Incidence and Immunopathology of Myositis in Rectal Cancer Patients Treated With Neoadjuvant Immune Checkpoint Inhibitors and Chemoradiotherapy: Findings From the CHINOREC Trial

Cross-sectional study of long-term Health-Related Quality of Life in stage III melanoma patients receiving neo-adjuvant versus adjuvant immune checkpoint inhibitors.

8645 Background: Immunotherapy has created a paradigm shift in the treatment of NSCLC. There is growing interest in the utility of immunotherapy alone or in combination with chemotherapy for NSCLC in the peri-operative setting with practice changing results demonstrated in several pivotal phase III clinical trials. Nevertheless, immune related adverse events (irAEs) are the main barrier in the care of patients treated with immune checkpoint inhibitors (ICIs) with grade ≥ 3 irAEs seen in 10-15% of patients. The present meta-analysis aims to compare rates of irAEs across different treatment settings in NSCLC to aid in individual patient treatment decisions. Methods: We extracted data from selected published phase III clinical trials which have led to the approval of PD-1/PDL-1 ICIs in the neoadjuvant, adjuvant, peri-operative and in the palliative setting. We excluded trials which did not have supplemental data on irAEs included with published results and trials of CTLA-4 inhibitors. A sensitivity analysis was performed to assess whether number of cycles correlated with toxicity rates. Results: Pooled data from 15 published phase III NSCLC clinical trials including 5918 patients were included. This included 1 neoadjuvant, 2 peri-operative, 3 adjuvant, and 9 palliative studies. One of the peri-operative trials included data on irAEs which occurred during the neoadjuvant/surgery phase only and this data was pooled within the neoadjuvant group. The ICI drugs included nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab +/- chemotherapy. This included a total of 2523 stage 1B-3C and 3395 stage IV patients. We found a 9.5% rate of grade 3-5 and 35.8% rate of all grade irAEs in palliative trials (n=3395). In contrast, neoadjuvant ICI (n=572) had a 3.5% rate of grade 3-5 and 16.8% of all grades irAEs. Peri-operative ICI (n=797) had a 5.4% rate of grade 3-5 and 24.47% all grades irAEs. Adjuvant ICI (n=1550) had a 7% rate of grade 3-5 and 38.52% rate of all grade irAEs. The relative risk (RR) between the palliative and the neoadjuvant setting of a grade 3-5 irAE is 2.35 (95% CI:1.54 to 3.59; p = 0.0001) and the RR of any irAE is 2.03 (95% CI: 1.69 to 2.43; p=0.0001). The following median number of ICI cycles was seen: neoadjuvant = 3.5, adjuvant = 18, peri-operative = 18, palliative = 10. Lower number of cycles did correlate with lower toxicity in the neoadjuvant setting but this was not seen in other treatment settings. Conclusions: Neoadjuvant, peri-operative and adjuvant ICI’s are associated with a lower rate of irAEs than that seen in palliative trials. A neoadjuvant-only approach is associated with the lowest rates of irAEs and this may be due to the lower number of cycles received. These findings have implications for individual patient treatment decisions and support the use of neoadjuvant immunotherapy in NSCLC.

To study the association of serum cardiac troponin T (cTnT) and cardiac troponin I (cTnI) with creatine kinase (CK) in patients with idiopathic inflammatory myopathies (IIM). We performed a retrospective study on patients with IIM followed by the rheumatology service of a county hospital from 2004 to 2008. Patients with myocardial ischemia and/or with renal failure were excluded. Clinical data including electromyogram, muscle biopsy, and CK, cTnT and cTnI were recorded. Patients who had simultaneous analysis of CK and cardiac troponin (cTnT or cTnI) levels were studied. CK levels were correlated with cTnT and cTnI by chi-square test and Spearman correlation. We identified 49 patients with IIM (69 observations) who satisfied our inclusion criteria. The primary diagnosis was polymyositis in 23, dermatomyositis in 16, and myositis associated with connective tissue disease in 10 patients. There were 33/49 women with average age 45.8 years. Twenty-eight patients with IIM had simultaneous CK and cTnT values assayed. Of those patients, 18/23 with elevated CK also had elevated cTnT, and 5/5 patients with normal CK levels had normal cTnT levels (p = 0.005). In 41 patients with IIM who had simultaneous CK and cTnI levels assayed, only 1/29 with elevated CK had elevated cTnI, and 12/12 patients with normal CK had normal cTnI (p = 0.5). CK correlated strongly with the cTnT (r = 0.62, p = 0.001) but did not correlate with cTnI. Elevated cTnT, but not cTnI, was highly associated with CK in patients with IIM despite the absence of myocardial ischemia.

