Locally advanced basal cell carcinoma (laBCC) remains a significant management challenge. Historically, surgery or radiotherapy represented the major treatment options. Recently, hedgehog inhibitors and checkpoint inhibitors have demonstrated significant activity. The optimal sequencing of these approaches is not yet known. We describe a case of laBCC that recurred after definitive radiotherapy. This patient was treated with neoadjuvant cemiplimab with minimal response. Cautious addition of vismodegib with ongoing cemiplimab treatment was well tolerated and resulted in significant tumor regression. A wide excision demonstrated a pathologic complete response. Further evaluation of cemiplimab and hedgehog inhibitor combination therapy in la BCC appears warranted.

9542 Background: Patients with BRAF-mutated melanoma are at increased risk of melanoma brain metastasis (MBM) which has historically led to worse outcomes. The prognosis of patients with MBM has improved with approval of immune checkpoint inhibitors (ICI) and targeted therapy. However, there is limited information on the impact of the MBM on outcomes in patients with BRAF mutations treated with frontline (1L) ICI. This study aims to describe clinical outcomes of patients with BRAF-mutated metastatic melanoma treated with 1L ICI in the community oncology setting, with a focus on patients with MBM. Methods: This was a retrospective observational cohort study of patients with BRAF-mutated metastatic melanoma who initiated 1L ICI (index) between 1/1/16-6/30/22 in The US Oncology Network and non-Network practices and were followed through 6/30/24. Patient characteristics and genomic alterations were sourced from structured electronic health records data and genomic testing results. Patients with mucosal or uveal melanoma, clinical trial participation, treatment for other primary cancers or evidence of co-mutations were excluded. Kaplan-Meier analyses of overall survival (OS), real-world time to treatment discontinuation (rwTTD) and time to next treatment (rwTTNT) were assessed from index, overall and in patients with MBM. Results: Of 798 metastatic melanoma patients with a BRAF mutation, 41 (5%) had documentation of a co-mutation and were excluded, resulting in 757 patients in the final analysis set. Median follow-up was 14.6 months, and median age at index was 64 years. Among patients with available data, most were male (63%), White (97%) and had an ECOG of 0-1 (87% among reported) within 60 days prior to index. Among patients with mutation-specific data (n=704), the most common mutation types were V600E (83%) and other V600 (13%) point mutations. The most common 1L ICI regimens were nivolumab+ipilimumab (45%), pembrolizumab (30%), and nivolumab (22%). MBM was documented in 46 (6%) patients at 1L ICI treatment initiation, and an additional 28 (4%) patients developed MBM during the follow-up period, resulting in a total of 74 (10%) patients with MBM. Conclusions: Although lower-than-expected rates of MBM were observed, in this large real-world dataset from the community setting, patients with a BRAF mutation had similar rwTTD, rwTTNT, and OS following ICI therapy, irrespective of the presence of MBM. It is reasonable to consider combination ICI therapy in BRAF mutant melanoma patients diagnosed with MBM who lack known contraindications. Further research on the impact of the somatic mutational background on MBM outcomes is ongoing. Outcome, median (95% CI) Overall (N=757) MBM, any time (N=74) OS, months 20.3 (16.6, 25.8) 20.3 (10.4, 33.8) rwTTD, months 3.5 (2.9, 3.9) 3.7 (2.4, 5.6) rwTTNT, months 5.7 (4.9, 6.5) 5.6 (3.7, 7.5)

Background: The immune checkpoint inhibitor cemiplimab has significant clinical activity in unresectable and metastatic cutaneous squamous cell carcinomas. There are limited real-world data available to assess the outcome of cemiplimab treatment in patients in a community practice setting. Methods: We conducted a retrospective analysis of treatment outcomes following cemiplimab treatment (350 mg IV every 3 weeks) of squamous cell skin cancer. An exploratory analysis was performed to evaluate patient subsets, including patients with locally advanced disease, regional or distant metastases, and “too numerous to count” primaries. Another small group of patients who did not respond to the initial four doses of cemiplimab were evaluated following added radiotherapy. Results: Of the 36 patients treated, 22 (61.1%) achieved complete remission, 10 (27.8%) experienced a partial response, 3 (8.3%) had stable disease, and 1 (2.8%) developed progressive disease. The median progression-free survival for the entire cohort was over 33 months. Overall, cemiplimab was well-tolerated, with no hospitalizations due to treatment-related toxicity. Conclusions: Cemiplimab produced complete remissions in over 60% of patients with locally advanced and metastatic squamous cell skin cancers, allowing elective treatment discontinuation. Addition of radiotherapy in cemiplimab-refractory patients appeared to increase tumor responsiveness. In contrast, patients with TNTC primary tumors frequently develop new primary skin cancers. Thus, improved treatment options for this patient subset are still needed.

