Cycles Of Pembrolizumab Research Articles

Pembrolizumab Induced Recall Dermatitis Occurring 5 Years After Radiotherapy

Background and Clinical Significance: Radiation recall dermatitis (RRD) following immune checkpoint inhibitor (ICI) therapy has been infrequently reported. Case Presentation: We present a 47-year-old female patient who developed RRD of the breast following three doses of pembrolizumab administered as an adjuvant treatment post-nephrectomy for Stage III renal cell carcinoma (RCC). Notably, the affected breast had previously undergone external beam radiotherapy 247 weeks earlier for Stage IA invasive ductal carcinoma. She had received no prior chemotherapy at any point. RRD manifested as breast induration, erythema, and peau d’orange, and contraction of breast volume was noted following three cycles of pembrolizumab on week 17 (400 mg dose every 6 weeks). The dermatitis responded rapidly to systemic corticosteroids and no treatment interruption was needed. Conclusion: To date, this is the longest reported interval from completion of radiotherapy to RRD. A literature search underscores the variability in presentation and management of ICI-associated RRD.

Efficacy, Safety, and Influence on Tumor Microenvironment of Neoadjuvant Pembrolizumab plus Ramucirumab for PD-L1 Positive NSCLC: A Phase 2 Trial (EAST ENERGY).

Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors (ICIs) has shown efficacy against many types of cancers, including non-small cell lung cancer (NSCLC). We investigated the feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a vascular endothelial growth factor (VEGF) receptor-2 antagonist for patients with PD-L1-positive NSCLC and its influence on the tumor microenvironment (TME). Patients with pathologically proven NSCLC with PD-L1-positive, clinical stage IB-IIIA were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every three weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response (MPR) rate by a blinded independent pathology review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on TME. The 24 eligible patients were enrolled between July 2019 and April 2022. The MPR rate was 50.0% (90% confidence interval, 31.9-68.1%). Six patients showed pathological complete response. Grade 3 adverse events (AEs) occurred in 9 patients (37.5%), including 3 immune-related AEs (acute tubulointerstitial nephritis in 2 cases and polymyalgia rheumatica in one). There were no grade 4 or 5 AEs. The transcriptome and multiplexed immunohistochemistry results suggested that tumors with greater CD8+ T-cell infiltration and higher expression of effector molecules at the baseline could show better sensitivity to treatment. This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible and anti-VEGF agents may enhance the effects of ICIs.

12459 Exceptional Response To A Single Dose Of Pembrolizumab As Salvage Therapy In A Patient With Metastatic Adrenocortical Carcinoma (ACC)

Abstract Disclosure: L. Branchaud-Croisetière: None. J. Castilloux: None. E. Turcotte: None. A. Bégin: None. M. St-Jean: Advisory Board Member; Self; GlaxoSmithKline, HRA Pharmaceuticals. Research Investigator; Self; AstraZeneca, Novo Nordisk, Spruce Biosciences. Speaker; Self; GlaxoSmithKline, Recordati Rare Diseases. In advanced ACC, limited effective treatment options are available beyond mitotane and cytotoxic chemotherapy. PD-L1 blockade has shown promising results in small numbers of advanced ACC. In ACC, the reported partial response rate to pembrolizumab is around 25%.[1] Only one case of a significant partial response to a single dose of Pembrolizumab as salvage therapy for metastatic ACC was previously published.[1] In April 2023, a 19-year-old woman presented with severe hypertension, hypokalemia and clinical signs of Cushing syndrome (CS). Thoraco-abdominal scan revealed a left-sided cluster of confluent adrenal masses (7.3 x 14.4 x 11.4 cm), a left cortical renal lesion (2.8x2x2.1cm), a right ovarian teratoma (7.9 x 7.8x7.9 cm) and at least 25 pulmonary micronodules. FDG-PET SCAN revealed a significant hypermetabolism of the left adrenal lesions (SUV 18.6), ovarian teratoma (SUV 5.5) and pulmonary micronodules (SUV 1.1-2). Cortisol and androgens secretion was confirmed biochemically. Initially, she was not candidate for a debulking surgery because the tumor was surrounding the aorta, and mesenteric arteries. Hypertension and hypokalemia were treated with spironolactone, amlodipine, amiloride and irbesartan. Cushing syndrome was treated with metyrapone. In April 2023, Etoposide-Doxorubicine-Cisplatin (EDP) was administered in combination with Mitotane (max: 8g/day). After 6 cycles of EDP-M the disease regressed slightly but was considered stable based on RECIST criteria. After 8 cycles, the follow-up imaging showed a progression of the adrenal lesion (9.2x18.2cm) but stable pulmonary micronodules. A biopsy of the adrenal lesion, for therapeutic purpose, revealed microsatellite stability (MSS). The patient refused germinal genetic testing. It was decided in multidisciplinary tumor board to try Pembrolizumab. In December 2023, she received one cycle of Pembrolizumab (140mg), but the treatment was complicated by grade 4 immune-mediated hepatitis. A few weeks following Pembrolizumab she completely normalized her blood pressure and hypokalemia despite cessation of all her anti-hypertensive drugs. Pembrolizumab and Mitotane were stopped and hepatitis completely resolved after two months of Mycophenolate Mofetil and ongoing decreasing dose of prednisone. In March 2024, CT scan showed a 60% regression of the adrenal mass (4.1 x 7.2 cm), stability of the renal lesion and ovarian teratoma and complete resolution of the pulmonary micronodules. We suspect an ongoing effect of immunotherapy and Mitotane, since Mitotane levels were still in the therapeutic range (15.1 mg/L) six weeks following cessation. Mitotane was resumed in March 2024. The patient will potentially have a resection of the left adrenal lesion in the next month. This is second published case of a significant response to Pembrolizumab as second-line therapy for advanced ACC. [1] Raj Net al. J Clin Oncol. 2020 Presentation: 6/1/2024

Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer.

In patients with early-stage triple-negative breast cancer, the phase 3 KEYNOTE-522 trial showed significant improvements in pathological complete response and event-free survival with the addition of pembrolizumab to platinum-containing chemotherapy. Here we report the final results for overall survival. We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response and event-free survival. Overall survival was a secondary end point. Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. At the data-cutoff date (March 22, 2024), the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated overall survival at 60 months was 86.6% (95% confidence interval [CI], 84.0 to 88.8) in the pembrolizumab-chemotherapy group, as compared with 81.7% (95% CI, 77.5 to 85.2) in the placebo-chemotherapy group (P = 0.002). Adverse events were consistent with the established safety profiles of pembrolizumab and chemotherapy. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in overall survival among patients with early-stage triple-negative breast cancer. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

Plasma Circulating HPV DNA Surveillance in a Patient With Nasopharyngeal Cancer.

Nearly one third of nasopharyngeal carcinomas (NPCs) in the United States are associated with human papillomavirus (HPV). Surveillance for Epstein-Barr virus (EBV)-negative subtypes is customarily based solely on imaging and physical examinations. We present a case of HPV-positive NPC using serial circulating tumor HPV DNA (ctHPVDNA) as a biomarker of disease status. A 58-year-old Caucasian female initially presented with T1N1M0 EBV-negative p16-positive squamous cell carcinoma of the nasopharynx and was treated with concurrent chemoradiation. Regional nodal recurrence identified 7 months post-radiotherapy was treated with salvage left neck dissection. Surveillance was supplemented using a commercially available polymerase chain reaction (PCR)-based ctHPVDNA assay. Rising ctHPVDNA levels at 9 and 10 months post salvage surgery prompted positron emission tomography (PET). Biopsy confirmed recurrence in avid right hilar and paraoesophageal lymph nodes. Following definitive radiotherapy to the involved nodes and concurrent pembrolizumab, posttreatment ctHPVDNA decreased to baseline, but then increased after 6 cycles of pembrolizumab. Follow-up PET found left mediastinal recurrence outside of the prior treatment field, which was treated with concurrent chemoradiation with cetuximab. Again, ctHPVDNA level dropped to baseline but increased 3 months postradiation. PET scan showed a left lung nodule, and the patient received systemic therapy. Plasma ctHPVDNA monitoring correlated well with disease activity in our patient with HPV-positive NPC. ctHPVDNA detected disease earlier than standard surveillance methods and allowed for earlier intervention. Larger studies are needed to validate the utility of HPV biomarker surveillance in NPC.

