Crystalline suspensions of monoclonal antibodies (mAbs) have great potential to improve drug substance isolation and purification on a large scale and to be used for drug delivery via high-concentration formulations. Crystalline mAb suspensions are expected to have enhanced chemical and physical properties relative to mAb solutions delivered intravenously, making them attractive candidates for subcutaneous delivery. In contrast to small molecules, the development of protein crystalline suspensions is not a widely used approach in the pharmaceutical industry. This is mainly due to the challenges in finding crystalline hits and the suboptimal physical properties of the resulting crystallites when hits are found. Modern advances in instrumentation and increased knowledge of mAb crystallization have, however, resulted in higher probabilities of discovering crystal forms and improving their particle properties and characterization. In this regard, physical, analytical characterization plays a central role in the initial steps of understanding and later optimizing the crystallization of mAbs and requires careful selection of the appropriate tools. This contribution describes a novel crystal structure of the antibody pembrolizumab and demonstrates the usefulness of small-angle X-ray scattering (SAXS) for characterizing its crystalline suspensions. It illustrates the advantages of SAXS when used to (i) confirm crystallinity and crystal phase of crystallites produced in batch mode; (ii) confirm crystallinity under various conditions and detect variations in crystal phases, enabling fine-tuning of the crystallizations for phase control across multiple batches; (iii) monitor the physical response and stability of the crystallites in suspension with regard to filtration and washing; and (iv) monitor the physical stability of the crystallites upon drying. Overall, this work highlights how SAXS is an essential tool for mAb crystallization characterization.

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OBJECTIVE: The number of available treatment options for urothelial carcinoma has increased recently. Upper tract urothelial carcinoma (UTUC) is relatively rare compared with bladder cancer. There are few reports on the efficacy of immune checkpoint inhibitors (ICIs) for metastatic UTUC, and ICIs may occasionally show less efficacy and cause severe side effects. Therefore, it is important to predict the treatment response and change the treatment strategy as appropriate. We investigated the prognostic factors for treatment response in patients with metastatic UTUC treated with pembrolizumab at our hospital.
METHODS: Patients who received pembrolizumab for UTUC between January 2018 and June 2023 were analyzed. Patients who presented with bladder cancer complications at initial diagnosis were excluded. The primary endpoints assessed were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted using laboratory values obtained before and after pembrolizumab administration. The relationship between cancer and inflammation is important. Therefore, we analyzed this relationship using prognostic factors for urothelial carcinoma as previously reported. Specifically, pretreatment C-reactive protein (CRP) level, neutrophil-to-lymphocyte ratio (NLR), and NLR/albumin values were examined.
RESULTS: Forty-seven patients were analyzed. The median PFS was 66 days (24-107 days), and the median OS was 164 days (13-314 days). A CRP level <1 before the first cycle was a useful factor in the multivariate analysis for both OS and PFS [OS: p=0.004, hazard ratio (HR)=3.244, 95% confidence interval (CI)=1.464-7.104; PFS: p=0.003, HR=2.998, 95%CI=1.444-6.225].
CONCLUSIONS: CRP level is a prognostic factor for pembrolizumab treatment response in patients with UTUC.

BACKGROUND: Since the imported PD-1 inhibitor pembrolizumab was listed in China in 2018, China has opened up the era of immunotherapy for malignant tumors, with several domestically produced PD-1 inhibitors coming onto the market one after another. To find out whether there are differences in the efficacy and safety of domestic and imported PD-1 inhibitors in patients with advanced non-small cell lung cancer, we conducted this retrospective study in two tertiary hospitals in China.
METHODS: Patients with advanced NSCLC treated with tislelizumab or camrelizumab or pembrolizumab who met the inclusion criteria were screened through the electronic medical record system. A total of 259 patients were screened, but due to the unbalanced baseline, we performed propensity score matching and finally included 149 patients in three groups: pembrolizumab (n = 38), tislelizumab (n = 38), and camrelizumab (n = 73), which had very balanced baseline characteristics in each group after propensity score matching treatment.
RESULTS: The results showed that the median progression-free period was 11.3 m vs 10.1 m vs 8.9 m; p = 0.754; and the objective response rate was 63.2% vs 50% vs 57.5%; P = 0.510 for pembrolizumab, tislelizumab, and carrelizumab, respectively. There was no significant difference in median PFS between PD-L1 expression subgroups. In terms of safety, only skin toxicity of any grade of carrelizumab was higher than that of the other two groups (p = 0.034), and the incidence of grade ≥ 3 adverse reactions was not statistically significant among the three groups.
CONCLUSIONS: In this real-world study, the efficacy and safety of the domestically produced tislelizumab, camrelizumab, and the imported pembrolizumab were comparable.

Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m2, autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%-smokers, 30.4%-non-White, 22.8%-elderly, 20.8%-ECOG PS ≥ 2, 15.7%-history of AIDs, and 4.7%-history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.

OBJECTIVE: Abiraterone acetate (abiraterone) plus prednisone is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our aim was to evaluate the efficacy and safety of pembrolizumab plus abiraterone in mCRPC.
METHODS: In cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573), patients were chemotherapy-naïve, had disease progression ≤6 mo before screening, and had either not received prior next-generation hormonal agents for mCRPC or had received prior enzalutamide for mCRPC and had disease progression or became intolerant to enzalutamide. Patients received pembrolizumab 200 mg intravenously every 3 wk plus abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily. The primary endpoints were safety, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3-modified RECIST v1.1 by BICR and overall survival (OS).
UNASSIGNED: For the 103 patients who were treated, median follow-up was 28 mo (interquartile range 26-31). The confirmed PSA response rate was 56% (58/103 patients). The ORR for patients with RECIST v1.1-measurable disease was 16% (6/37 patients). Median rPFS was 15 mo (95% confidence interval 9.2-22) and median OS was 30 mo (95% confidence interval 23-not reached); the estimated 24-mo OS rate was 58%. In total, 91% of patients experienced treatment-related adverse events, and 39% experienced grade 3-5 events. Grade 3/4 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 12% and 6.8% of patients, respectively. One patient died due to treatment-related myasthenic syndrome. Study limitations include the single-arm design.
CONCLUSIONS: Pembrolizumab plus abiraterone and prednisone demonstrated antitumor activity and acceptable safety in patients with chemotherapy-naïve mCRPC. Higher incidence of grade 3/4 elevated ALT/AST occurred than was reported for the individual agents.
RESULTS: For patients with metastatic castratation-resistant prostate cancer, the drug combination of pembrolizumab plus abiraterone and prednisone showed antitumor activity and acceptable safety.

Patients with early-stage triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence even with neoadjuvant and adjuvant treatment with pembrolizumab. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload, improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with pre-treated metastatic TNBC. Moreover, preclinical data suggest that topoisomerase I inhibitors may enhance the effects of immune checkpoint inhibitors through activation of the cGAS-STING pathway. Here we describe the international randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial, which evaluates the efficacy and safety of sacituzumab govitecan plus pembrolizumab versus treatment of physician\'s choice (pembrolizumab ± capecitabine) among patients with early-stage TNBC with residual invasive disease after neoadjuvant therapy.Clinical Trial Registration: NCT05633654 (ClinicalTrials.gov)Other Study ID Number(s): Gilead Study ID: GS-US-595-6184Registration date: 1 December 2022Study start date: 12 December 2022Recruitment status: Recruiting.
AFT-65/ASCENT-05/OptimICE-RD is an ongoing clinical trial that is testing a new treatment combination for patients with stage II or III triple-negative breast cancer (TNBC). Stage II–III means the cancer is confined to the breast and/or nearby lymph nodes and can be surgically removed. However, there remains a risk that the cancer could recur after surgery. To reduce this risk, patients with stage II–III TNBC receive anti-cancer medication before and after surgery. For some patients, receipt of anti-cancer medication before surgery produces a pathologic complete response (pCR), meaning there is no observable cancer left behind at surgery. Patients with a pCR have a lower risk of recurrence than patients with residual disease.The AFT-65/ASCENT-05/OptimICE-RD trial includes people with stage II-III TNBC who have residual cancer after completing their course of pre-surgery anti-cancer medication. All participants have any remaining cancer in their breast and/or lymph nodes removed surgically, after which they are randomly assigned to receive one of two treatments. The experimental therapy consists of pembrolizumab along with a medication called sacituzumab govitecan, which kills cancer cells directly and may strengthen the anti-cancer immune response. Pembrolizumab strengthens the anti-cancer immune response, so the hypothesis of this trial is that the two medications will be more effective together. The control therapy consists of pembrolizumab, alone or in combination with a chemotherapy medication called capecitabine, which is the current standard of care. To study the effectiveness of each treatment, the researchers are following up with all participants to learn if and when their breast cancer returns.

