Case Report on a Rare Malignancy: Anorectal Melanoma

Introduction: Melanoma of the rectum is an extremely rare disease. The median survival rate is 2-5 years. Current treatment for this aggressive cancer is resection if possible and consider adjuvant or neoadjuvant radiotherapy;immunotherapy in nonresectable cases. Given the rapid spread of disease due to its submucosal growth and metastasis pattern, there is low success rates with treatments. Case Description/Methods: An 84-year-old male presented to the emergency department with an acute COVID-19 infection. The patient was also found to have gram-negative septicemia on blood cultures, so a CT abdomen/pelvis was performed (Figure 1a). The CT showed rectal wall thickening. A flexible sigmoidoscopy was planned for a future outpatient visit after recovering from his acute infection. The patient, however, developed an acute onset of dyspnea and had a high probability V/Q scan while in the hospital. He was started on anticoagulation, and shortly after starting therapy the patient developed bright red rectal bleeding. Due to the new onset of rectal bleeding it was decided to expedite the sigmoidoscopy. The sigmoidoscopy was performed in the hospital showing an ulcerated partially black pigmented non- obstructing medium-sized mass that was partially circumferential involving one-third of the lumen (Figure 1b). A biopsy of the lesion was taken using cold-forceps. The pathology stained positive for S100 consistent with melanoma. The diagnosis of anorectal melanoma was made, and colorectal surgery was consulted. The patient was deemed not to be a surgical candidate secondary to age and active COVID-19 infection. Oncology was consulted, and it was decided to start the patient on radiation and immunotherapy with a PD-1 inhibitor. Discussion(s): The symptoms of anorectal melanoma can be subtle and in this case report completely asymptomatic. Symptoms to be aware of are rectal bleeding and tenesmus. Diagnosing melanoma on sigmoidoscopy can be challenging as most tumors are not pigmented. Biopsies should be taken and sent for immunohistochemical staining for S100, if positive the patient should have a PET scan. Treatment choices for the tumor are based on staging. In a resectable tumor sphincter-saving local excision with radiotherapy to the site of the tumor and the pericolic and inguinal lymphatics is recommended. For unresectable tumors or tumors with distant metastasis, immunotherapy with PD-1 inhibitors (nivolumab and ipilimumab) is an emerging treatment choice.

Multi-centre review of systemic anti-cancer prescribing patterns and treatment drop off rates in the United Kingdom 2018-2021

Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over recent years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. There is ongoing discussion amongst oncology professionals about how best to optimise treatments in terms of sequencing to maximise the potential number of lines or to give the best treatments first. A previous south-west UK audit was completed in 2021 reviewing the drop off rates across 5 UK sites identifying that 69% of patients were able to receive second line therapy and 34% were able to receive third line therapy. Method(s): In this study we conducted retrospective analysis of all patients who commenced treatment with SACT for mRCC between 1st January 2018 and 30th June 2021 in 18 centres across the 4 nations of the United Kingdom. All NHS reimbursed treatment options including the COVID interim treatment guideline options were included. Patients who received SACT as part of a clinical trial were also included. Patients who continued on their respective lines of treatment were censored. We also identified patients who had been on a period of active surveillance before staring SACT in this cohort. Result(s): 1549 patients (71% male: 29% female) were included. IMDC subgroup patients included 21.6%favourable, 52.3% intermediate, 25.1%poor and 1% unavailable. 9.1% of patients had been on active surveillance before starting SACT - defined as a period of longer than 3 months from mRCC diagnosis to starting SACT. Of those patients that started SACT 60.5% of eligible patients had 2nd line therapy, 25.3% had 3rd line, 7.2% received 4th line therapy and only 1% had 5th line therapy. In the 1st line setting 58.9% received single agent VEGF TKI, 24.5% received combination ipilimumab and nivolumab (IO-IO) immunotherapy, 14 % received IO/ VEGF TKI combination and 2.6% received other/trial treatment. The single agent VEGF TKI ratio for 1st line SACT declined year by year with rising IO-IO and IO/VEGF TKI combination ratios seen. In the secondand third-line settings cabozantinib (33.2% 2nd line and 44.4% 3rd line) and nivolumab (32.8% 2nd line and 22.6% 3rd line) were the most common options. Disease progression or death was the most common cause of SACT discontinuation amounting to 57.4%, 62.5% and 79% of SACT cessation in the 1st, 2nd and 3rd lines respectively. Treatment toxicity SACT discontinuation rates were 22.8%, 21.4% and 10.9% for 1st, 2nd and 3rd lines respectively. Conclusion(s): These results suggest that with more treatment options available, including combination/immunotherapy therapies, more patients are able to receive second- and third-line therapies. That said there remains significant drop off rates mostly driven by disease progression that would support the use of our most effective therapies in the upfront setting.

