Subsequent Systemic Therapy Research Articles

RADT-10. CEREBELLAR RE-IRRADIATION AFTER WHOLE BRAIN RADIOTHERAPY SIGNIFICANT SYMPTOM RELIEF WITH MINIMAL TOXICITY IN METASTATIC BRAIN PATIENTS

Abstract INTRODUCTION Whole-brain irradiation (WBRT) remains a standard treatment for patients with extensive brain metastases, providing symptom relief and prolonging survival. However, patients often experience recurrent metastases, necessitating re-irradiation. This study evaluates the efficacy and safety of cerebellar-only re-irradiation for improving symptoms and reducing toxicity in patients with recurrent cerebellar metastases following WBRT. METHODS A retrospective review was conducted on patients who underwent cerebellar re-irradiation between 2017 and 2023 after prior WBRT for symptomatic cerebellar metastases. Clinical, dosimetric, and outcome data were collected. Symptom improvement was assessed based on patient, caregiver, and physician reports three months post-treatment. RESULTS The study included 56 patients with a median age of 53 years. Symptom domains included gait dysfunction, nausea/vomiting, dysarthria, movement disorder, dizziness, and headache. Breast cancer was the most common histology. The median interval from WBRT to cerebellar re-irradiation was 15 months. Symptomatic improvement was observed in 75% of patients, with notable improvements in nausea/vomiting (84.6%) and headache (80%). Age, dose deliver and time from WBRT were significant for clinical improvement. Dexamethasone use decreased in 76.3% of patients post-treatment. Radiological responses correlated with clinical improvements in 90% of cases. Only one patient developed symptomatic radiation necrosis. Six-month overall survival and progression-free survival were 50% and 39.2%, respectively. CONCLUSION Cerebellar-only re-irradiation is an effective and safe option for managing recurrent cerebellar metastases, significantly improving symptoms with minimal toxicity. This approach also allows for subsequent systemic therapy or radiosurgery for supratentorial lesions, potentially reducing the need for additional WBRT. Further studies are required to validate these findings in larger cohorts.

Time to Next Treatment Following Sub-Ablative Progression Directed Radiation Therapy for Oligoprogressive Non-Small-Cell Lung Cancer.

We aimed to evaluate whether progression-directed radiation therapy (PDRT) can prolong the initiation of a subsequent systemic therapy regimen in a cohort of patients with oligoprogressive NSCLC. A retrospective analysis was conducted on NSCLC patients who underwent PDRT for extracranial oligoprogressive NSCLC, defined as limited (up to five) progressing lesions following initial complete, partial, or stable response to systemic therapy according to REC1ST 1.1 and/or PERCIST 1.0 criteria. Cox proportional hazard regressions were performed to identify factors influencing time to next treatment (TTNT), which was considered the primary endpoint. Forty patients were analyzed. First, second, and ≥3 lines of systemic therapy were administered in 22 (58.2%), 14 (27.2%), and 4 (14.6%) cases, respectively. The median total dose was 36 Gy (range: 12-60) in five fractions (1-10), with a median biological effective dose for tumor control (BED10) of 52 Gy (26.4-151.2). After a median follow-up of 11 months (2-50), PDRT delayed further systemic therapy in 32 (80.0%) treatments. Median TTNT was not reached at 8 months (1-47) with a one-year Kaplan-Meier estimate of 81.4% (95% CI: 75.0% to 87.8%). No >grade 3 adverse event was observed. On multivariate analysis, patients with ≥3 lines of systemic therapy and/or with larger CTV volumes did not benefit from PDRT. Despite the use of sub-ablative doses, our findings show that PDRT represents an effective, safe, and viable option for oligoprogressive NSCLC. Patients irradiated early during their systemic treatment course, with a low volume of disease and nonmetastatic oligoprogression, could derive substantial benefits from PDRT.

Outcomes Following Treatment for Progression in Patients Treated With Durvalumab Consolidation in LA-NSCLC