Prostate cancer is one of the most prevalent malignancies in men. In the United States, 1 in 8 men will be diagnosed with prostate cancer in their lifetime. Specifically, studies have delved into male subgroups that present a heightened risk for prostate cancer. Despite such high prevalence, prostate cancer can be heterogeneous and carry complexities that manifest differently between individuals. Metastatic hormone-sensitive prostate cancer (mHSPC) often has an abbreviated, aggressive disease course, and can have varying presentations with different molecular profiles that determine response/resistance to the approved treatments targeting the androgen-receptor pathway (eg, enzalutamide, apalutamide, darolutamide, and abiraterone acetate). We present a case of mHSPC quickly progressing to mCRPC, found to have microsatellite instability in mCRPC and excellent response to pembrolizumab, which raises the critical issues of early molecular testing and treatments personalized for the individual patient.

BACKGROUND: In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab+chemotherapy then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522.
METHODS: Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel+carboplatin then 4 cycles of doxorubicin (or epirubicin)+cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. EORTC QLQ-30 and QLQ-BR23 were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1/cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with ≥60%/80% completion/compliance were assessed using a longitudinal model (no alpha error assigned).
RESULTS: Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab+chemotherapy [N = 762] vs placebo+chemotherapy [N = 383]) in LS mean change from baseline to week 21 in QLQ-C30 GHS/QoL, emotional functioning, and physical functioning were -1.04 (95% CI, -3.46 to 1.38), -0.69 (95% CI, -3.13 to 1.75), and -2.85 (95% CI, -5.11 to - 0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [N = 539] vs placebo [N = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI, -2.60 to 1.77), -0.60 (95% CI, -2.99 to 1.79), and -1.57 (95% CI, -3.36 to 0.21).
CONCLUSIONS: No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab+chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo+chemotherapy in early-stage TNBC.
BACKGROUND: ClinicalTrials.gov, NCT03036488.

Advanced recurrent endometrial cancer (EC) has a poor prognosis and new treatment options are needed. In 2013, EC was classified by genomic analysis into four groups: the POLE ultra-mutated group, the MSI-high hypermutated group (MSI-H), the copy number low group, and the copy number high group. The prognosis differs based on the classification, which should enable the individualization of treatment. The MSI-H and POLE types can induce PD-L1 expression in cancer cells. Among the gynecological cancers, EC exhibits the highest levels of PD-1 and PD-L1 expression and has the highest proportion of MSI-H. Thus, an immune checkpoint inhibitor (ICI) is expected to be effective. The first ICI to show efficacy in recurrent EC was the anti-PD1 antibody pembrolizumab, which exhibited efficacy in MSI-H EC. The combination of pembrolizumab and the multi-kinase inhibitor lenvatinib significantly prolongs OS/PFS compared with single-agent chemotherapy in previously treated recurrent EC, regardless of MSI status. ICIs are now moving from second-line and beyond to first-line treatment regimens. The efficacy of paclitaxel plus carboplatin (TC) and ICI combinations compared with TC have been demonstrated, including an ongoing Phase III trial comparing chemotherapy with the combination of pembrolizumab and lenvatinib. Although ICIs are becoming the mainstay of EC, they cause systemic inflammatory side effects known as irAEs. The incidence of irAEs is higher for combination therapy with CT or lenvatinib compared with ICI therapy alone. Even though they are rarely fatal, irAEs should be addressed promptly.