PURPOSE:Patients with metastatic melanoma frequently develop brain metastases. Due to recent advances in melanoma therapy, we evaluated the timing of brain metastases diagnosis in relation to outcome during melanoma immunotherapy. METHODS:Patients who received 1st -line treatment with ipilimumab plus nivolumab for metastatic melanoma were identified via a database search. Patient characteristics and outcomes were recorded. RESULTS:Of 73 patients that met study criteria, 20 patients developed brain metastases (27.4%). Of these 20 patients, 14 had brain metastases at diagnosis of metastatic disease, Only 6 progressed in the brain following immunotherapy. All but one patient with brain metastases at diagnosis were symptomatic. Following immunotherapy, 4/15 (all with BRAF V600E mutations) achieved complete remissions and prolonged survival. Each of these patients was able to undergo elective treatment discontinuation. One additional patient developed stable disease. Delayed brain metastases proved to be infrequent (6/59 patients). Delayed brain metastases were always diagnosed within the first 15 months of treatment. Five of these 6 patients died, with a median progression-free survival of only 2.1 months. CONCLUSION:Brain metastases frequently complicated the course of metastatic melanoma. Patients with symptomatic brain metastases at diagnosis had a potential for durable remissions following multidisciplinary treatment, particularly if a BRAF V600E mutation was present. This included 2 of 10 patients who were on steroid treatment prior to the start of immunotherapy. Treatment with combination immunotherapy seemed to reduce the development of subsequent brain metastases. Patients who developed delayed brain metastases had a very poor outlook, despite attempted salvage therapy.

Abstract Melanoma brain metastases (MBM) are a frequent complication of advanced stage disease. MBM are an important cause of morbidity and mortality during disease progression. We report a retrospective cohort study of patients treated with combined ipilimumab and nivolumab as initial therapy for metastatic melanoma to identify and evaluate the clinical course of patients who developed brain metastases in the “real world setting.” The aim of our study was (1) to determine the frequency and timing of brain metastases onset and (2) to characterize the incidence and timing of brain metastases following first line combined ipilimumab-nivolumab therapy. We evaluated 73 patients. Only 20 (27.4%) patients developed MBM. The majority of these patients were identified at initial evaluation of metastatic disease (20.5%), while the rate of CNS progression during immunotherapy was low (6.9%). Patient treatment response, progression-free survival (PFS), overall survival, and neurologic progression-free survival (CNS PFS) were evaluated. We observed that patients with MBM at diagnosis of metastatic disease had improved PFS and CNS PFS, compared to patients who progressed in the CNS following treatment. Despite the presence of symptomatic MBM at diagnosis, 27% of patients with MBM at diagnosis achieved a durable complete remission (NED). Of note, all responding patients presented with neurologic symptoms associated with their brain metastases, and half of them were receiving systemic steroids at the time of treatment. In contrast, patients with delayed onset of brain metastases had an extremely poor outcome, with a median PFS of only 4.8 months. Thus, in patients presenting with MBM at diagnosis of metastatic disease, combined ipilimumab/nivolumab therapy has significant clinical activity. Furthermore, checkpoint inhibitor therapy appears to reduce the frequency of delayed onset brain metastases. However, novel treatment options need to be developed to more effectively treat patients who progress in the CNS following initial combination therapy.