Acute kidney injury (AKI) post-mRNA SARS-CoV-2 vaccine in patients with cancer, treated with immune check point inhibitor (ICPi): An immune double whammy!

Background: Immune check point inhibitors (ICPi) have become the first line treatment for most of the cancers and have shown promising results. However, they can provoke reactions, the most feared being immune related adverse events (irAE). Case presentation: We present a series of three cases, of patients recieving ICPi. All three patients developed AKI after administration of SARS-CoV-2 mRNA vaccine. Two patients had kidney-biopsy-proven acute interstitial nephritis (AIN) which responded to ICPi discontinuation and treatment with steroids. One had presumed AIN based on the high levels of CRP and urine retinol binding protein to creatinine ratio and responded to cessation of ICPi alone. Conclusion(s): These three cases demonstrate that a strong immune response from the SARS-CoV-2 mRNA vaccine combined with an uninhibited immune system under influence of ICPi led to an amplification of autoimmunity leading to AKI presenting as AIN.Copyright © The Author(s) 2022.

Side effects, toxicity and ADRs of monoclonal antibodies in multiple organ systems

The review of publications on the safety profiles of three different immunosuppressants and immunomodulators (Alemtuzumab (ALZ), ipilimumab and nivolumab) published between January 2021 and April 2022 are being reported in this chapter. Alemtuzumab (ALZ), a humanized CD52 monoclonal antibody has been widely used in the treatment of Multiple sclerosis (MS). Nivolumab and ipilimumab are known as immune checkpoint inhibitors (ICIs), and both are commonly used in treatment of metastatic cancers. All three medications are still widely used by prescribers for these high-impact disease states, but post-study side effects are still being reported regularly. For example, the combination of ipilimumab and nivolumab is known to cause hypophysitis, which can manifest in different clinical presentations, levels of severity, and other comorbidities in patients. As another example, alemtuzumab has been linked to thyroid dysfunction, causing issues like Graves' hyperthyroidism. With the incidence of COVID-19, these medications have also resulted at putting patients at risk of contracting this new, viral disease, mainly due to immunosuppressive effects. Hence, knowing any recurrent and new adverse reactions are critical to provide the best combination of patient treatment while maintaining the integrity of drug monitoring. Additionally, recurrence of side effects can be prevented or appropriately prepared for during the course of treatment.

MA06.05 Consolidation Nivolumab and Ipilimumab or Nivolumab Alone Following Concurrent Chemoradiation for Patients with Unresectable Stage III NSCLC