IntroductionPACIFIC established consolidative durvalumab for LA-NSCLC, but only about half of patients completed a year of therapy. Data on treatment patterns and outcomes after durvalumab are limited. MethodsOur analysis included patients from a US nationwide database with LA-NSCLC who received consolidative durvalumab between 2017 and 2023 and had subsequent systemic therapy, classified as PD-L1 monotherapy, PD-L1+chemotherapy, chemotherapy alone, PD-L1+CTLA4, or targeted therapy (TT). Time to next treatment (TTNT) was analyzed from durvalumab start and finish to next line of therapy initiation. Overall survival (OS) from start of postdurvalumab therapy was analyzed using Kaplan Meier methodology. ResultsOur cohort included 751 patients, median age 68 (IQR, 61-74), 53% female, 80% White, 91% ECOG 0-1, 90% smoking history, and 53% nonsquamous histology. The most common postdurvalumab treatment was chemotherapy alone in 349 (46%), followed by PD-L1+chemotherapy in 147 (20%), PD-L1 monotherapy in 114 (15%), and TT in 104 (14%).Median duration of durvalumab treatment was 5.5 months (IQR 2.3-10.6); only 9% of patients received a full year of durvalumab, and 64% started next treatment within a year of initiation. Patients treated with chemotherapy-containing regimens had shorter TTNT from durvalumab start/end, as well as shorter median OS [10.8 (5.6-18.8) months for chemotherapy and 12.9 (6.0-24.2) months for chemoimmunotherapy, versus 23.8 (8.7-34.5) months for PD-L1 monotherapy and 30.1 (9.5-NR) months for TT (P < .001)]. ConclusionPatients treated with systemic therapy after consolidative durvalumab, particularly those requiring chemotherapy-based treatment, have poor outcomes and are in need of improved treatment strategies.

WHOLE BRAIN RADIOTHERAPY FOR INTRACRANIAL METASTATIC DISEASE IN NON-SMALL CELL LUNG CANCER: THE WESSEX EXPERIENCE

Abstract AIMS The QUARTZ trial (2016) reported that corticosteroid therapy was non-inferior to whole brain radiotherapy(WBRT) for non-small cell lung cancer (NSCLC) with regards overall survival(OS). This is a single centre experience of WBRT for NSCLC in the post-QUARTZ era and in the context of the changes in clinical practice over the past 8 years. METHOD Single centre retrospective observational study. Patients included with NSCLC treated with WBRT for radiologically confirmed intracranial (IC) metastatic disease January 2018 to December 2022. OS, baseline tumour/patient characteristics and lines of treatment were recorded from medical records. Data compiled using Excel and statistical analysis using the R language for statistical programming. RESULTS 62 patients were included, median age 64 (37 -82). 29(46.8%) were Performance status 0-1. 50(80.6%) received 20Gy in 5 fractions, 12(19.4%) received 30Gy in 10 fractions. PDL1 &amp;gt;50% in 14(22.6%), EGFR mutation positive in 10(16.1%), 0(0%) ALK/ROS mutations. 9(14.5%) had received prior radiotherapy(RT) for IC disease (SRS:8, partial brain VMAT:1). 20(32.3%) had IC disease at presentation. Median OS 68 days (95%CI:58-111;range12-777) in keeping with QUARTZ results (median OS 65 days, 95%CI:50- 78). Univariate analyses demonstrated: subsequent systemic therapy (p=0.0022), receiving immunotherapy (p=0.002) and baseline performance status (p=0.0017) associated with improved OS. PDL1 &amp;gt;50%, EGFR mutation positive, RT dose, prior systemic therapy, histological subtype, presence of a targetable mutation, first or subsequent IC treatment did not predict survival. The chi-squared test was used to compare differences in the groups with OS&amp;gt;100days(n=22) and OS&amp;lt;100days(n=40). Systemic therapy after WBRT(p=0.0011) and immunotherapy treatment(p=0.0092) were significant differences between the cohorts and associated with improved survival. CONCLUSION This data supports conclusions of QUARTZ study and it remains difficult to define a role for WBRT in the management of IC disease in NSCLC. There is a cohort who have better OS, though we believe this may be related to systemic therapy (particularly immunotherapy) exposure.