149 Background: Clinical data demonstrating remarkable anti-tumor activity of immune checkpoint inhibitors (ICI) in patients with mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) and preclinical data suggesting enhanced efficacy of ICIs in the neoadjuvant setting than in the adjuvant setting led to numerous studies with neoadjuvant ICI in various tumor types including in dMMR CRC. We performed a systematic literature review of the published studies reporting the efficacy and safety of neoadjuvant ICIs in patients with localized dMMR CRC. Methods: Medline and Embase were searched for eligible case reports, case series, and clinical trial reports. Eligibility criteria included: 1. patients aged 18 years or older, 2. localized dMMR CRC, and 3. received neoadjuvant therapy primarily with ICI. Patients receiving radiation or chemotherapy along with ICI were excluded. The systematic review was conducted according to the PRISMA harms guidelines. Results: The database search yielded 143 citations which were reviewed by 3 authors (UG, KV, and SC), and 14 citations fulfilled all criteria for inclusion. The analysis included 173 patients with colon cancer (CC) and 19 with rectal cancer (RC). Among the patients with CC, 41 (24 %) received single-agent programmed death 1 (PD-1) blocker, and 132 (76 %) received dual blockade with an anti-PD-1 agent plus an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agent. Resection was performed in 171/173 (99%) patients, and 117/171 (69%) achieved complete pathological response (pCR). After median follow-up ranging between 8 and 15 months, none of the patients experienced cancer relapse. Among patients with RC, 16/19 (84%) received a PD-1 blocker, and 3 (16%) received dual PD-1 plus CTLA-4 blocker. Complete clinical response (cCR) was reported in 14/19 (74%) patients, and of the 5 patients who underwent surgery, 4 (80%) achieved pCR. All patients remained progression-free after median follow-up ranging from 6 to 12 months. Cancer progression or death on neoadjuvant ICI was not reported in any studies with CC or RC patients, and only two studies reported grade 3+ toxicity in 3% of CC patients. Conclusions: Neoadjuvant therapy with ICIs results in a remarkably high rate of clinical and pathological tumor regression with negligible safety concerns in patients with dMMR localized CRC. Well-designed clinical trials with long-term follow-up are needed to evaluate the organ-sparing potential of neoadjuvant ICI therapy in patients with dMMR CRC.

Recent studies have investigated the combination of immune checkpoint inhibitors (ICIs) with (neo)adjuvant chemotherapy in early-stage breast cancer. However, there is an ongoing debate about the optimal approach for integrating this strategy. To evaluate the association of neoadjuvant ICIs with pathologic complete response (pCR) across molecular phenotypes, to quantify the survival benefits of ICIs beyond pCR status, and to estimate the incidence of specific adverse events. The PubMed database was searched on December 10, 2023, to identify all potential eligible studies. Randomized clinical trials (RCTs) that assessed (neo)adjuvant ICI plus chemotherapy in early breast cancer. Data from the eligible RCTs were extracted by 2 reviewers. An extracted individual patient data meta-analysis and a trial-level random-effect meta-analysis were performed. Outcomes were pCR, event-free survival (EFS) in patients with and without pCR, and adverse events. Hazard ratios were estimated using stratified Cox proportional hazards regression models. Nine RCTs involving 5114 patients met the inclusion criteria (2097 triple-negative breast cancer [TNBC], 1924 hormone receptor-positive [HR+]/ERBB2-negative [ERBB2-], and 1115 ERBB2+ tumors). In TNBC, the addition of ICIs was associated with an improved pCR rate regardless of programmed cell death ligand 1 (PD-L1) status (absolute improvement, >10%). In HR+/ ERBB2- tumors, the administration of ICIs was associated with improved pCR only in the PD-L1-positive (PD-L1+) population (absolute improvement, +12.2%), whereas no benefit was observed in ERBB2+ tumors. In patients with TNBC achieving a pCR, the addition of ICIs was associated with improved EFS (hazard ratio, 0.65; 95% CI, 0.42-1.00), resulting in a 5-year EFS of 92.0% with ICIs compared with 88.0% without them. In patients with residual disease, ICIs also showed better EFS (hazard ratio, 0.77; 95% CI, 0.61-0.98), resulting in a 5-year EFS of 63.3% with ICIs and 56.1% without them. Adjuvant ICI did not show numerical improvement in patients with either pCR or residual disease (all hazard ratios >1). During the neoadjuvant treatment, the incidence of grade 3 or greater immune-related adverse events with ICI was 10.3%. These findings suggest that neoadjuvant ICI therapy improves efficacy outcomes in early-stage TNBC and PD-L1+ HR+/ERBB2- tumors with an acceptable safety profile; however, no benefit was observed with adjuvant ICI. Given the financial and toxicity costs associated with ICIs, future research should prioritize identifying patients most likely to benefit from the addition of ICIs to neoadjuvant chemotherapy.