798. FEASIBILITY AND EFFICACY OF CISPLATIN, PACLITAXEL AND IMMUNE CHECKPOINT INHIBITORS AS CONVERSION THERAPY FOR LOCOREGIONALLY UNRESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Induction therapy followed by conversion surgery is potentially curative for locoregionally unresectable esophageal squamous cell carcinoma (ESCC). However, the optimal induction treatment strategy is unclear. The study aimed to evaluate the feasibility and efficacy of cisplatin, paclitaxel and immune checkpoint inhibitors as conversion therapy for locoregionally unresectable ESCC. Methods Clinicopathological variables of cT4b ESCC patients who received neoadjuvant chemoimmunotherapy were retrieved from the prospective database of the Surgical Esophageal Cancer Patient Registry in West China Hospital, Sichuan University. Enhanced computed tomography, ultrasonography and bronchoscopy were routinely used for the diagnosis. The treatment protocol of neoadjuvant chemoimmunotherapy included 2 cycles of immunotherapy plus chemotherapy with the interval of 3 weeks among each cycle. All patients received 2 cycles of Pembrolizumab (200 mg, D1), Sintilimab (200 mg, D1), Tislelizumab (200 mg, D1) or Camrelizumab (200 mg, D1) intravenously. Concurrently all patients received 2 cycles of cisplatin (75 mg/m2 of body-surface area, D1) and paclitaxel (175 mg/m2 body-surface area, D1) intravenously. The perioperative parameters and short-term surgical outcomes were presented (Table). Results Between January 2020 and December 2022, a total of 317 ESCC patients who underwent neoadjuvant chemoimmunotherapy followed by surgery were screened. Twenty cT4b patients with middle or upper thoracic ESCC were finally enrolled in this study. Pretreatment tumor invades the trachea (4, 20%), left main bronchus (16, 80%), and aorta (6, 30%), respectively. All the patients were successfully performed by McKeown minimally invasive esophagectomy except for one patient conversion to thoracotomy. R0 resection was achieved in 15 patients, 4 patients underwent R1 resection and 1 patient underwent R2 resection. Mean operation duration was 290.4 ± 57.5 min. Mean estimated blood loss was 94.4 ± 108.8 ml. Three patients had postoperative pneumonia, two patients had postoperative pleural effusion and one patient had postoperative recurrent laryngeal nerve paralysis. No patient had postoperative anastomotic leak. No postoperative reoperation was needed and there was no perioperative mortality. Mean length of hospital stay was 10.9±1.4 days. 90-day mortality occurred in one patient with postoperative multiple systemic metastasis. Fifteen patients are alive with a median follow up of 18 months. One patient died with regional lymph node recurrence and three patients died with hematogenous dissemination. Conclusion Multimodal treatment strategy combining immunotherapy and chemotherapy may convert unresectable tumors into potentially operable ones, and achieved favorable survival. Longer follow-up and larger sample size are needed to verify our preliminary results.

NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer.

LBA3504 Background: The prognostic advantage of early stage deficient-MMR/MSI-High colorectal cancer (CRC) is lost after relapse. Hence, there is a clinical imperative to maximise the chance of cure in early-stage disease. Tumour mutation burden (TMB) is an emerging biomarker for response and clinical benefit to immunotherapy in the advanced setting. NEOPRISM-CRC (Neoadjuvant PembRolizumab In Stratified Medicine – ColoReCtal) is the first multicentre Phase II Trial to determine if neoadjuvant pembrolizumab is efficacious and safe, prospectively stratified to TMB. Methods: The trial population included patients (pts) with operable high-risk stage 2 or stage 3 dMMR/MSI-High CRC. Pts with tumours that were TMB high or medium (≥6 mutations/Mb on FoundationOneCDx test) received 3 cycles of pembrolizumab (200mg every 3 weeks) and underwent surgery within 4-6 weeks of last cycle. Pts with TMB low tumours (≤5 mutations/Mb) underwent surgery 4-6 weeks after 1 cycle of pembrolizumab. The primary end point was pathological complete response rate (pCR). Secondary endpoints included 3-year relapse free survival, overall survival, safety, and health-related quality of life. The trial also incorporated translational endpoints to explore relationships between possible predictive novel biomarkers and response to pembrolizumab in blood, tumour tissue and microbiome. We required 19 pts with TMB high or medium tumours to detect a pCR after 3 cycles of neoadjuvant pembrolizumab of 33% (minimum of 10%), with one-sided 5% significance level and 80% power (A’Hern single stage). The trial would be considered a success if ³5/19 of those pts achieved pCR. To achieve this number, we aimed to recruit 32 patients in total. Results: The trial opened on 20th July 2022 and 32 pts were rapidly enrolled. The pCR primary endpoint analysis was performed on 1st March 2024. The primary endpoint was exceeded with the pCR in the intent to treat pts (N=32) as well as the pCR in evaluable tumours shown in Table 1. Median TMB was 42 mutations/Mb (4-82). There was only 1 TMB low tumour and no TMB medium tumours. In the TMB high-medium cohort there were 32 evaluable resected tumours as 1 pt had 3 synchronous primaries, and 1 pt did not undergo surgery due to toxicity as well as pt choice. There were no immune-related toxicities >Grade 3. At a median follow-up of 6 months (range 2-15), no pts have had disease recurrence. Conclusions: Neoadjuvant pembrolizumab for early stage deficient-MMR/MSI-High CRC is highly efficacious and safe. Longer follow up is needed to assess relapse free survival and translational biomarker work is ongoing. Clinical trial information: NCT05197322 . [Table: see text]

Pembrolizumab-induced myocarditis: A systematic review of case reports.