Introduction: The PACIFIC trial demonstrated that a year of consolidation PD-(L)1 inhibition following concurrent chemoradiation (CRT) for unresectable stage III NSCLC improves overall survival (OS). The optimal duration of consolidation IO therapy in this setting is undefined. Studies in metastatic NSCLC demonstrate that combination PD-(L)1/CTLA-4 inhibition improves OS over chemotherapy alone. This trial evaluated the use of combination Nivolumab (N) plus Ipilimumab (IPI) or N alone for up to 6 months in unresectable stage III NSCLC after concurrent CRT. Methods: This is a randomized phase II, multicenter trial of 105 pts with unresectable stage IIIA/IIIB NSCLC. All pts received concurrent CRT and were then enrolled and randomized 1:1 to receive N 480mg IV q4wks (Arm A) for up to 24 weeks or N 3mg/kg IV q2 wks + IPI 1mg/kg IV q6 wks (Arm B) for up to 24 weeks. The primary endpoint is 18-month PFS compared to historical controls of CRT alone for arm A (30%) and CRT followed by Durva for arm B (44%). Secondary endpoints include OS and toxicity. Results: From 9/2017 to 4/2021, 105 pts were enrolled and randomized, 54 to N alone (A) and 51 to N + IPI (B). The baseline characteristics for arm A/B: median age (65/63), male (44.4%/56.9%), stage IIIA (55.6%/56.9%), stage IIIB (44.4%/43.1%), non-squamous (57.4%/54.9%), and squamous (42.6%/45.1%). The percentage of pts completing the full treatment was 70.4% in A and 56.9% in B (p=0.15). Median f/u was 24.5 and 24.1 months on A and B, respectively. The 18-month PFS was 62.3% on A (p <0.1) and 67% on B (p <0.1), and median PFS was 25.8 months and 25.4 months, respectively. Median OS was not reached on either arm, but the 18- and 24-month OS estimates were 82.1% and 76.6% for A and 85.5% and 82.8% for B, respectively. Treatment-related adverse events (trAE) on arm A/B were 72.2%/80.4%, and grade ≥3 trAEs on arm A/B were 38.9%/52.9%. There was 1 grade 5 event in each arm (COVID19-A, Cardiac Arrest-B). The number of pts with grade ≥2 pneumonitis were 12 (22.2%) in A and 15 (29.4%) in B, with 5 (9.3%) and 8 (15.7%) grade ≥3 events, respectively. The most common (>10%) non-pneumonitis trAEs in A were fatigue (31.5%), rash (16.7%), dyspnea (14.8%), and hypothyroidism (13%), and in B were fatigue (31.4%), diarrhea (19.6%), dyspnea (19.6%), pruritus (17.7%), hypothyroidism (15.7%), rash (15.7%), arthralgia (11.8%), and nausea (11.8%). Conclusions: Following concurrent CRT for unresectable stage III NSCLC, both N and N + IPI demonstrated improved 18-month PFS compared with historical controls despite a shortened interval (6 months) of treatment. OS data are still maturing but 18- and 24-month OS estimates compare favorably to prior consolidation trials. Toxicity for N alone was similar to prior single-agent trials, and the combination of N + IPI resulted in a higher incidence of trAE’s, although consistent with prior reports. Keywords: Consolidation Immunotherapy, Stage III NSCLC

PD1 inhibition effect on immunization with MRNA vaccines against SARS-CoV-2

Background: We provide care for the rural, low-income, and underserved population of Oroville. The community has a vaccination rate of 50% and booster rate of over 20% in the 3rd year of the ongoing global SARS-CoV-2 pandemic in 2022. During this period, a subset of our cancer patients benefited from the use of immune checkpoint inhibitors. Methods: This is a cross-sectional observational study of the effectiveness of a mRNA-based vaccine in medical care workers compared to patients with systemic malignancies treated with immunomodulation of PD-1 and CTLA-4 inhibitors. The study was approved by the hospital IRB. We evaluated the total anti-Spike protein antibody titer using a commercial semi-quantitative assay, Labcorp Test #164090. All subjects received 3 doses of the mRNA vaccine. We excluded anyone who was administered therapeutic monoclonal antibodies (mAb) or had a recent infection within 120 days. Results: Subjects with systemic malignancies were significantly older, p = 0.0001 by t-test: median age: 76, range: 64-82, compared to health care workers: median age: 52, range: 21-75. Accrual had to be prematurely stopped upon the arrival of Omicron wave in the community. Out of the seven subjects treated with immunomodulation, six received nivolumab, including two in combination with ipilimumab. One subject received pembrolizumab. Six of the subjects had metastatic disease: one was treated adjuvantly for locally advanced esophageal adenocarcinoma. The rest had NSCLC and one case of urothelioma. We divided the groups to those who had the highest titer of antibody versus everybody else and found a similar distribution in both groups using the Chi2 test. The vast majority of the healthcare workers, 24/27 or 89%, had above the upper limit antibody titer. Patients with systemic malignancy, 5/7 or 71%, had above the upper limit antibody titer p = N.S. Conclusions: Three doses of the mRNA vaccine provided high titers irrespective of frailty or age. We hypothesize that immunomodulation could favorably affect vaccination response.

Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067

Background: Durable clinical benefit has been achieved with nivolumab (NIVO) + ipilimumab (IPI), including an overall survival (OS) of 49% and a melanoma-specific survival (MSS) of 56%, with median MSS not reached (NR) at 6.5-y minimum follow-up. Here we report sustained efficacy outcomes at 7.5 y. Methods: Patients (pts) with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1:1 and stratified by PD-L1 status, BRAF mutation status, and metastasis stage to receive NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314);NIVO 3 mg/kg Q2W + placebo (n = 316);or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) and OS with NIVO + IPI or NIVO alone versus IPI. Results: With a minimum follow-up of 7.5 y, median OS remained stable at 72.1 mo (NIVO + IPI), 36.9 mo (NIVO), and 19.9 mo (IPI);median MSS was NR, 49.4 mo, and 21.9 mo, respectively (Table). While the objective response rate remained stable at 58% (NIVO + IPI), 45% (NIVO), and 19% (IPI), median duration of response had now been reached for NIVO at 90.8 mo and remains NR and 19.2 mo for NIVO + IPI and IPI, respectively. Subsequent systemic therapy was received by 36%, 49%, and 66% of NIVO + IPI-, NIVO-, and IPI-treated patients, respectively, and median time to that therapy was NR (95% CI, 45.9-NR), 24.7 mo (16.0-38.7), and 8.0 mo (6.5-8.7). Of patients alive at 7.5 y, 106/138 (77%, NIVO + IPI), 80/115 (70%, NIVO), and 27/60 (45%, IPI) were off treatment and had never received subsequent systemic therapy. No change to the safety summary was observed with additional follow-up;updated health-related quality of life data will be reported. Of the 10 new deaths since the 6.5-y follow-up (ie, 5 NIVO + IPI;3 NIVO;2 IPI), none were treatment-related;4 were due to melanoma progression;1 was due to an unknown cause;and 5 were due to other causes, but not associated with a COVID diagnosis. Conclusions: The 7.5-y follow-up continues to demonstrate the durability of responses with NIVO + IPI and an ongoing survival plateau. A substantial difference in median OS and MSS between patients treated with NIVO + IPI or NIVO was observed in descriptive analyses.

Increased incidence of immune-mediated myocarditis in advanced skin malignancies treated with immune checkpoint inhibitors in the COVID-19 era

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced stage skin malignancies. Immunotherapy related adverse events (irAE) are toxicities associated with ICI therapy. Myocarditis is a rare life-threatening irAE. We attempt to characterize cases of myocarditis related to ICI therapy that have occurred since the start of the COVID-19 pandemic. Methods: We performed a single-center, retrospective cohort analysis of patients with advanced stage skin cancers who were treated with ICIs and identified cases of ICI-mediated myocarditis. ICI-mediated myocarditis was defined as evidence of myocardial injury in the setting of irAEs and exclusion of cardiovascular causes. Clinicopathologic variables and clinical outcomes were assessed in these patients. Results: A review of 361 patients that received ICI from 9/2014 - 10/2019 found 0 cases of ICI-mediated myocarditis. From 11/2019 - 12/2021, an additional 425 patients were identified of whom 11 (2.6%) developed ICI-mediated myocarditis. 10 patients had melanoma and 1 patient had Merkel cell carcinoma. 10/11 patients were male. 9/11 were treated with anti-PD-1 monotherapy and 2/11 were treated with ipilimumab with nivolumab. All patients had elevated high sensitivity troponin (median 361 pg/mL on presentation, reference range 0-19 pg/mL). 11/11 patients presented with elevated CPK (median 1734 IU/L, reference range 38-240 IU/L) and 8/11 presented with elevated AST:ALT ratio (median 1.58:1) on routine screening which prompted further investigation. 1 patient tested positive for COVID-19 13 days after initial biochemical concern for myocarditis, and 5 patients had received COVID-19 vaccines between 2.5-11 months prior to myocarditis onset. All patients were treated with high dose steroids, and 4 were treated with abatacept. 2 patients died within 30 days after diagnosis of myocarditis and 2 patients later died from malignancy progression. 2 patients developed progressive disease and 1 was successfully rechallenged with ICI with no myocarditis recurrence. 2 patients remain on active surveillance, 2 continue on a steroid taper, and 1 was lost to follow up. All patients with at least 5 months of follow up from myocarditis onset (n = 5) had persistently elevated HS-troponin despite normalization of CPK levels. Conclusions: In this single center study, we noted an increase in the frequency of ICI-mediated myocarditis in patients with advanced skin cancers during the pandemic era (2.6% vs 0% prepandemic) which is higher than reported in the literature (0.04-1.14%). The impact of COVID-19 during this time is suspicious and warrants further investigation. Therefore, we suggest heightened awareness in the COVID-19 era that elevated CPK levels and AST:ALT ratios merits further diagnostic investigation of ICI-mediated myocarditis.

