Durable complete response to pembrolizumab in microsatellite stable colorectal cancer

IntroductionImmunotherapy by checkpoint inhibitors, i.e., anti-programmed death-1(PD-1) or anti-programmed death-ligand 1 (PD-L1) antibodies, has gained more attention managing solid tumors. Pembrolizumab (an anti-PD-1 antibody) in metastatic colorectal cancer (CRC) was approved in 2017 by the US FDA.Reason for the reportPembrolizumab is not effective in microsatellite stable, mismatch-repair-proficient (MSS-pMMR) molecular phenotype, which comprises most CRC patients. In this report, we present the first case of metastatic CRC with a dramatic and durable response to pembrolizumab despite being of MSS-pMMR phenotype.Case summaryA 34-year-old woman, presented seven years ago with T3N2bM0 colon cancer and an appendix carcinoid tumor. The last relapse with bilateral pulmonary metastases was refractory to all treatments. Although it seemed unresponsive to immunotherapy because of MSS molecular phenotype, due to the high expression level of PD-L1 (85%), we started treatment with pembrolizumab 200 mg every three weeks and continued for the overall 19 courses. Surprisingly, a rapid and complete response was observed that last until now, i.e., 17 months after discontinuation of pembrolizumab.OutcomeDespite non-promising results in the current clinical trials, MSS-pMMR colorectal cancer patients'' deprivation from immunotherapy seems not to be reasonable. There are ongoing clinical trials on checkpoint inhibitors either alone or in combination with other drugs. However, immunostaining for PD-L1 should be considered as a possible response predictor.Graphical abstractImmunotherapy either by cell-based approaches or by checkpoint inhibitors may revolutionize cancer treatmentPembrolizumab has been approved by the FDA in 2017 for colorectal cancer.However, MSS-pMMR molecular phenotype which comprises the majority of CRC patients, has not shown a good response to checkpoint inhibitors.We present a MSS-pMMR case with complete and durable response to pembrolizumabWe suggest immunostaining for PD-L1 as a possible response predictor to checkpoint inhibitors     

Immune checkpoint blockade for unresectable or metastatic uveal melanoma: A systematic review

BackgroundThe use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM.MethodsWe performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies.ResultsOut of 1327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n = 162), 4 phase II trials (n = 171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3 mg/kg in 5 trials (n = 186) with a response rate of 0 to 5%. Two reports investigated ipilimumab at 10 mg/kg (n = 45) with radiological responses observed in 0 to 6.5%. The median progression-free survival (PFS) was below 3 months and the median overall survival was 5.2–9.8 months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6 to 36%). Two studies investigated pembrolizumab (2 mg/kg) and nivolumab (3 mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9 months.ConclusionsUM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.     

Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors

The advent of immunotherapy has heralded a number of significant advances in the treatment of particular malignancies associated with poor prognosis (melanoma, non-small-cell lung, renal and head/neck cancers). The success witnessed with therapeutic agents targeting cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and programmed cell death ligand 1 immune checkpoints has inevitably led to an explosion in their clinical application and the subsequent recognition of specific toxicity profiles distinct from those long recognised with chemotherapy. Consequently, as the utility of such therapies broaden, understanding the nature, timing and management of these immune-related adverse events (irAEs) becomes increasingly significant. Although neurological irAEs are considered relatively rare in comparison with hepatitis, colitis, pneumonitis and endocrinopathies, one emerging side-effect is myasthenia gravis (MG). Among the 23 reported cases of immune checkpoint inhibitor-associated MG, 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG. The average onset of symptoms was within 6 weeks (range 2–12 weeks) of treatment initiation. In addition, there was no consistent association with elevated acetylcholine antibody titres and the development of immune checkpoint inhibitor-related MG. Significantly, there was a 30.4% MG-specific-related mortality, which further emphasises the importance of early recognition and robust treatment of this toxicity. In addition to a review of the existing literature, we present a new case of pembrolizumab-induced MG and provide insights into the underlying mechanisms of action of this phenomenon.     