e14605 Background: Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized cancer therapy but are associated with immune-related adverse events (irAEs), including myocarditis, which can have serious clinical consequences. This systematic review aims to comprehensively analyze case reports to better understand pembrolizumab-induced myocarditis. Methods: Using keywords of "pembrolizumab" or "Keytruda" and "myocarditis" in the PubMed/Medline, ScienceDirect and clinicaltrials.gov databases and manual searches on Google Scholar, we reviewed all cases reported up to the year 2023. In total, 296 studies received primary screening. Duplicated articles and those meeting the exclusion criteria (not myocarditis, not human, not English, trials done in vitro, combination immunotherapies) were excluded. Review articles, retrospective studies, systematic reviews, and meta-analyses were also excluded. Finally, 45 studies matching the inclusion criteria were included (total of 46 patients). Data on patient demographics, clinical presentation, diagnostic criteria, management strategies, and outcomes were extracted and analyzed. Results: In the included 46 patients, the mean age was 65.5 years, with a slight male predominance (56.5%). Predominant cancer types included lung cancer (30.4%), thymoma (15.2%), melanoma (13.0%), and genitourinary cancers (13.0%). 45.7% of patients developed myocarditis after their first cycle of Pembrolizumab while 41.3% developed myocarditis after two cycles. 47.8% of patients presented with dyspnea, 23.9% with fatigue, 10.9% with chest pain, while 13% of the patients were asymptomatic and were subsequently diagnosed with myocarditis while presenting with other immune-related adverse events. Troponin levels were assessed in 45 individuals, with only 2.2% (one patient) having normal levels. ECG changes included ST segment elevation in 21.7%, conduction abnormalities (RBBB 15.2%, LBBB 6.5%, AV block 26.1%, and one unspecified conduction abnormality) in 50%, and arrhythmias in 37% of cases. Treatment included steroids for all, with varying outcomes. Four patients each received one of the following treatments: batacept, ruxolitinib, alemtuzumab, and methotrexate. All four of these patients showed improvement. Two patients received infliximab (4.3%) and both of them died. Outcomes revealed 34.8% mortality, 63.0% improvement, and 2.2% deterioration, including one sudden cardiac death 35 days post-discharge. Conclusions: Pembrolizumab-induced myocarditis is a rare but potentially life-threatening irAE. This systematic review provides a comprehensive overview of the clinical characteristics, diagnostic challenges, treatment approaches, and outcomes of this condition. Further research is needed to elucidate the underlying mechanisms and identify risk factors for pembrolizumab-induced myocarditis, enabling early detection and prevention strategies.

EFFECT-neo: A phase 3 study of pembrolizumab plus chemotherapy versus chemotherapy as neoadjuvant therapy in patients with resectable locally advanced head and neck squamous cell carcinoma.

TPS6123 Background: There is still a huge need for treatment of operable locally advanced head and neck squamous cell carcinoma (LA HNSCC). Multiple phase 2 studies have shown that PD-1 combined with chemotherapy has good short-term efficacy, especially the pathological complete response (pCR) rate exceeds 30%, which is also considered to be an important factor in the survival benefit that neoadjuvant immune therapy may bring. The randomized, open-label, phase 3 EFFECT-neo study (NCT06102395) will evaluate efficacy and safety of pembrolizumab plus chemotherapy versus chemotherapy as neoadjuvant therapy in patients with resectable LA HNSCC. Methods: Patients with untreated LA HNSCC who met the inclusion criteria will be randomly assigned 1:1 to two treatment arms. Experimental group will be given 2 cycles of pembrolizumab (200mg d1, Q3W) + chemotherapy (perfer TPF regimens) . Control group will undergo 2 cycles of chemotherapy. Both two arms should finish imaging evaluation, and If the result is CR after neoadjuvant treatment, radiotherapy (RT) (60-70Gy) ± chemotherapy (investigator's choice) will be given as adjuvant treatment; if the result are PR or SD, surgery (within 2 weeks) will be performed, and then RT ± chemotherapy will be given. If the imaging evaluation is PD, patients will be received standard treatment. Enrolled patients must closely monitor the adverse reactions of chemotherapy and record the time, grade, treatment measures, outcomes, etc. All patients will be reviewed every 3 months for 1 year; after 1 year, they were reviewed every 6 months for 3 years; patient recurrence and survival data were recorded. Eligibility criteria will include age ≥18 years; untreated with immunotherapy, resectable, stage III/IVB HNSCC (AJCC Cancer Staging Manual, 8th edition); ECOG performance status 0-2; and the investigators believe that patients can safely receive pembrolizumab combined with chemotherapy in neoadjuvant chemotherapy. Randomization treatment will continue until disease progression, unacceptable toxicity, or decision to withdraw. Primary end points is pCR, defined as the absence of residual invasive squamous cell carcinoma within the primary tumor specimen on resection/needle biopsy (Patients with CR imaging results will undergo multi-point biopsy). Secondary end points include objective response rate, 1-year and 2-year event-free survival rates, 2-year overall survival rate, functional preservation rate, safety and Karnofsky performance status. Recruitment is ongoing and will continue until 272 patients are enrolled. Clinical trial information: NCT06102395 .