A Case of MyastheniaGravis and Myositis after Immunotherapy and COVID Vaccine

Objective: To explore triple overlap syndrome and immune effects of COVID-19 vaccination. Background: Neurologic immune related adverse events (nIRAE) are potential complications of Immune Checkpoint Inhibitors (ICI). nIRAE of the Peripheral Nervous System (PNS) can present fulminantly, especially myositis, myasthenia gravis (MG), and overlap syndrome of myositis, MG, and myocarditis. Design/Methods: NA Results: 77-year old male with metastatic melanoma presented to hospital with leg weakness, hoarseness, dyspnea, and ptosis 1 week after first cycle of ipilimumab and nivolumab and 3 days after COVID-19 vaccine. He had bradycardia with heart block, and hepatorenal failure. Exam was remarkable for dysarthria, right eye ptosis, hip flexion weakness 4+/5, without fatigability. Labs showed CK 21,325, Troponin-T 4,888, Aldolase 307, AChR antibody positive, and AntiStriated Muscle Antibody 1:3840. Vital Capacity (VC) was 1.9L and Negative Inspiratory Force (NIF) -20cmH2O. Patient received BiPAP, plasmapheresis, and methylprednisolone 1000mg. After this, he developed fatigability of ocular muscles, voice, and proximal arms;VC dropped to 1.3L. He was diagnosed with triple overlap syndrome, but MG manifested after receiving first dose of high-dose steroids. Heart biopsy showed lymphohystiocytic inflammation. Muscle biopsy showed focal and dispersed lymphomononuclear cell endomysial infiltration. Electromyography demonstrated patchy myositis in lower extremities. Patient completed 3 days of high-dose steroids, 5 days of plasmapheresis, abatacept, and rituximab, followed by slow steroid taper. He did not require intubation despite tenuous respiratory status. Conclusions: nIRAE of the PNS are rare potential complications of immunotherapy, usually presenting by 6 weeks, although overlap syndrome can present hyper-acutely after 1 dose. Our patient presented 1 week after first treatment, perhaps influenced by COVID vaccine. Management of nIRAE is consensus-based, as no standard evidence-based treatment exists. Our patient was successfully treated with plasmapheresis prior to high-dose steroids (obviating steroid-induced myasthenic crisis), abatacept and rituximab. The myasthenic crisis was successfully managed with BiPAP, avoiding intubation, and he ultimately improved.

OUTCOMES OF NEPHRECTOMY FOR RENAL CELL CARCINOMA WITH VENOUS THROMBUS FOLLOWING IMMUNE CHECKPOINT INHIBITOR THERAPY: A MULTICENTER COLLABORATIVE STUDY

INTRODUCTION AND OBJECTIVE: Nephrectomy and venous thrombectomy is a challenging procedure with potential morbidity and mortality. Despite the increasing use of immune checkpoint inhibitors (ICI) in the management of advanced renal cell carcinoma (RCC), data regarding the outcomes of venous thrombectomy following ICI is limited. We evaluated the feasibility and perioperative outcomes of nephrectomy and venous thrombectomy following ICIs. METHODS: Patients with locally advanced or metastatic RCC with venous thrombus undergoing nephrectomy following ICI therapy were evaluated in four high-volume US academic centers between June 2017 and June 2021. Clinical data, perioperative outcomes, and 90-day complications were recorded. RESULTS: Out of 79 patients who received post-ICI nephrectomy, 27 had venous thrombus. Median (IQR) age was 64 (55-71) years. ICI regimens were Nivolumab ± Ipilimumab (n=19), and Pembrolizumab± Axitinib (n=8). Nephrectomy was indicated following either a good clinical response to ICI (n=24) or as a palliative surgery (n=3). Venous thrombi levels are shown in Table-1. Among all patients, 26 (96%) underwent radical and 1 (4%) partial nephrectomy;12 (44.5%) open, 12 (44.5%) robotic and 3 (11%) laparoscopic. One robotic case converted electively to open. Vascular procedures included renal vein thrombectomy (n=6), IVC thrombectomy and primary repair (n=19), IVC patch repair (n=1), and suprarenal cavectomy (n=1). No intraoperative complications were reported. Nine patients showed no viable tumor in the thrombus, of whom 2 had complete response in the primary tumor as well (ypT0N0). 90-day complication rate was 33% (n=9), with 8 patients (30%) requiring readmission (Table-2). One death was reported within 90 days due to COVID-19 infection. CONCLUSIONS: Nephrectomy and venous thrombectomy following systemic immune checkpoint inhibitor therapy is feasible. One third of patients show no viable tumor in the thrombus. Larger studies are needed to predict pathological response.

Sequential Combination of a Strong Interferon Inducer Viral Vector With Low Doses of Nivolumab Plus Ipilimumab Could Provide Functional Cure in Chronic Hepatitis B Virus infections: Technical Report Proposing a New Modality.