Supplemental table 1 and supplemental figure 1

Mucosal melanoma represents an uncommon melanoma subtype. Wide excision has long represented the standard therapeutic approach. Unfortunately, there is a high relapse rate and mortality. Neoadjuvant therapy with ipilimumab plus nivolumab has shown significant activity in cutaneous melanoma. We present two cases of mucosal melanoma, each with potential regional dissemination, who were treated with neoadjuvant immunotherapy with minimal toxicity. Both patients were closely monitored and achieved radiologic and pathologic complete responses. These patients were able to avoid radical surgery and related functional consequences. Both patients remain recurrence-free with protracted follow-up. The potential usefulness of neoadjuvant immunotherapy as an organ preservation strategy in mucosal melanoma deserves further evaluation in prospective clinical trials.

Previous studies suggested that somatic BRAF and NRAS mutations in metastatic melanoma increase the risk for brain metastases. The risk related to other non-overlapping “driver” mutations is unknown. We performed a retrospective evaluation of the incidence, timing, and outcome of brain metastases in a population of melanoma patients that underwent uniform next-gen sequencing. All patients were treated with initial checkpoint inhibitor therapy. Seventeen of 88 patients (20.0%) developed brain metastases. Eleven patients had brain metastases at diagnosis (12.9%). These were all patients with BRAF V600 or NF1 mutations. Only six patients with NRAS, NF1, KIT, or BRAF mutations (including fusions/internal rearrangements experienced delayed CNS progression following immunotherapy (7.1%)). No “quadruple negative” patient developed brain metastases. Patients with brain metastases at diagnosis had a better outcome than those with delayed intracranial progression. Current predictive markers, (LDH, tumor mutation burden, and PDL1) were poorly correlated with the development of brain metastases. Treatment with immunotherapy appears to reduce the incidence of brain metastases. Next-gen molecular sequencing of tumors in metastatic melanoma patients was useful in identifying genetic subpopulations with an increased or reduced risk of brain metastases. This may allow eventual personalization of screening strategies.

AbstractPurpose: The efficacy of immune checkpoint blockade in gestational trophoblastic neoplasia (GTN) remains uncertain. We report the results of the GTN cohort of SWOG S1609 dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART). Patients and Methods: This prospective, open-label phase II trial evaluated ipilimumab plus nivolumab across multiple rare tumor cohorts, including GTN. Eligible patients received nivolumab 240 mg, i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks. The primary endpoint was overall response rate [ORR; complete response (CR) + partial response (PR)] by quantitative serum beta human chorionic gonadotropin (β-hCG); secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Results: Four patients with refractory GTN enrolled and received therapy. At 11 months of ongoing follow-up, 3 of 4 patients responded [ORR = 75% (CR, 25%, n = 1, tumor mutation burden = 1 mutation/megabase; PD-L1 tumor proportion score = 50%); PR, 50%, n = 2)]. Responders included malignant gestational trophoblastic neoplasm (n = 1, CR, PFS 11+ months) and choriocarcinoma (n = 2, both PRs, PFS 10+ and 6+ months). One patient with epithelioid trophoblastic tumor experienced disease progression. The 6-month PFS was 75% [95% confidence interval (CI), 43%–100%], and the median PFS was not reached (range, 35–339+ days); all 4 patients were alive at last follow-up. Two patients experienced grade 3 immune-related toxicity (arthralgia and colitis); there were no grade ≥4 events. Conclusions: Ipilimumab plus nivolumab demonstrated efficacy in chemotherapy-refractory GTN, an ultra-rare cancer affecting young women. Three of 4 patients achieved ongoing objective responses with a reasonable safety profile at 6–11+ months.