A phase 2 study to evaluate efficacy and safety of PRGN-2009, a novel gorilla adenovirus-based immunotherapy, in combination with pembrolizumab versus pembrolizumab monotherapy in patients with recurrent or metastatic cervical cancer.

TPS5623 Background: The association between cervical cancer and human papillomavirus (HPV) is well understood, with nearly all cervical cancer known to be caused by high risk HPV infection. HPV16 and HPV18 are the most common high-risk HPV types and are responsible for about 70% of cervical cancer cases. Recurrent or metastatic cervical cancer is currently treated with pembrolizumab alone or in combination with chemotherapy, however t there remains a significant need for treatments for patients that recur or do not respond at all to pembrolizumab treatment. PRGN-2009 is a gorilla adenovirus-based immunotherapy targeting cancers caused by HPV16 or HPV18. PRGN-2009 includes a novel HPV antigen design to induce HPV16/18-specific T cell immune responses against cancer cells. The rationale for combining the PRGN-2009 with immune checkpoint inhibitor is based on preclinical and clinical data demonstrating that combination of cancer vaccines and immune checkpoint inhibitors can trigger intensified immunogenicity leading to increased antitumor efficacy compared to either treatment alone. PRGN-2009 has been characterized in both in vitroand in vivostudies to support the scientific rationale and the safety of PRGN-2009 has been demonstrated in evaluated in initial Phase 1/2 studies in patients with HPV+ malignancies. Methods: This is a randomized, Phase 2 study to evaluate efficacy and safety of PRGN-2009 in combination with pembrolizumab compared to pembrolizumab alone in patients with recurrent or metastatic cervical cancer. Key inclusion criteria include recurrent or metastatic cervical cancer (histologically or cytologically confirmed) resistant to pembrolizumab. Subjects will be randomized 1:1 to Cohort 1: Combination of PRGN-2009, 5 x 1011 PU (Day 0, Day 21 and Day 42, then q6w), plus pembrolizumab, 400mg q6w, or to Cohort 2: pembrolizumab alone (400 mg q6w). Subjects randomized to Cohort 2 (pembrolizumab monotherapy) and who have confirmed disease progression (per RECIST 1.1) after at least one cycle of pembrolizumab and have had no Grade ≥ 3 adverse events related to treatment will be offered the option to crossover to Cohort 1 (PRGN-2009 plus pembrolizumab). All subjects will be evaluated for safety and efficacy of PRGN-2009 in combination with pembrolizumab, and for biological correlative assays. The primary endpoint is objective response rate (ORR) following treatment with PRGN-2009 in combination with pembrolizumab or pembrolizumab monotherapy, and will be tested using Fleming’s two-stage design and the stopping boundaries for futility and efficacy applied. The study is currently recruiting patients with recurrent or metastatic cervical cancer (NCT06157151). Clinical trial information: NCT06157151 .

Abstract PO2-25-03: Deciphering the immune molecular signature associated with pembrolizumab efficacy in the neoadjuvant setting of Triple-Negative Breast Cancer patients: a single-centre experience

