective response rate (38.1% vs. 15.2%, P = .037) and disease control rate (81.0% vs. 52.2%, P = .032). In our study population, patients with lower LDH had superior progression-free survival (PFS) and overall survival(OS) (mPFS, 5.4 vs. 2.8 months, P < .001; mOS, 13.3 vs. 3.6 months, P < .001). Liver metastasis was verified to be a negative prognostic factor for PFS (2.4 vs. 7.8 months, P < .001) and OS (5.7 vs. 18.0 months, P < .001). The most common irAEs were hypothyroidism (13.4%) and rash (10.5%). Our study demonstrated that the pretreatment inflammatory markers were independent predictors for tumor response, and the baseline LDH level and liver metastasis were potential prognostic markers of survival in patients with pancreatic cancer treated with PD-1 inhibitors.

Different associations between organ-specific immune-related adverse event and survival in non-small cell lung cancer patients treated with programmed death-1 inhibitors-based combination therapy.

The profile of immune-related adverse events (irAEs) due to programmed death-1 (PD-1) inhibitors-based combination therapy in advanced non-small cell lung cancer (NSCLC) and its relationship with survival have not been fully described. Designed to capture the spectrum of irAEs and explore the association between irAEs and clinical outcomes in patients with NSCLC. This retrospective single-center study included patients with advanced NSCLC treated with PD-1 inhibitors (mainly in combination with chemotherapy) at Jiangsu Cancer Hospital. The relationship between irAEs and survival was explored using landmark analysis and time-dependent Cox regression. The subgroup analyses focused on investigating the effects of organ-specific irAE, irAE grade, and steroid dose used to treat irAE. This study included 301 patients, 199 of whom received PD-1 inhibitors plus chemotherapy. The most common irAEs were skin toxicity (19.3%), endocrinopathy (21.3%), and pneumonitis (17.6%). In the entire cohort, the median progression-free survival (PFS) for patients developing and not developing irAE was 12.3 and 10.7 months (p < 0.001), and the median overall survival (OS) was 23.5 months and 20.1 months (p = 0.137), respectively. Subgroup analyses indicated that grade 3 or higher irAE, high steroid dose, and immune-related pneumonitis were detrimental to OS, whereas skin toxicity was beneficial to survival. These findings were further corroborated by both landmark analyses and Cox regression models conducted over four time points (1, 3, 6, and 12 months). In the real world, NSCLC patients receiving PD-1 inhibitor-based combination therapy (particularly combined with chemotherapy) experience longer PFS with irAE, though not necessarily OS. Immune-related skin toxicity is associated with a better prognosis, whereas pneumonitis grade ⩾3 irAE and high steroid dose compromise survival. Clinicians should remain cognizant of the organ-specific manifestations of irAE and take proactive measures to mitigate the progression of irAE.

Comparison of the Impact of Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Dual Combination Therapy and Immune Checkpoint Inhibitor Plus Tyrosine Kinase Inhibitor Combination Therapy in Patients with Advanced Renal Cell Carcinoma.

The prognostic impact of immune-related adverse events during immune checkpoint inhibitor-based combination therapy for advanced renal cell carcinoma remains unclear, especially in terms of differences between regimens. We aimed to clarify the prognostic impact of immune-related adverse events in patients with advanced renal cell carcinoma receiving immune checkpoint inhibitor dual combination therapy (IO-IO) or immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy (IO-TKI). We retrospectively evaluated the data of 148 patients who received immune checkpoint inhibitor-based combination therapy as first-line therapy. Patients were divided into two groups based on regimens, namely IO-IO and IO-TKI. The associations between immune-related adverse event development and outcomes, such as progression-free survival, overall survival, and objective response rate, were compared between the two groups. In the IO-IO and IO-TKI groups, 67 of 91 (74%) and 31 of 57 (54%) patients, respectively, experienced at least one immune-related adverse event and the rate was significantly higher in the IO-IO group (p = 0.0204), where immune-related adverse events development was significantly associated with longer progression-free survival (p < 0.0001) and overall survival (p = 0.0102), and a higher objective response rate (p = 0.0028). A multivariate analysis revealed immune-related adverse event development as an independent factor for longer progression-free survival (hazard ratio, 0.25; p < 0.0001) and overall survival (hazard ratio, 0.42; p = 0.0287). There were no significant associations between immune-related adverse events and progression-free survival, overall survival, or objective response rate in the IO-TKI group. The development of immune-related adverse events was positively associated with the outcome of patients with advanced renal cell carcinoma treated with IO-IO combination therapy; no such correlation was observed for IO-TKI combination therapy.

Frontline immune checkpoint inhibitor-based combination therapy in metastatic renal cell carcinoma patients with poor performance status

BackgroundImmune checkpoint inhibitor-based combination therapy (ICI-based combination) is a new standard of care for metastatic clear cell renal cell carcinoma (mRCC) in the frontline setting. Patients with poor performance status (PS) (≥2) were excluded from pivotal trials. Hence, the activity and safety of ICI-based combination therapy in this group of patients is still unknown. MethodsWe performed a multicentre retrospective study of PS ≥2 mRCC patients who received frontline ICI-based combination, either nivolumab-ipilimumab (NI) or pembrolizumab-axitinib (AP). Patients' characteristics, clinical outcomes, and toxicity were collected. We analysed overall response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS) and grade ≥3 adverse events (G ≥ 3AEs). The association between the predictive biomarker IPI (immune prognostic index) and ORR/PFS/OS was also evaluated. ResultsWe identified 70 mRCC patients with PS ≥2 treated with ICI-based combination across 14 institutions between October 2017 and December 2021, including 45 and 25 patients were treated with NI and AP, respectively. Median age at diagnosis was 63 years, 51 (73%) were male, only 17 (24%) had prior nephrectomy, 50 (71%) had synchronous metastatic disease at diagnosis, and 16 (23%) had brain metastases. Sixty-one (87%) and 9 (13%) patients had ECOG (Eastern Cooperative Oncology Group) PS 2 and 3, respectively, and 25 (36%) and 45 (64%) patients were intermediate and poor International Metastatic RCC Database Consortium (IMDC) risk, respectively. Among all, 91% were clear cell RCC, 7 patients had sarcomatoid features. At the time of the analysis (median follow-up 11.1 months), 41% patients were dead. Median PFS and mOS in the entire cohort were 5.4 months and 16.0 months, respectively; ORR was 31%. No significant differences in ORR, PFS, OS, or G ≥3AEs were seen between NI and AP. The intermediate and poor IPI groups were significantly associated with reduced ORR and shorter PFS. ConclusionWe report the first cohort of PS ≥2 mRCC patients treated with frontline ICI-based combination therapy. The survival outcomes in our cohort were inferior to that reported in pivotal trials. No significant differences in ORR, PFS, OS or toxicity were seen between NI and AP. Prospective real-world studies are needed to confirm these results.