帕博利珠单抗相关爆发性心肌炎一例

免疫检查点抑制剂(ICIs)是近年来肿瘤治疗领域的最重要进展之一。随着ICIs适应证的不断拓展及国内原研药相继进入临床,ICIs将用于越来越多的肿瘤患者,然而ICIs的严重不良反应尚未引起临床医师的广泛关注。该文报道1例肝癌术后复发接受帕博利珠单抗治疗引起爆发性心肌炎的病例,患者主要表现为心肌酶升高,难治性心律失常,伴有肝损伤,呼吸衰竭等,虽经积极抢救最终死亡。该例提示ICIs相关免疫性心肌炎早期症状不典型,但疾病呈爆发性进展,需要临床医师早期识别,及早干预。     

一例帕博利珠单抗联合化疗致剥脱性皮炎患者的护理体会

总结1例帕博利珠单抗联合化疗后出现剥脱性皮炎的护理体会,主要包括控制感染、皮肤护理、管道护理、饮食护理(或营养支持)、心理护理,医护联合制定个性化的治疗护理方案。发病两周后,最初的皮疹开始消失,随后发展为严重的剥脱性皮炎,随后出现弥漫性皮肤色素沉着,经过精心的治疗和护理,患者顺利康复出院。文章旨在分析综合护理干预措施的应用价值,总结肿瘤免疫治疗联合化疗出现严重皮肤不良反应的治疗处置与护理干预经验,以确保肿瘤患者免疫用药的安全性。     

Surgical Safety of Radical Cystectomy and Pelvic Lymph Node Dissection Following Neoadjuvant Pembrolizumab in Patients with Bladder Cancer: Prospective Assessment of Perioperative Outcomes from the PURE-01 Trial

No data are available on the surgical safety of radical cystectomy (RC) and pelvic lymph node dissection (PLND) after the administration of checkpoint inhibitors. We aimed at reporting the first prospective rigorous assessment of perioperative outcomes after RC and extended PLND following neoadjuvant pembrolizumab in a contemporary cohort of patients with muscle-invasive bladder cancer (MIBC) enrolled in the PURE-01 trial. From February 2017 to June 2019, a total of 68 consecutive patients who received three courses of 200 mg pembrolizumab intravenously every 3 wk and were subsequently treated with either open or robot-assisted RC and PLND at a single high-volume tertiary referral center were identified. All men had prospectively collected data about intra- and postoperative outcomes. Postoperative complications were graded according to the Clavien-Dindo system. Perioperative data were prospectively and systematically collected during patient interviews at 90 d after surgery according to the European Association of Urology (EAU) Guidelines Panel recommendations on reporting and grading complications. Overall, 52 (77%) versus 16 (23%) patients underwent robot-assisted versus open RC, and 31 patients (46%) received an orthotopic neobladder. Median blood loss and length of stay were 150 ml and 12 d, respectively. Overall, 52 (77%), 47 (69%), and 22 (32%) patients experienced any-grade complications, grade ≥2 complications, and readmission at 90 d, respectively. High-grade complications (defined as Clavien-Dindo ≥3a) were observed in 23 patients (34%). The most frequent complications were fever (n = 35, 52%) and ileus (n = 21, 31%). None of the patients experienced perioperative mortality at 90 d. Our data represent the first prospective evidence supporting the surgical safety of RC and PLND in patients with N0M0 MIBC who received neoadjuvant immunotherapy with pembrolizumab.Patient summaryThe current study represents the first prospective evidence supporting the surgical safety of radical cystectomy and pelvic lymph node dissection in patients with nonmetastatic bladder cancer who received neoadjuvant immunotherapy with pembrolizumab.     

Pembrolizumab for the treatment of bladder cancer

Introduction: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies.

Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab.

Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy.     

Remarkable response with pembrolizumab plus albumin-bound paclitaxel in 2 cases of HER2-positive metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy

In clinical practice, one subgroup patients of breast cancer might have developed resistance to multi-anti-HER2 targeted drugs(trastuzumab, lapatinib and/or T-DM1) and can not benefit from the anti-HER2 targeted therapy continuously. We attempt to change the next therapic way for these patients. Two patients with metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy were treated with pembrolizumab (2 mg/Kg, day1) plus albumin-bound paclitaxel (125 mg/m², day1,8) every 3 weeks. CT evaluation and HER2 ECD test were performed every 2 cycles. Both of the two patients achieved remarkable response with Partial Remission (PR), meanwhile serum HER2 ECD levels (the upper normal limit is 15 ng/ml) showed a remarkable decreases(compared to the base line decreases 75% and 60% respectively). The results indicate that regimen of pembrolizumab combination with albumin-bound paclitaxel might produce response in patients with HER2-positive metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy.     

Safety and Efficacy of PD-1 Inhibitors Among HIV-Positive Patients With Non–Small Cell Lung Cancer

Introduction

Despite widespread administration of programmed death receptor 1 (PD-1) pathway inhibitors among individuals with NSCLC, little is known about the safety and activity of these agents among human immunodeficiency virus (HIV) – infected patients since this population has largely been excluded from immunotherapy clinical trials.