Neoadjuvant immunotherapy and chemoradiotherapy for mismatch repair proficient locally advanced rectal cancer: A systematic review and meta-analysis.

Towards less mutilating treatments in patients with advanced non-melanoma skin cancers by earlier use of immune checkpoint inhibitors

Elevated plasma cardiac troponin T (cTnT) levels in patients with neuromuscular disorders may erroneously lead to the diagnosis of acute myocardial infarction or myocardial injury. In 122 patients with Pompe disease, the relationship between cTnT, cardiac troponin I, creatine kinase (CK), CK-myocardial band levels, and skeletal muscle damage was assessed. ECG and echocardiography were used to evaluate possible cardiac disease. Patients were divided into classic infantile, childhood-onset, and adult-onset patients. cTnT levels were elevated in 82% of patients (median 27 ng/L, normal values <14 ng/L). Cardiac troponin I levels were normal in all patients, whereas CK-myocardial band levels were increased in 59% of patients. cTnT levels correlated with CK levels in all 3 subgroups (P<0.001). None of the abnormal ECGs recorded in 21 patients were indicative of acute myocardial infarction, and there were no differences in cTnT levels between patients with and without (n=90) abnormalities on ECG (median 28 ng/L in both groups). The median left ventricular mass index measured with echocardiography was normal in all the 3 subgroups. cTnT mRNA expression in skeletal muscle was not detectable in controls but was strongly induced in patients with Pompe disease. cTnT protein was identified by mass spectrometry in patient-derived skeletal muscle tissue. Elevated plasma cTnT levels in patients with Pompe disease are associated with skeletal muscle damage, rather than acute myocardial injury. Increased cTnT levels in Pompe disease and likely other neuromuscular disorders should be interpreted with caution to avoid unnecessary cardiac interventions.

Neoadjuvant immunotherapy in gastrointestinal cancers – The new standard of care?

e20009 Background: The application of immune checkpoint inhibitors (ICIs) in early-stage lung cancer is fraught with unresolved issues, and there are no clinical studies directly comparing the efficacy of ICIs used in neoadjuvant, adjuvant, and neoadjuvant followed by adjuvant therapy across different perioperative time points in non-small cell lung cancer (NSCLC). Consequently, the optimal timing for immunotherapy in surgically resectable NSCLC remains uncertain. Methods: This study encompassed 536 patients with stage II-III NSCLC, diagnosed and treated across multiple centers from January 2019 to December 2022. Clinical data for all patients ultimately included in the study were retrospectively collected. The primary endpoints evaluated were event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) . Secondary endpoints included pathological complete response (pCR) and major pathological response (MPR). Propensity score matching was utilized to mitigate confounding factors, comparing the efficacy of ICIs across different treatment modalities and time dimensions during the perioperative period of lung cancer. Results: The integration of neoadjuvant ICIs with chemotherapy was observed to significantly enhance pCR ( p &lt; 0.001), MPR ( p &lt; 0.001), EFS ( p = 0.002), and OS ( p &lt; 0.001) in comparison to neoadjuvant chemotherapy alone. Similarly, the combination of adjuvant ICIs with chemotherapy markedly improved DFS ( p = 0.034) and OS ( p = 0.021) relative to adjuvant chemotherapy alone. Building on these insights, we further delineated the efficacy of ICIs across distinct temporal dimensions within the perioperative interval, categorizing patients into three groups: neoadjuvant ICIs plus chemotherapy, adjuvant ICIs plus chemotherapy, and a sequential regimen of neoadjuvant followed by adjuvant ICIs plus chemotherapy. The analysis revealed no significant differences in DFS and OS among the three patient groups for stage II NSCLC. In contrast, for stage III NSCLC, both neoadjuvant ( p = 0.015) and sequential treatment approaches ( p = 0.047) demonstrated significantly improved DFS outcomes compared to the adjuvant protocol, with no substantial statistical difference noted between the neoadjuvant and sequential treatments ( p = 0.274). Furthermore, the sequential regimen outperformed the adjuvant strategy in OS ( p = 0.020). However, when comparing the neoadjuvant strategy with either the adjuvant ( p = 0.054) or sequential approaches ( p = 0.717), there were no statistically significant variances detected. Conclusions: For individuals with resectable stage III NSCLC, perioperative administration of neoadjuvant and sequential adjuvant ICIs appears to confer enhanced survival advantages. Future efforts should focus on refining treatment strategies for early-stage NSCLC, aiming to deliver enhanced survival benefits to patients.