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and is characterized by a high rate of recurrence, despite the improvement of the therapeutic approaches in recent years. Neoadjuvant chemotherapy (NACT) is the standard treatment for early-stage TNBC. Achieving a pathological complete response (pCR) is considered an essential prognostic factor for long-term outcomes. However, the percentage of pCR patients after NACT is limited to 30-40%, thus requiring the implementation of novel therapeutic strategies. Recently, by applying a morphology-guided spatial transcriptomic approach on Tru-Cut biopsies, we showed that intratumoral infiltrating lymphocytes (iTILs) and stromal Natural Killer (NK) cells are major determinants of chemotherapy efficacy in TNBC. These data highlight a complex three-dimensional organization of the tumor landscape and underline how spatiality and molecular activation of immune cells are essential to enhance the efficacy of neoadjuvant NACT in TNBC. The fact that immune cells are important players in this setting is corroborated by the clinical success shown by the KEYNOTE-522 study. This trial paved the way for the use of immunotherapy in neoadjuvant settings, obtaining a significant improvement in the patient’s overall response compared to standard NACT. Still, the implementation of chemotherapy with immunotherapy in the TNBC neoadjuvant treatment implicates several compelling questions, including how to further increase the percentage of patients with a complete response, overcoming resistance mechanisms, and how to improve the personalization of treatment, evaluating which patients can benefit from a therapy de-scalation or another combined therapeutic strategy. In this prospective cohort study, we decided to define the relevance of different immune populations in affecting pembrolizumab efficacy in the neoadjuvant treatment of TNBC patients. We treated 40 patients with an early-TNBC diagnosis with the KEYNOTE-522 regimen that consists of four cycles of an intravenous infusion of pembrolizumab plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab plus epirubicin and cyclophosphamide. Only patients with evident side effects to immunotherapy administration were a priori excluded. Currently, 18 patients ended the neoadjuvant schedule and underwent surgical excision. Our data indicate that 15 patients displayed a pCR at the end of the therapy, whereas 3 patients displayed only partial response. To further clarify the immune dynamics that lead to a complete response to pembrolizumab in these patients, we collected peripheral blood before and after neoadjuvant treatment to isolate peripheral blood mononucleated cells (PBMCs). We applied a single-cell transcriptome analysis to shape any variations in circulating immune cells occurring during neoadjuvant treatment and associated with patient response. In addition, we collected residual tumors at surgery from partial responders and derived three-dimensional organoids that recapitulate the characteristics of the original patient tumor. These ex vivo organoid-based platforms are applied to clarify the molecular mechanisms driving neoadjuvant resistance. To this aim, we are performing co-cultures with autologous immune cells to identify novel combined therapeutic strategies to rescue pembrolizumab efficacy in these models. Overall, our study is defining the immune-related molecular mechanisms driving pembrolizumab and chemotherapy response in the neoadjuvant treatment of TNBC patients. Our findings can improve our understanding of which immune populations are determinant players in anti-TNBC immune response and can be proposed as novel biomarkers of pembrolizumab efficacy during the neoadjuvant treatment. Citation Format: Elisa Gasparini, Gloria Manzotti, Moira Ragazzi, Benedetta Donati, Federica Torricelli, Elisa Salviato, Alessandra Bisagni, Eleonora Zanetti, Alessandra Bologna, Saverio Coiro, Rita Vacondio, Guglielmo Ferrari, Giancarlo Bisagni, Carmine Pinto, Alessia Ciarrocchi, Francesca Reggiani. Deciphering the immune molecular signature associated with pembrolizumab efficacy in the neoadjuvant setting of Triple-Negative Breast Cancer patients: a single-centre experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-25-03.

Pembrolizumab-Induced Pancytopenia: A Case Report

Introduction: Immunotherapy is increasingly acknowledged as an effective treatment for metastatic melanoma. Hematological immune-mediated adverse events are rarely reported. In this article, we report a case of a patient who developed pancytopenia following administration of pembrolizumab. Case Report: A 63 -year-old woman, followed for a scalp melanoma with pulmonary metastasis developed severe pancytopenia after receiving 4 cycles of pembrolizumab. Outcome and Management: Following the appearance of the adverse effect, Pembrolizumab was stopped. A series of blood tests were performed in order to get the reasons of this event. The patient received high-dose of corticosteroids with tapering the dose over 6 weeks, and blood transfusion was required. Discussion: Checkpoint inhibitors (ICI) stimulate both humoral and cellular immune responses against tumor antigens, potentially resulting in immune-related adverse effects, including hematological issues like pancytopenia. Due to the substantial morbidity and mortality linked to ICI-induced pancytopenia, further data is essential to formulate evidence-based management guidelines.

Impact of neoadjuvant pembrolizumab adherence on pathologic complete response in triple-negative breast cancer: a real-world analysis.

The addition of pembrolizumab (pembro) to neoadjuvant chemotherapy (NAC) is standard of care for the treatment of early triple-negative breast cancer (TNBC) after KEYNOTE-522 trial demonstrated improved pathologic complete response (pCR) rates with the combination. However, the optimal treatment strategy for TNBC remains uncertain as questions persist about which patients benefit from pembro and the best treatment schedule and regimen. We identified real-world clinical characteristics and treatment variables associated with response to NAC plus pembro. Patients with early TNBC treated with NAC plus pembro between February 2020 and September 2023 were identified. Univariate and multivariate analysis was performed using logistic regression to identify factors associated with pCR. Cox proportional hazard prediction models were used to identify predictors of invasive disease-free survival and overall survival in this cohort. A pCR was achieved in 75 (63.6%) of 118 patients. Age at diagnosis (P = .04), Ki-67 (P = .004), duration from start of pembro to surgery (P = .006) and NAC to surgery (P = .01), number of cycles of pembro (P = .04) and NAC (P = .02), and completion of at least 8 cycles of pembro (P = .015) and NAC (P = .015) were each significantly associated with pCR in univariate analysis. In multivariate analysis, patients younger than 55 years at time of diagnosis (vs age > 55 years) and those completing at least 8 cycles of pembro remained predictive of pCR (OR's 2.50, 2.49, P = .035 and .037, respectively). In this real-world analysis of patients with TNBC treated with NAC plus pembro, younger age and the completion of at least 8 cycles of pembrolizumab were associated with pCR.