Long follow-up time is needed for overall survival (OS) data to mature for early-stage melanoma. This retrospective study aimed to describe the relationships between OS and two intermediate endpoints – real-world recurrence-free survival (rwRFS) and real-world distant metastasis-free survival (rwDMFS) – for patients with stage IIB or IIC melanoma that was completely resected from 1 January 2008 to 31 December 2017, with follow-up to 31 December 2020. We used three different approaches to describe the relationships: estimates of correlation using Kendall τ rank correlation; comparisons of all-cause survival with/without recurrence or distant metastasis using adjusted Cox proportional hazard models; and landmark analyses of all-cause survival stratified by recurrence status at 1–5 years. During a 39-month median follow-up from surgical resection, 223/567 patients (39%) experienced recurrence, among whom 171/567 patients (30%) developed distant metastasis. Median OS from surgical resection was 117.6 months [95% confidence interval (CI), 104.7-not reached], median rwRFS was 49.8 months (95% CI, 39.6–61.0), and median rwDMFS was 70.9 months (95% CI, 58.4–89.1). We observed strong correlations between rwRFS and OS, and between rwDMFS and OS (Kendall τ of 0.73 and 0.82, respectively). Risk of death was significantly greater after recurrence (all-cause survival adjusted hazard ratio [HR], 7.48; 95% CI, 4.55–12.29) or distant metastasis (adjusted HR, 11.00; 95% CI, 6.92–17.49). Risk of death remained significantly elevated with recurrence or distant metastasis by landmark years 1, 3, and 5 after surgical resection. These findings support the use of recurrence/rwRFS and distant metastasis/rwDMFS as surrogate endpoints for OS after complete resection of stage IIB or IIC melanoma.

Immune-mediated diarrhea represents a serious complication of checkpoint inhibitor therapy, especially following ipilimumab-based treatment. Efficient diagnosis and control of diarrhea remains an ongoing challenge. We developed an accelerated management paradigm for patients with ipilimumab-induced diarrhea. Patients who developed significant diarrhea (>five loose stools/day) were presumed to be developing immune colitis. Therapy was interrupted and patients were treated with a methylprednisolone dose pack. If diarrhea was not completely resolved, high-dose steroids and infliximab were promptly added. Only non-responding patients underwent further evaluation for infection or other causes of diarrhea. A total of 242 patients were treated with ipilimumab-based regimens. Forty-six developed significant diarrhea (19%) and thirty-four (74.4%) had a rapid resolution of diarrhea following glucocorticosteroid and infliximab treatment. The median time to resolution of diarrhea was only 8.5 ± 16.4 days. Accelerated treatment for presumed immune-mediated diarrhea resulted in the rapid control of symptoms in the majority of patients. There were no intestinal complications or deaths. Immunosuppressive therapy for diarrhea did not appear to decrease the remission rate or survival. After the control of diarrhea, most patients were able to continue their planned immunotherapy. Further testing in 11/46 patients with unresponsive diarrhea revealed additional diagnoses, allowing their treatment to be adjusted.

PDF file - 278KB, Pre- and post-treatment PET scans showing evidence of major tumor response and MART-1-specific TCR transgenic cell levels in patient F5-10.

"CLO23-068: Effectiveness and Toxicity of Cetuximab With Concurrent Radiotherapy in Locally Advanced Cutaneous Squamous Cell Skin Cancer: A Case Series" published on 31 Mar 2023 by National Comprehensive Cancer Network.

PDF file - 243KB, Lack of autoreactivity to bone marrow cells in patient F5-10.

PDF file - 128KB, Transduction efficiencies of infused transgenic cells.

BACKGROUND:Treatment for locally advanced cutaneous squamous cell cancers (laCSCC) remains poorly defined. Most laCSCC tumors express high levels of epidermal growth factor receptors (EGFR). Cetuximab has activity in other EGFR expressing cancers and enhances the effectiveness of radiotherapy. METHODS:A retrospective review of institutional data identified eighteen patients with laCSCC treated with cetuximab induction and concurrent radiotherapy. The loading dose of cetuximab was 400 mg/m² IV. Subsequent weekly doses of 250 mg/m² IV were infused throughout the period of radiation. The treatment doses ranged from 4500-7000 cGy, with a dose fraction of 200-250 cGy. RESULTS:The objective response rate was 83.2% with 55.5% complete responses and 27.7% partial responses. Median progression-free survival was 21.6 months. Progression-free survival was 61% at 1 year and 40% at 2 years. With longer follow-up, some patients developed a local recurrence (16.7%), distant metastases (11.1%) or a second primary cancer (16.3%). Cetuximab was well tolerated, with 68.4% patients experienced only mild acneiform skin rash or fatigue (Grade 1 or 2). Radiotherapy produced expected side effects (skin erythema, moist desquamation, mucositis). DISCUSSION:Cetuximab plus radiotherapy represents an active and tolerable treatment option for laCSCC, including patients with contraindications for checkpoint inhibitor therapy.