BackgroundMyotoxicities (myositis, myocarditis or rhabdomyolysis) are rare (incidence 0.21%) but potentially life-threatening immune-mediated adverse reactions (IMARs) of immune checkpoint inhibitors (ICI), such as ipilimumab (IPI) or nivolumab (NIVO), with a...

An elevation of cardiac injury markers including creatinine kinase (CK), myoglobin (Myo) and cardiac troponin T (cTnT) has been observed in elite athletes following strenuous exercise. The mechanism and significance of this observation however have not been fully elucidated. The goals of this study were: 1) to determine whether these changes in biomarkers also occur in a large, heterogeneous group of non-elite athletes; and 2) to identify possible clinical or biochemical associations. We recruited 129 non-elite runners in 2006, 61 individuals who were taking part in the half (13.1 miles) marathon and 68 individuals participating in the full (26.2 miles) marathon. Demographic data and blood samples were collected for analysis of CK, Myo, cTnT, and Creatinine (Cr) levels within two hours of race start, at race completion, and 1-h post-race for both patient cohorts. In the 61 individuals (40 males, 40+/-12 yrs) completing the half marathon in a mean time of 150+/-20 min, 90.3%, 65.2%, and 30.6% of the subjects exhibited significant elevations in Myo, CK, and cTnT, respectively immediately post race and 100%, 74.9% and 45.9% in the same biomarkers one hour-post race. In the 68 individuals (44 males, 42+/-14 yrs) completing the full marathon in a mean time of 310+/-30 min, 95.3%, 70.2% and 35.7% exhibited significant elevations in Myo, CK and cTnT respectively immediately post race and 100%, 78.5% and 52.8% in the same biomarkers one hour-post race. The elevation in cTnT levels post-race were modestly associated with the time required to complete the race for the entire cohort of marathon runners. The serum levels of Cr, CK, and Myo post-race did not correlate however with age, sex, BMI, level of training, or prior marathon experience. Elevations of cardiac injury markers in non-elite athletes are extremely common following the completion of endurance events and correlate to the increased endurance time. Whether the increase in the levels of these enzymes represents true myocardial injury or a result of the release of cTnT from the myocytes requires further investigation.

Background: Immune checkpoint inhibitor (ICI)-related myositis with myocarditis is a rare but potentially fatal immune-related adverse event. However, its clinical features, response to immunosuppressive treatment, and prognosis remain poorly understood. Here, we describe the clinical course of patients with ICI-related myositis overlapping with myocarditis treated at our institution and a systematic review focusing on the response to immunosuppressive therapy. Methods: We identified patients who developed ICI-induced myositis with myocarditis and were treated at our hospital using a retrospective chart review of electronic medical records. For the systematic review, studies reporting ICI-induced myositis with myocarditis were identified using the Cochrane Library and PubMed databases. Results: Of the 625 patients treated with ICIs, four developed myositis with concurrent myocarditis. All the patients received immunosuppressive therapy. We assessed the activity of myocarditis and myositis based on temporal changes in troponin and creatine kinase (CK) levels. In all patients, peak troponin values appeared later than the peak CK values (median, 17 days). The median time from the start of ICI therapy to the peak of troponin and CK levels was 42.5 and 28 days, respectively. In all patients, CK levels decreased rapidly and steadily after the initiation of immunosuppressants. However, troponin levels were unstable and increased. In all patients, CK levels normalized within one month (range, 12–27 days), but troponin levels took several months to normalize (range, 84–161 days). Fourteen cases of ICI-related myositis with myocarditis were included in the systematic review. Of the 14 cases, 12 (86%) had their CK level decreased after the initial steroid treatment, but the troponin level increased and was higher than that before the start of treatment. In addition, the peak troponin values appeared later than the peak CK values (a median of 6.5 days). Eight (89%) of 9 long-term follow-up patients had troponin levels above the normal range even after CK normalization. Conclusion: In most cases of ICI-related myositis with myocarditis, troponin levels increased after the initial steroid treatment despite decreased CK levels, and exceeded pre-steroid levels. In addition, troponin remained elevated for several months after CK normalized.

