Not Waiting to Progress; How the COVID-19 Pandemic Nudged Neoadjuvant Therapy for Stage III Locally Advanced Melanoma Patients.

Background: Early-phase neoadjuvant trials have demonstrated promising results in the utility of upfront immunotherapy in locally advanced stage III melanoma and unresected nodal disease. Secondary to these results and the COVID-19 pandemic, this patient population, traditionally managed through surgical resection and adjuvant immunotherapy, received a novel treatment strategy of neoadjuvant therapy (NAT). Methods: Patients with node-positive disease, who faced surgical delays secondary to COVID-19, were treated with NAT, followed by surgery. Demographic, tumour, treatment and response data were collected through a retrospective chart review. Biopsy specimens were analysed prior to the initiation of NAT, and therapy response was analysed following surgical resection. NAT tolerability was recorded. Results: Six patients were included in this case series; four were treated with nivolumab alone, one with ipilimumab and nivolumab and one with dabrafenib and trametinib. Twenty-two incidents of adverse events were reported, with the majority (90.9%) being classified as grade one or two. All patients underwent surgical resection: three out of six patients following two NAT cycles, two following three cycles and one following six cycles. Surgically resected samples were histopathologically evaluated for the presence of disease. Five out of six patients (83%) had ≤1 positive lymph node. One patient showed extracapsular extension. Four patients demonstrated complete pathological response; two had persisting viable tumour cells. Conclusions: In this case series, we outlined how in response to surgical delays secondary to the COVID-19 pandemic, NAT was successfully applied to achieve promising treatment response in patients with locally advanced stage III melanoma.

A case of refractory pelvic squamous cell carcinoma of unknown primary that responded to nivolumab.

Cancer of unknown primary (CUP) is a heterogeneous group of metastatic tumors with a usually unfavorable prognosis. A 33-year-old female was diagnosed with pelvic squamous cell carcinoma of unknown primary. The tumor was p16-positive, suggesting that it was human papillomavirus (HPV)-related. The tumor progressed for 4 months after concurrent chemoradiotherapy (initial treatment) and was refractory to paclitaxel plus carboplatin (second-line therapy). Liquid-based cancer genomic profiling identified five pathogenic variants, including Neurofibromin1 (NF1) (p.T1690Mfs*5); however, due to the lack of domestic clinical trials, the patient could not receive genome-based molecular-target therapies. Simultaneously, nivolumab was administered to the patient post its approval in Japan for CUP. The tumor responded to nivolumab, accompanied by decreased levels of tumor markers. NF1 mutations and HPV-related carcinogenesis may be associated with a favorable response to nivolumab treatment. It may therefore serve as a potential treatment against cancers of unknown primaries.

Encephalopathy after COVID-19 vaccination during treatment with nivolumab: A case report.

Vaccination is useful for the prevention of COVID-19 and is recommended for everyone, especially people with a weakened immune system. However, various neurological complications have been reported following vaccination. Here, we report the case of a 25 years-old, Japanese man, who presented with acute encephalopathy two days after the second dose of the COVID-19 vaccine. He had been treated with nivolumab, a medication used to treat cancer. He had a high fever and was confused upon admission, and the antibody test was positive for anti-myelin oligodendrocyte glycoproteins. Abnormal signal intensity at the splenium corporis callosi was observed on diffusion-weighted imaging of the brain. We diagnosed him with autoimmune encephalitis and initiated intravenous methylprednisolone, after which, the patient's symptoms rapidly subsided.

Time and productivity loss associated with immunotherapy infusions for the treatment of melanoma in the United States: a survey of health care professionals and patients.

INTRODUCTION: A new dosing schedule for the oncology immunotherapy pembrolizumab, every 6 weeks (Q6W), has been approved by the U.S. FDA, reducing the frequency of visits to infusion centers. We quantified the time spent by oncologists, nurses, patients, and caregivers per melanoma-related immunotherapy infusion visit to evaluate its potential impact. METHODS: Surveys were self-completed by 100 oncologists, 101 oncology nurses, and 100 patients with melanoma across the U.S. to quantify the time spent per infusion visit with pembrolizumab (Q3W or Q6W), nivolumab (Q2W or Q4W), or nivolumab+ipilimumab (nivolumab in combination: Q3W; nivolumab maintenance: Q2W or Q4W). Time measures included traveling, waiting, consultation, infusion, post-treatment observation, and caregiving. Respondents were also surveyed regarding the impact of the COVID-19 pandemic on infusion treatments. RESULTS: Responses deemed valid were provided by 89 oncologists, 93 nurses, and 100 patients. For each new [returning] patient treated with pembrolizumab, nivolumab or nivolumab+ipilimumab, oncologists reported to spend an average of 90 [64], 87 [60] and 101 [69] minutes per infusion visit (p-value for between-group difference = 0.300 [0.627]). For first [subsequent] treatment cycles, nurses reported spending 160 [145] average minutes per visit for nivolumab+ipilimumab, versus roughly 120 [110] for the single agents (p-value for between-group difference = 0.018 [0.022]). Patients reported to spend an average of 263, 382, and 224 minutes per visit at the center for pembrolizumab (N = 47), nivolumab (n = 34), and nivolumab+ipilimumab (n = 15) respectively (p-value for between-group difference = 0.0002). Patients also reported that their unpaid (N = 20) and paid caregivers (N = 41) spent with them an average of 966 and 333 minutes, respectively, from the day before to the day after the infusion visit. CONCLUSION: Less frequent immunotherapy infusion visits may result in substantial time savings for oncologists, nurses, patients, and caregivers.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms following nivolumab and ipilimumab in a pediatric patient with melanoma.