Based on the recommendation of the International Coalition to Eliminate hepatitis B virus (ICE-HBV), we intend to mimic the spontaneous resolution of HBV infection to achieve a functional cure of chronic hepatitis B virus (HBV) infection. To this end, we propose sequential targeting of the innate and adaptive host immune responses. Long-term suppression of HBV replication and hepatitis B surface antigen (HbsAg) production will be achieved first by inducing a strong innate immune response. The clinically validated viral superinfection therapy (SIT) will be administered, which employs an attenuated, non-lytic, double-stranded RNA (dsRNA) infectious bursal disease virus (IBDV) that provides an exceptionally strong interferon (IFN) response. Then, the exhausted HBV-specific T cell function will be restored by blocking the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) receptors with immune checkpoint inhibitors (ICIs). In order to minimize any risk of toxicity, off-label low doses of nivolumab (0.5 mg/kg) plus ipilimumab (0.3 mg/kg) will be administered, the safety and efficacy of which has already been demonstrated in 131 unselected stage IV cancer patients. We predict that this combination therapy will provide sustained off-treatment virological and clinical responses during a relatively short treatment period.

A multicenter real-world study reviewing systemic anticancer treatment choices and drop off rates between treatment lines for metastatic renal cell carcinoma in the United Kingdom: In the immunotherapy era

Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over the last few years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. A previous real world study in the UK had demonstrated a significant attrition rate between each line of therapy suggesting less than half of patients who received first line SACT then received second line therapy and less than a fifth of first line SACT patients reach third line. Methods: We conducted a retrospective analysis of all patients treated between January 2018 and end of June 2021 to see if advancement in treatment options had impacted on the drop-off rates. Data was collected from 5 UK sites. Patients were identified from electronic SACT database. All reimbursed treatment options including the COVID interim treatment guidelines options were included. Patients who received SACT as part of a clinical trial were also included. Patients who remained on the respective lines of treatment were censored. Results: Data for 515 patients (372 male: 143 female) who received first-line SACT for mRCC were included in the analyses. IMDC prognostic groups were 103 favourable, 236 intermediate, 127 poor (49 not available). On progression 69% of patients were able to receive second-line therapy and 34% were able to receive third-line therapy. Of the 515 first-line therapies, 24% of patients received frontline ipilimumab and nivolumab, 10% received TKI and IO combination and 63% received single agent VEGF TKI. Second-line nivolumab or cabozantinib (43% and 40% respectively) were the most commonly prescribed options. Third-line cabozantinib 61% and nivolumab 16% remain the most used options. Across all lines of therapy progressive disease was the primary reason for discontinuation. 5% switched treatment due to toxicity. Conclusions: These results suggest that, with more treatment options available, including combination/ immunotherapy therapies, more patients are able to receive second and third-line therapies. Despite this, nearly one third of patients only receive one line of treatment which highlights the need to deliver the most efficacious treatments first to optimise patient outcomes. Moreover, single agent TKI was the most commonly used first-line SACT despite advances in the management pathway. Data analysing the impact of COVID on treatment selection will be presented.

Checkpoint Inhibitors and Induction of Celiac Disease-like Condition.

Immune checkpoint inhibitors herald a new era in oncological therapy-resistant cancer, thus bringing hope for better outcomes and quality of life for patients. However, as with other medications, they are not without serious side effects over time. Despite this, their advantages outweigh their disadvantages. Understanding the adverse effects will help therapists locate, apprehend, treat, and perhaps diminish them. The major ones are termed immune-related adverse events (irAEs), representing their auto-immunogenic capacity. This narrative review concentrates on the immune checkpoint inhibitors induced celiac disease (CD), highlighting the importance of the costimulatory inhibitors in CD evolvement and suggesting several mechanisms for CD induction. Unraveling those cross-talks and pathways might reveal some new therapeutic strategies.