Background Myositis is an infrequent (&amp;lt;1%) but potentially life-threatening (case fatality rate 40-50%) immune-related adverse event (irAEs) of immune checkpoint inhibitors (ICI), such as ipilimumab (IPI) and nivolumab (NIVO). The true incidence is likely to be underestimated and may not be representative for curative neoadjuvant treatment approaches in gastrointestinal (GI) cancers, especially in combination with chemoradiotherapy (CRT). Currently, the summary of product characteristics (SmPC) does not suggest any pre-emptive screening or surveillance. Methods The CHINOREC study is an ongoing prospective, randomized, open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with intermediate to locally advanced rectal cancer (LARC) receive either neoadjuvant CRT alone or in combination with a single dose of IPI and 3 cycles of NIVO, following surgical resection. Patients are monitored at baseline and throughout the whole study period for myotoxicity biomarkers, including cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Findings From 06/2020 to 11/2023, 80 patients have been enrolled of whom 50 patients were randomized to the CRT+IPI/NIVO arm. Six patients (12%) developed biopsy-verified myositis. Myositis treatment was promptly implemented using a pragmatic step-up approach. Patients received glucocorticoids (GC) with concomitant intravenous immunoglobulin (IVIG). If myotoxicity biomarkers did not improve, patients received infliximab (INFLIXI) and/or plasma exchange (PLEX). Although all patients had strikingly elevated cTnT (median peak 284 ng/L, 95% CI 39-3097), cTnI levels remained largely normal, correlating with a negative cardiac magnetic resonance (CMR). All patients underwent successful tumor surgery without any major surgical complication. As of today, all patients' creatine kinase (CK) and myoglobin (MB) levels have normalized and they are tumor free without any major sequela. Interpretation Longitudinal biomarker screening (cTnT/cTnI) for ICI-induced myotoxicities is pivotal in curative neoadjuvant-treated cancer patients to initiate an early counter treatment in a holistic step-up approach, without compromising oncological principles.

ImportanceColorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) account for 15% of all CRCs. Deficient MMR is a predictive biomarker associated with responsiveness to immune checkpoint inhibitors (ICIs) in solid tumors, including CRC. The remarkable effectiveness of ICIs in metastatic CRC has led to their evaluation in the neoadjuvant and adjuvant treatment of localized disease.ObservationsMultiple prospective phase 2 studies in limited numbers of patients with localized dMMR CRC demonstrate high complete clinical and pathological response rates (60%-100%) to neoadjuvant ICIs, with low rates of grade 3 or higher ICI-related toxic effects. Given the median follow-up of 12 to 25 months in these studies, longer-term monitoring is needed to determine the durability of response and to ensure that oncologic outcomes are not compromised in patients undergoing nonoperative management. Neoadjuvant ICI therapy is especially attractive for patients with rectal cancer given the significant morbidity that accompanies pelvic irradiation and total mesorectal excision. Ongoing and planned prospective phase 2 trials will provide further data on important issues, including optimal neoadjuvant treatment duration, ICI monotherapy vs combination, and the need for adjuvant ICI therapy.Conclusions and RelevanceWhile this review found that early results of neoadjuvant immunotherapy for localized dMMR CRC show high rates of major and complete pathological response, longer-term follow-up data are needed to ensure that oncologic outcomes are not compromised and are ideally improved. Neoadjuvant ICI therapy in localized dMMR CRC represents a potential paradigm shift with implications for organ preservation.