Triple-induction treatment for locally advanced non-small cell lung cancer: a case report of pathological complete response

BackgroundIn patients with resectable stage III non-small cell lung cancer (NSCLC), induction chemoimmunotherapy followed by surgical resection has shown unprecedented rates of pathological response and event-free survival. However, a triple-induction including radiochemotherapy and immunotherapy followed by surgical resection has not been routinely established in clinical practice.Case presentationWe report the case of a 47-year-old patient with stage IIIA NSCLC who was treated in a combined concept including induction concurrent radiochemotherapy, followed by 4 cycles of pembrolizumab and subsequent intrapericardial left-sided pneumonectomy. Histological analysis revealed a pathological complete response.ConclusionsThe case demonstrates that the combination of neoadjuvant chemo-, radio- and immunotherapy in advanced NSCLC may lead to a relevant down-staging and may enable a R0-resection of a borderline resectable tumor. However, the combination of four different treatment modalities requires resilience and a good performance status. A triple induction treatment may be a promising option for selected patients with locally advanced NSCLC and good performance status.

Phase 1 study of pembrolizumab plus chemotherapy in Japanese patients with extensive-stage small-cell lung cancer

SummaryBackgroundPart E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with previously untreated extensive-stage small-cell lung cancer (ES-SCLC).MethodsPatients received 4 cycles of pembrolizumab (200 mg) every 3 weeks in combination with cisplatin (75 mg/m2) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 1; with carboplatin (AUC 5 mg/mL/min) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 2; or with cisplatin/etoposide and pegfilgrastim (3.6 mg; cycle 1, day 4) in cohort 3. Combination therapy was followed by pembrolizumab monotherapy (31 cycles). The primary endpoint was safety and tolerability (including dose-limiting toxicities; DLTs).ResultsFifteen patients were included in the study (cohort 1, n = 6; cohort 2, n = 6; cohort 3, n = 3). Median time from treatment allocation to data cutoff was 22.1 months (range, 4.1‒32.4 months). DLTs occurred in 3 patients in cohort 1 (one patient with grade 4 laryngeal stenosis and grade 3 febrile neutropenia; two patients with grade 3 febrile neutropenia); no patients in cohorts 2 or 3 experienced DLTs. Grade ≥ 3 treatment-related adverse events included leukopenia (67%) and neutropenia (87%). Among all patients, ORR was 67% (95% CI, 38%‒88%) and median DOR was 4.5 months (range, 2.8‒28.8 months). Median PFS was 4.2 months (95% CI, 3.0‒7.8 months) and median OS was 22.1 months (95% CI, 7.4‒25.9 months).ConclusionPembrolizumab in combination with platinum-etoposide therapy had manageable toxicity with no new safety signals and was associated with antitumor activity in Japanese patients with ES-SCLC.Trial RegistrationClinicalTrials.gov, NCT01840579.

Immunoglobulin G4-related Autoimmune Pancreatitis and Hypopituitarism Following Immune Checkpoint Inhibitor Therapy: A Case Report.

A 70-year-old man underwent nephrectomy for renal cell carcinoma followed by 3 cycles of pembrolizumab as adjuvant chemotherapy. Three months later, he complained of appetite loss. He was diagnosed with secondary adrenal insufficiency and pancreatic tumor. Amylase and immunoglobulin G (IgG) 4 levels were normal. The differential diagnosis poses challenges in distinguishing pancreatic cancer, renal cell carcinoma metastasis, and autoimmune pancreatitis, necessitating tumor resection surgery. A histological examination revealed IgG4-related sclerosing pancreatitis. Postoperatively, there was no recurrence of pancreatitis. It is essential to consider the potential development of IgG4-related diseases after the administration of immune checkpoint inhibitors.

Vesical Imaging-Reporting and Data System use predicting the outcome of neoadjuvant pembrolizumab in muscle-invasive bladder cancer.