Top ten news (except COVID) in 2020 oncology

Despite the many challenges faced in 2020, we have seen impressive progress in many areas of cancer research. Twenty-one novel oncology drugs were approved by the U.S. Food and Drug Administration (FDA). Although cancer is one of the major public health problems worldwide, cancer mortality projections for 2021 confirm the persistent declines in cancer mortality in EU and US for many specific cancers. The breast cancer treatment landscape has evolved in the past year and several new drugs approved in 2020 as antibody drugs conjugates (ADC) sacituzumab in TNBC and fam-trastuzumab deruxtecan-nxki (T-DXd) in metastatic HER2 positive BC, as well as tucatinib, a small kinase inhibitor. A few very important clinical trial /RxPONDER, ADAPT, PRIME II/ presented last year support de-escalation of adjuvant chemotherapy and radiation, sparing patients from some of the side effects that can accompany treatments. In ovarian cancer five-year follow-up data from the SOLO-1 trial continue to show progression-free survival benefit of olaparib as maintenance therapy following platinum-based chemotherapy in the frontline setting. In the final analysis of SOLO-2 trial, maintenance olaparib provided an improvement of 12.9 months in median OS vs placebo in women with relapsed BRCA-related ovarian cancer who had responded to their most recent platinum-based chemotherapy after having received at least one more line of chemotherapy.In 2020 first new treatment for hepatocellular carcinoma approved in more than ten years according to the data from phase III IMbrave 150 trial. In that study, which includes 501 patients the combination of atezolizumab and bevacizumab provides the longest survival seen in a front-line phase III study in advanced HCC, confirming atezo + bev as a standard of care for previously untreated, unresectable HCC.In the field of thoracic oncology there were some very important news in 2020, potentially practice changing. Osimertinib, next generation EGFR-TKI, standard first line therapy in metastatic EGFR-mutated advanced NSCLC was successfully used, in ADAURA study, in adjuvant setting vs placebo (planned treatment duration three years), in resected NSCLC patients, stage IB-IIIA. Patients might had adjuvant chemotherapy also, and there was no outcome differences between these two groups. Overall, there was a 79% reduction in the risk of disease recurrence or death (DFS HR was 0.21, p<0.0001). Lorlatinib is the third generation of ALKinhibitors in the treatment of advanced NSCLC. The results of CROWN study where lorlatinib was given in the first line treatment were presented at ESMO 2020. In this randomized study, comparing lorlatinib with crizotinib, lorlatinib was superior in the term of PFS, HR was 0.28, p<0.001, this superiority was particularly pronounced in intracranial disease, where the percent of intracranial response was 82% in lorlatinib arm and only 23% in crizotinib arm, and percent of complete response per CT was 71% vs 7%. Lorlatinib has been recently approved for patients with advanced ALK-positive NSCLC, irrespectively of treatment line. Also of interest were two studies that inovatively used immunologic drugs as a combination in advanced NSCLC: in Check Mate 9LA randomized study, cytotoxic chemotherapy was given in paralell with nivolumab + ipilimumab for first two cycles, and compared with four cycles of chemoherapy. Median OS was significantly better: 15.6 vs 10.9 months, HR 0.66 and a overall response rate was 38% vs 25%. CITYSCAPE study give us inovative combination of two immuno-oncology drugs, tiragolumab as TIGIT inhibitor, and standard atezolizumab. Median PFS was particularly longer in the population of patients with high PD-L1 expression (NE vs 4.11 months, HR 0.30). In gastrointestinal oncology, last year will be remembered by introducing immunotherapy in first line treatment of metastatic colorectal cancer for patients with MSI-H tumors. In KN177, such patients were randomized to receive pembrolizumab or standard chemotherapy+/-biologic therapy, and after second interim analysis, there was a ery clear adventage for pembrolizumab in terms of mPFS (16.5 vs 8.2 months) and duraton of response (at 24 months, 83% vs 35%). The results are impressive, and it is for expected to be confirmed by OS adventage in future analyses. In urological oncology, JAVELIN Bladder 100 study demonstrated that the maintenance avelumab + best supportive care is superior over best supportive care alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma. In overall population, OS was 21.4 vs 14.3 months, HR 0.69, p<0.001, and the results are even better in PD-L1 positive population, with HR 0.56. These results are very probably practice changing, since cytotoxic chemotherapy have very modest achievements in the field of urothelial cancer.

Cabopoint: A phase II study of second-line cabozantinib in patients with metastatic renal cell carcinoma (RCC)