Drug-induced hypersensitivity syndrome (DIHS) is a type of severe cutaneous adverse reaction (SCAR). DIHS typically occurs 2-6 weeks after initiation of the offending medication. We report a case of DIHS in a pediatric patient undergoing treatment of metastatic melanoma with nivolumab and ipilimumab.

A case of cytokine release syndrome accompanied with COVID-19 infection during treatment with immune checkpoint inhibitors for non-small cell lung cancer.

Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. A 70-year-old man who was diagnosed with a postoperative recurrence of lung adenocarcinoma received nivolumab, ipilimumab, pemetrexed and carboplatin every 3 weeks for two cycles followed by nivolumab and ipilimumab, which resulted in a partial response. Four days after the dose of nivolumab, the patient returned with diarrhea and fever. The patient was diagnosed with COVID-19 infection accompanied by severe colitis. Although intensive care was performed, the patient suddenly went into cardiopulmonary arrest. Examination revealed an abnormally high interleukin-6 level, suggesting CRS. This is the first report of a patient with CRS accompanied with COVID-19 infection during treatment with ICIs. Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. Here, we report a case of non-small cell lung cancer with CRS caused by COVID-19 infection during treatment with nivolumab and ipilimumab. Fever is a common event in cancer patients, especially in COVID-19-infected patients, but when fever develops during cancer immunotherapy, CRS should always be kept in mind.

Clinical course of COVID-19 infection in a melanoma patient treated with nivolumab and bempegaldesleukin: a case report.

The exact impact of immune checkpoint inhibitors in the course and outcome of COVID-19 in cancer patients is currently unclear. Herein, we present the first description of an elderly melanoma patient who developed COVID-19 pneumonia while under treatment with nivolumab and bempegaldesleukin in combination with an investigational PEGylated interleukin (IL-2). We present the clinical characteristics and the laboratory and imaging findings of our patient during the course of COVID-19 pneumonia. Moreover, we discuss the currently available data regarding the mechanism of action of immune checkpoint inhibitors and IL-2 analogs in the treatment of COVID-19. The administration of these agents did not have a negative effect on the outcome of COVID-19 pneumonia in an elderly melanoma patient.

Immune checkpoint inhibitors represent a major advance in the treatment of several solid malignancies, including melanoma. Bempegaldesleukin is an investigational PEGylated IL-2 that is being evaluated, in combination with nivolumab, in the management of a variety of cancers. The immunomodulation caused by these agents may also modify the immune response in COVID-19. Currently available data regarding the impact of immune checkpoint inhibitors in reducing the severity of COVID-19 in patients with cancer are mixed, whereas no clinical data are available for bempegaldesleukin. Herein, we report the case of an elderly female melanoma patient who developed COVID-19 pneumonia while under treatment with nivolumab and bempegaldesleukin. The administration of these agents did not have a negative effect on the outcome of COVID-19 pneumonia in our patient.

Immune checkpoint inhibitors in kidney transplant recipients: a multicentre, single-arm, phase 1 study.