To evaluate the predictive capability of the pre- and post-pembrolizumab Vesical Imaging-Reporting and Data System (VI-RADS) to identify ypT0N0 or ypT≤1N0 response in muscle-invasive bladder cancer (MIBC) within the PURE-01 trial (ClinicalTrials.gov identifier: NCT02736266). Patients were staged with bladder multiparametric magnetic resonance imaging (mpMRI) before and after treatment (three cycles of pembrolizumab) prior to radical cystectomy (RC). Logistic regression models were used to analyse the pre- and post- pembrolizumab VI-RADS against ypT≤1N0 and ypT0N0 response. The VI-RADS scores were dichotomised between 0 and 3 (0 = no evidence of disease) and 4-5. Event-free survival (EFS) and overall survival (OS) analyses were performed. Comprehensive genomic profiling and transcriptome-wide expression profiling data were matched with the VI-RADS scores. In total, 110 patients underwent centrally reviewed scans (N = 220 mpMRI), treated between February 2017 and July 2020. Both pre- and post-pembrolizumab VI-RADS 0-3 scores were the only significant covariates that predicted the ypT≤1N0 endpoint in multivariable analyses, and the strongest effect was seen with post-pembrolizumab VI-RADS 0-3 predicting the ypT≤1N0 response (P < 0.001). The area under the curve for this model was 0.90. Post-pembrolizumab VI-RADS 0-3 also predicted a longer EFS (P < 0.001) and OS (P = 0.044). The scores of several gene signatures from baseline tumours differed between the pre-pembrolizumab VI-RADS 0-3 and 4-5 categories. Post-pembrolizumab VI-RADS scores are strongly associated with pathological downstaging and survival. VI-RADS scores were also characterised by distinct biomarker features. These results indicate that the VI-RADS is emerging as an important tool for designing next-generation trials for MIBC.

A Phase Ⅱ Study of Ubenimex Combined With Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non–Small-Cell Lung Cancer: TORG2241 (UBE-Q)

BackgroundAccording to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non–small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. Patients and MethodsThis prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee. ConclusionsThis is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies.

Real-world data on efficacy and safety of pembrolizumab in the first-line treatment of metastatic lung cancer in patients with PD-L1 expression >0% - a single center experience.

With the advent of immunotherapy, there has been a significant improvement in the outcomes of non-small cell lung cancer treatment. Several clinical trials have confirmed the efficacy and safety of pembrolizumab, but research with real-world data is needed to confirm the findings from clinical trials. In this retrospective study, data on the treatment of lung cancer with pembrolizumab were analyzed in 78 patients who started pembrolizumab therapy as first-line treatment for metastatic disease at University Hospital Centre Osijek, from May 15, 2018, until December 31, 2021. November 30, 2022, was set as the last date of data monitoring. Patients who had received less than 3 cycles of pembrolizumab were excluded from the study. The main objectives of the study were OS (overall survival) and PFS (progression-free survival). The differences in the incidence and type of adverse events between the two groups of patients were also compared. Kaplan-Meier analysis of the survival determined that the median OS was 20 months and PFS was 13 months. Although OS and PFS are longer in patients with PD-L1 (programmed death-ligand 1) ≥ 50%, the differences are not statistically significant. The most commonly reported adverse events related to pembrolizumab treatment were gastrointestinal adverse events. No significant differences were found in the frequency of occurrence of certain adverse events between the two groups of patients. This study demonstrates that real-world data for pembrolizumab treatment of non-small cell lung cancer confirm the efficacy and safety indicated by clinical trials. Nevertheless, it is necessary to assess the patient's general condition more objectively before starting the treatment.

Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of Malignant Esophago-Gastric Diseases (PROCEED): Assessment of Pathologic Response in a Prospective, Phase II Single-Arm Trial

A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgical resection. Historical pathologic complete response (pCR) rate after CRT with carboplatin/paclitaxel per the CROSS trial was 23%. The efficacy of immune checkpoint inhibition in the adjuvant setting has since been demonstrated in this patient population. The primary objective of this trial was to investigate whether neoadjuvant CRT combined with pembrolizumab improves pCR compared to the historical control of CRT alone. Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab combined with CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy in 25 fractions with concurrent, weekly carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of pembrolizumab were administered as neoadjuvant therapy. Patients also received three cycles of adjuvant pembrolizumab after surgical resection. Baseline characteristics were collected. Pathologic response was scored from 0-3 based on tumor regression grading (TRG), with 0 indicating a complete response, 1 indicating marked response (<10% residual disease), 2 indicating partial response, and 3 indicating poor or no response. The percentage of patients with pCR and major pathologic response (MPR, score of 0-1) are described. Accrual of this trial is now complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 89% of enrolled patients are male, and 94% are white. 97% of patients have an esophageal primary. One patient withdrew from the study prior to completing neoadjuvant therapy due to a severe drug reaction. Two other patients did not undergo surgery, one due to preference and the other due to development of metastatic disease. Of 32 remaining eligible patients, 28 have completed neoadjuvant therapy and surgical resection to date. 100% of patients underwent IMRT/VMAT. 27/28 (97%) patients underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR, and 14/28 (50%: 95% CI: 31%, 68%) patients achieved an MPR. Patients undergoing neoadjuvant CRT combined with pembrolizumab for EGA experienced a higher rate of pCR/MPR compared to historical controls treated with CRT alone. This phase II trial demonstrates the efficacy of this treatment paradigm, which warrants assessment in future prospective studies.