Background: Cabozantinib is an approved therapy for advanced RCC (in the USA) and in treatment-naive patients with intermediate/poor risk, as well as following VEGF-targeted therapy (in Europe). Trial design: Cabopoint (NCT03945773) is a phase II, open-label study of cabozantinib in adults with unresectable, locally advanced or metastatic clear-cell RCC, whose disease progressed after checkpoint inhibitor therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. A target of 250 patients at 50 European sites will receive cabozantinib (60 mg once daily;self-administered at home) for ≤ 18 months after the last patient receives their first dose. Safety assessments will occur every 2 weeks up to week 4, then every 4 weeks. Patients may continue cabozantinib after disease progression if there is clinical benefit. During follow-up, patients who discontinue early will be contacted every 12 weeks to assess survival and subsequent therapy. Each cohort will have an interim analysis when 60% of patients reach 12 months of follow-up. Cabopoint has been adjusted to allow the trial to continue during the COVID-19 outbreak, protecting participants in compliance with the study protocol.1 Alternative arrangements include: study drug dispensation to the participant's home if they cannot attend the study site;safety assessments at the study site or remotely at a local health care provider, within the protocol defined window;tumour assessments at a local radiology facility if they cannot attend the study site. Enrolment is permitted if the patient can be managed in compliance with the protocol and alternative arrangements.1 The limitations, risks and impact on data privacy of such arrangements will be accounted for and documented.

A case of novel coronavirus disease after combination therapy with nivolumab and ipilimumab for metastatic renal cell carcinoma.

INTRODUCTION: We present a case of novel coronavirus disease-2019 that underwent combination therapy with nivolumab and ipilimumab for metastatic renal cell carcinoma. CASE PRESENTATION: A 50-year-old man complained of anorexia and weight loss. Contrast-enhanced computed tomography revealed a solid mass of 57 mm in diameter with cysts in the right kidney, along with liver, lung, and multiple bone metastases. Computed tomography-guided biopsy of the right kidney was performed, and a diagnosis of clear cell renal cell carcinoma was made. Three weeks after nivolumab and ipilimumab administration, the patient contracted coronavirus disease-2019. Anticoagulation therapy (dalteparin) was administered for 4 days once infection was confirmed, after which dexamethasone was administered for 10 days. The patient survived without experiencing worsened respiratory symptoms. CONCLUSION: We administered nivolumab and ipilimumab combination therapy as treatment for metastatic renal cell carcinoma. No side effects or immune-related adverse events were observed for a short time.

Sargramostim and immune checkpoint inhibitors: combinatorial therapeutic studies in metastatic melanoma.

The use of immune checkpoint inhibitors in patients with metastatic melanoma generates clinical benefit, including improved survival. Yet disease resistance and immune-related adverse events persist as unmet needs. Sargramostim, a yeast-derived recombinant human GM-CSF, has shown clinical activity against diverse solid tumors, including metastatic melanoma. Here we review the use of sargramostim for treatment of advanced melanoma. Potential sargramostim applications in melanoma draw on the unique ability of GM-CSF to link innate and adaptive immune responses. We review preclinical and translational data describing the mechanism of action of sargramostim and synergy with immune checkpoint inhibitors to enhance efficacy and reduce treatment-related toxicity.

Lay abstract Immune checkpoint inhibitors are medications that help the immune system to fight cancer. Side effects with these medicines may occur because the immune system may attack healthy cells. Sargramostim is a medication that is similar to a protein in the body (GM-CSF). Studies have shown that sargramostim can fight cancer, including melanoma. When sargramostim is used with immune checkpoint inhibitors, the body's natural defense to fight cancer (the immune system) is boosted and some side effects are reduced. This article reviews how GM-CSF is thought to boost the immune system's response against cancer in the laboratory and in animal models. We also review the use of sargramostim alone and combined with ipilimumab in patients with advanced melanoma.

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 .

Recent Advances in Pathology: the 2021 Annual Review Issue of The Journal of Pathology.

The 2021 Annual Review Issue of The Journal of Pathology contains 14 invited reviews on current research areas of particular importance in pathology. The subjects included here reflect the broad range of interests covered by the journal, including both basic and applied research fields but always with the aim of improving our understanding of human disease. This year, our reviews encompass the huge impact of the COVID-19 pandemic, the development and application of biomarkers for immune checkpoint inhibitors, recent advances in multiplexing antigen/nucleic acid detection in situ, the use of genomics to aid drug discovery, organoid methodologies in research, the microbiome in cancer, the role of macrophage-stroma interactions in fibrosis, and TGF-ß as a driver of fibrosis in multiple pathologies. Other reviews revisit the p53 field and its lack of clinical impact to date, dissect the genetics of mitochondrial diseases, summarise the cells of origin and genetics of sarcomagenesis, provide new data on the role of TRIM28 in tumour predisposition, review our current understanding of cancer stem cell niches, and the function and regulation of p63. The reviews are authored by experts in their field from academia and industry, and provide comprehensive updates of the chosen areas, in which there has been considerable recent progress. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.