BACKGROUND: Most kidney transplant recipients with cancer stop or reduce immunosuppressive therapy before starting treatment with an immune checkpoint inhibitor, and approximately 40% of such patients will develop allograft rejection. Isolated immunosuppression reduction might be associated with organ rejection. Whether immunosuppression manipulation, immune checkpoint inhibition, or both, induce organ rejection is difficult to ascertain. The aim of this study was to examine the risk of allograft rejection with immune checkpoint inhibitor exposure when baseline immunosuppression was left unchanged. METHODS: We conducted a multicentre, single-arm, phase 1 study in three hospitals in Australia. Kidney transplant recipients aged 18 years or older with incurable, locally advanced cancer or defined metastatic solid tumours were eligible if they had a creatinine concentration of less than 180 mmol/L, no or low concentrations of donor-specific HLA antibodies, and an Eastern Cooperative Oncology Group status of 0-2. Patients received standard doses of nivolumab (3 mg/kg intravenously every 14 days for five cycles, then 480 mg every 28 days for up to 2 years). The primary endpoint was the proportion of patients with irretrievable allograft rejection and no evidence of tumour response. Primary outcome analyses and safety analyses were done in the modified intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Register, ANZCTR12617000741381, and is completed. FINDINGS: Between May 31, 2017, and Aug 6, 2021, 22 kidney transplant recipients with various solid tumours were screened and enrolled, four of whom chose not to proceed in the study and one of whom had unexpected disease progression. 17 patients (six [35%] women and 11 [65%] men; median age 67 years [IQR 59-71]) were allocated treatment with nivolumab and were included in the analyses. The trial was then stopped due to ongoing difficulties with running clinical trials during COVID-19 health restrictions. Patients were treated with a median of three infusions (IQR 2-10) and median follow-up was 28 months (IQR 16-34). No patients had irretrievable allograft rejection without evidence of tumour response. There were no treatment-related deaths or treatment-related serious adverse events. The most common grade 3 or grade 4 adverse events were decreased lymphocyte count in four (24%) patients, fever or infection in four (24%) patients, decreased haemoglobin in three (18%) patients, and increased creatinine in three (18%) patients. INTERPRETATION: Maintaining baseline immunosuppression before treatment with an immune checkpoint inhibitor in kidney transplant recipients might not affect expected efficacy and might reduce the risk of allograft rejection mediated by immune checkpoint inhibitors. FUNDING: Bristol Myers Squibb.

Type 1 Diabetes Mellitus Associated with Nivolumab after Second SARS-CoV-2 Vaccination, Japan.

Recently, along with increasing use of immune checkpoint inhibitors such as nivolumab, the incidence of immune-related adverse events, including type 1 diabetes mellitus, has become a serious problem. We report a patient who had immune checkpoint inhibitor‒associated type 1 diabetes mellitus that developed after a second mRNA-based SARS-CoV-2 vaccination.

Safety and Efficacy of Extended Interval Dosing for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer During the COVID-19 Pandemic.

INTRODUCTION: Extended interval (EI) dosing for immune checkpoint inhibitor (ICI) mono- or consolidation therapy initiated due to the COVID-19 pandemic led to a significant reduction in ICI-related site visits for patients with stage III and IV non-small cell lung cancer. Here we report the safety and efficacy compared to standard dose (SD) schedules. METHOD: In this retrospective analysis, patients who received ICI mono- or consolidation therapy, or adjuvant ICI therapy were assessed. Safety and efficacy of EI dosing with data of SD schedules were compared. RESULTS: One hundred seventeen patients received EI dosing for ICI and 88 patients SD. Patient characteristics were comparable. We observed 237 adverse events in the EI dosing cohort versus 118 in the SD group (P= .02). Overall, there was no difference in the occurrence of grade ≥3 adverse events (EI dosing: 21/237 [8.9%]; SD group: 20/118 [17.0%], P = .42), except for the pembrolizumab EI dosing cohort. Of all patients who received an EI dosing schedule, however, only 8 (6.8%) were reduced to SD because of toxicity. In 5 (4.3%) patients ICI was permanently stopped because of severe toxicity compared to 11 (12.5%) discontinuations in the SD group. Short-term treatment interruption occurred with similar frequencies in both groups. Progression-free survival and overall survival were comparable in patients receiving pembrolizumab and in those receiving adjuvant durvalumab. Progression-free survival and OS were better in the EI dosing cohort of nivolumab. CONCLUSION: EI dosing for ICI did not lead to an increase of clinically relevant toxicities resulting in dose reduction and/or treatment discontinuation. Efficacy of EI dosing of pembrolizumab and durvalumab were comparable to SD. Based on our safety and efficacy data EI dosing for ICI seems a safe and effective strategy.

Delayed Metastatic Polypoid Nodular Melanoma Diagnosis During COVID-19 Pandemic, Successful Treatment With Surgery and Nivolumab.

Patients with polypoid (pedunculated) melanoma have the poorest 5-year survival rate compared with all other variants of nodular melanoma, presenting with increased thickness, incidence of metastasis, and rates of ulceration. There are few published reports regarding the pathogenesis and treatment of polypoid melanomas. We report the successful treatment of a rapidly developing red nodular polypoid melanoma with metastasis using surgery followed by anti-PD-1 antibody nivolumab in a SARS-CoV-2-positive patient who delayed seeking care due to the COVID-19 pandemic. J Drugs Dermatol. 2021;20(12):1343-1345. doi:10.36849/JDD.6071.