Function-limiting arthropathy is an uncommon toxicity of immune checkpoint inhibitor therapy. We analyzed the clinical features and outcome of this toxicity in a series of cancer patients. Patients treated with methotrexate, infliximab, or adalimumab were identified in our patient care database. Individual patient records were reviewed for concomitant checkpoint inhibitor treatment to analyse patient characteristics and clinical outcome. Sixteen patients were identified that met study requirements. Ten patients developed seronegative arthropathy consisting of severe arthralgia’s and morning stiffness as a de novo immunologic adverse event. Five patients eventually achieved symptom resolution and five required ongoing treatment. Arthritis-related toxicity caused a treatment delay in 5/10 of these patients, but only one required treatment discontinuation. Six additional patients had pre-existing symptomatic inflammatory arthritis. Four reported flares during treatment, two achieved complete symptom resolution with treatment and two require ongoing therapy. Only one of these six patients had a treatment delay. Median time to onset of arthropathy was 1.3 ± 1.5 months in patients with pre-existing arthritis versus 5.2 ± 10.7 months in patients who developed arthropathy as an adverse event (p=.037). There is relatively little information about function-limiting arthropathy associated with checkpoint inhibitor treatment. Median time to symptoms was significantly shorter in patients with pre-existing arthritis versus those who developed arthropathy due to treatment. Patients with flares of pre-existing arthritis during treatment were more likely to achieve resolution of their symptoms and less likely to have treatment delays than patients who develop de novo arthropathy.

A 35-y old healthy sportsman complained paroxysmal dyspnea and migrating erythema some weeks after jogging in the woods. Non-invasive diagnostic tools excluded pathologic findings. A personal smartwatch was lent by his cardiologist, on-demand Remote ECG monitoring was started, and paroxysmal complete AV block was diagnosed. In Emergency Department AV block was confirmed. Empiric intravenous prednisolone 25 mg every 8 hours was administered in the suspicion of a hypersensitive milieu. AV block completely recovered in a few hours. Laboratory tests showed elevated C-reactive protein and neutrophilic leukocytosis. Serological screening highlighted anti-Borrelia burgdorferi antibodies, suggesting a Lyme’s carditis related AV block. Oral Doxycycline led to complete clinical and laboratory parameters normalization in one week. 1 year loop recorder monitoring showed no further AV block relapse with nocturnal sinus bradycardia only. To the best of our knowledge, this is the first report describing Smartwatch-enhanced complete AV block diagnosis; we noticed as well a sudden resolution of Lyme’s carditis related av block parallelly to empiric Steroid therapy.

Nevoid basal-cell carcinoma syndrome (Gorlin syndrome) is characterized by numerous cutaneous basal cell carcinomas mediated by mutations in the hedgehog pathway. Vismodegib or sonidegib represent promising treatment options. We identified 10 Gorlin patients who were treated with sonidegib (n = 6) or vismodegib (n = 4) between March 2012 and March 2022. We analyzed the activity, toxicity, and duration of the response to oral hedgehog inhibitors. The number of new tumors that developed prior to treatment or after treatment as well as the time of response and durability of responses were assessed. All patients achieved a complete remission. With a 30.7 ± 48.4-month median follow-up, the drug treatment significantly reduced the number of new basal cell cancers from a mean of 28.3 ± 24.6 prior to treatment to a mean of 1.4 ± 2.0 during treatment (p = 0.0048). The median time to develop a new basal cell cancer was 47.3 months. Three patients eventually developed localized recurrences. After resection, ongoing treatment suppressed the development of additional lesions. One patient developed numerous new drug-resistant basal cell cancers and died of acute leukemia. Six patients required treatment modifications for toxicity. Sustained hedgehog inhibitor treatment can suppress the progression of both new and existing basal cell carcinomas for an extended period. Drug administration schedule adjustments improved tolerance without altering efficacy, potentially contributing to a prolonged response duration.

PDF file - 148KB, Supplementary Table 1. Toxicities and response to therapy with the subsequent protocol amendments.