[A Case Report of Checkpoint Inhibitor Pneumonitis Caused by PD-1
Antibody-Safety and Effectiveness of Pirfenidone].

BACKGROUND: Immune checkpoint inhibitor associated pneumonia (CIP) is a serious side effect of immune checkpoint inhibitors. There is a consensus on the treatment of acute phase of CIP, but the treatment of pulmonary interstitial fibrosis after the acute phase is still a clinical problem to be solved. METHODS: The diagnosis and treatment of a non-small cell lung cancer (NSCLC) patient with immune checkpoint inhibitor associated pneumonia in the Stereotactic Radiotherapy Department of Qingdao Central Hospital were retrospectively analyzed, and literatures were reviewed. RESULTS: A 70-year-old male patient was diagnosed with Poorly differentiated squamous cell carcinoma of left lung with mediastinal lymph node metastasis T3N3M0 stage IIIc, EGFR/ALK/ROS1/RAF negative, PD-L1 (22c3) immunohistochemistry negative. After the progression of first-line chemotherapy, the patient was diagnosed as immune checkpoint inhibitor associated pneumonia grade 3 during second-line monotherapy with Nivolumab. After initial high-dose glucocorticoid pulse therapy, the lung computed tomography (CT) imaging and clinical symptoms of the patients were partially relieved, and then pirfenidone (300 mg tid) was given orally for more than 11 months. During the treatment of pirfenidone, the CT imaging and clinical symptoms of the patients were significantly improved, and there were no other adverse reactions except grade 1 nausea. During this period, chemotherapy and Anlotinib was given concurrently with pirfenidone and showed good safety profile. CONCLUSIONS: This case report is the first report of pirfenidone in the treatment of CIP, which provides a new idea for the clinical practice and research of CIP treatment.

Presumed complement-mediated, checkpoint inhibitor-induced, thrombotic microangiopathy in a patient with metastatic melanoma.

Immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs), but haematological irAEs are rare. We report a case of presumed complement-mediated thrombotic microangiopathy (CM-TMA) in a 78-year-old man with metastatic melanoma following treatment with ICIs. Following two doses of combination nivolumab and ipilimumab therapy, he developed microangiopathic haemolytic anaemia, thrombocytopenia and increased creatinine. ADAMTS13 activity was preserved, CH50 was high, haptoglobin was depleted and a blood film demonstrated fragments. Given this constellation of findings, a diagnosis of CM-TMA was made. Immunotherapy was held and the patient received steroids and supportive care. Six months after his last dose of immunotherapy, he has no evidence of melanoma or CM-TMA. CM-TMA should be suspected in patients on ICI with unexplained anaemia and thrombocytopenia with preserved ADAMTS13 activity. Suspicion of complement dysregulation may have therapeutic implications, such as the necessity of complement pathway inhibition.

NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients. METHODS: NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy. DISCUSSION: Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1 .

Neoadjuvant PD-1 Inhibitors and Chemotherapy for Locally Advanced NSCLC: A Retrospective Study.

BACKGROUND: Stage III non-small cell lung cancer (NSCLC) encompasses a variety of local invasion and nodal involvement and its management is still under debate. Immune checkpoint inhibitors (ICIs) have been shown to improve the survival in metastatic NSCLC, but are far from being accepted as an induction therapy. METHODS: We retrospectively collected data of all patients who received induction ICIs (nivolumab or pembrolizumab) and chemotherapy (carboplatin with paclitaxel) for stage IIIA-B NSCLC followed by surgery in our unit between January 2019 and March 2020. RESULTS: Of the 12 patients (9 men, 3 women) 6 had a squamous cell carcinoma, 4 had adenocarcinoma, 1 had an undifferentiated adenocarcinoma, and 1 had adeno-squamous carcinoma. Seven patients had stage IIIA disease and 5 had stage IIIB. After induction therapy, 6 patients had stable disease and 6 had a partial response. The median tumor reduction was 3.05 cm (range, 2.30-8.70 cm). All patients, but 1 due to the COVID-19 outbreak, had no delay in surgery. Two patients experienced myelosuppression after induction therapy, 2 had minor adverse effects. Three patients had postoperative complications not related to the induction therapy. All patients had a pathologic response: 5 complete, 4 major, and 3 partial. Eleven patients are alive (mean follow-up, 18.17 ± 4.97 months) and free of disease. CONCLUSIONS: Induction ICI chemotherapy may be a valid treatment in patients with locally advanced NSCLC, providing important tumor downstaging and rendering patients operable. In our experience patients had few side effects and a good pathologic response.

Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.

After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.