Prior Local Therapy and First-Line Apalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Preclinical studies suggest that exposure to prostate-directed local therapy (LT) may influence the efficacy of subsequent systemic therapy including androgen receptor pathway inhibitors. However, there is insufficient clinical evidence to support this premise in patients with nonmetastatic castrate-resistant prostate cancer (nmCRPC). To determine whether exposure to prior prostate-directed LT (radical prostatectomy [RP], radiation therapy [RT], or both) played any effect-modifying role in the treatment effect of apalutamide on metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC. This post hoc secondary analysis used individual patient data from SPARTAN (Study of Apalutamide [ARN-509] in Men With Non-Metastatic Castration-Resistant Prostate Cancer), a phase 3, double-blinded, placebo-controlled randomized clinical trial conducted at 332 sites in 26 countries. Between October 14, 2013, and December 15, 2016, patients with nmCRPC and a prostate-specific antigen doubling time of 10 months or less were randomly assigned to apalutamide vs placebo; all patients received androgen deprivation therapy. The final data analysis was performed on December 31, 2023. Prior prostate-directed LT. Separate Cox proportional hazards regression models were constructed for OS and MFS, which included prior LT, treatment group, and an interaction term, in addition to a minimally sufficient set of confounders. Adjusted hazard ratios (HRs) with 95% CIs for MFS and OS were determined for the apalutamide groups with or without prior LT. Among the 1179 evaluable patients included in this analysis, 795 received prior LT and 384 did not. The median age of patients with and without prior LT was 70 (IQR, 45-90) years and 75 (IQR, 50-95) years, respectively. The median follow-up was 52.0 (IQR, 51.5-52.8) months. A differential treatment effect of apalutamide on MFS was observed between patients with and without prior LT (P for interaction = .009), with greater benefits for those with prior LT (adjusted HR, 0.22 [95% CI, 0.17-0.27]) compared with those without prior LT (adjusted HR, 0.35 [95% CI, 0.25-0.51]). However, there was insufficient evidence of a differential treatment effect on OS among subgroups stratified by exposure to prior LT (P for interaction = .23), with improved OS in the subgroup with prior LT (adjusted HR, 0.72 [95% CI, 0.57-0.92]) but no significant difference in OS in the subgroup without prior LT (adjusted HR, 0.92 [95% CI, 0.64-1.31]). This post hoc analysis of the SPARTAN trial provides evidence of an interaction between prior LT and apalutamide in patients with nmCRPC, with a clinically significant and more favorable treatment effect from apalutamide on MFS among patients with prior LT. Further studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT01946204.

Dosimetric and Clinical Prognostic Factors in Single-Isocenter Linac-Based Stereotactic Radiotherapy for Brain Metastases.

Background/Objectives: To report on predictive factors in Linac-based SRT for single and multiple BM. Methods: Consecutive patients receiving either one or three fractions of single-isocenter coplanar VMAT SRT were retrospectively included. The GTV-PTV margin was 1-2 mm. The delivered target dose was estimated by recalculating the original plans on roto-translated CT according to errors recorded by post-treatment CBCT. The Kaplan-Meier method estimated local progression-free survival (LPFS), intracranial progression-free survival (IPFS), and overall survival (OS). Log-rank and Wilcoxon-Mann-Whitney tests evaluated inter-group differences, whereas Cox regression analysis assessed prognostic factors. Results: Fifty females and fifty males, with a median age of 69 years, received 107 SRTs. A total of 213 BM (range, 1-10 per treatment) with a median volume of 0.22 cc were irradiated with a median minimum BED of 59.5 Gy. The median delivered GTV D95 reduction was -0.3%. The median follow-up was 11 months. Nineteen LP events and a 1-year LC rate of 90.1% were observed. The GTV coverage did not correlate with LC, while the GTV volume was a risk factor for LP, with the 1-year rate dropping to 73% for volumes ≥ 0.88 cc. The median LPFS, IPFS, and OS were 6, 5, and 7 months, respectively. Multivariate analysis showed that patients with melanoma histology and those receiving a second or subsequent systemic therapy line had the worst outcomes, whereas patients with adenocarcinoma histology and mutations showed better results. Conclusions: The accuracy and efficacy of the Linac-based SRT approach for BM were confirmed, but the dose distribution alone failed to predict the treatment response, suggesting that other factors must be considered to maximize SRT outcomes.

Performance status improvement and advances in systemic treatment after brain metastases resection: a retrospective single-center cohort study of non-small cell lung cancer patients

BackgroundBrain metastasis (BrM) is prevalent among patients with NSCLC, and surgical resection of BrM constitutes a promising treatment strategy for local management and histopathological diagnosis, although it is offered for a select group of patients. Limited information exists concerning the improvement in performance status (PS) following BrM resection or the outcomes stratified by subsequent systemic therapy.MethodsWe conducted a retrospective single-center cohort study including NSCLC patients with surgically resected BrM and focused on the improvement in PS and subsequent therapy after BrM resection.Results71 patients were included, and the median overall survival was 18.3 months (95% confidence interval [95% CI]: 8.7, not reached). Patients with NSCLC who underwent surgical resection of BrM showed significant improvement in PS (18% and 39% showed ECOG PS of 0–1, before and after BrM resection, respectively [p = 0.006]), and patients with PS improvement were younger than those with PS unimprovement (median, 62 years versus 66 years; p = 0.041). Regarding subsequent systemic therapy after BrM resection, 21 patients (30%) received cytotoxic chemotherapy, 14 patients (20%) received tyrosine kinase inhibitors (TKIs), 3 patients (4%) received immune checkpoint inhibitors (ICIs), and 21 patients (30%) received no subsequent therapy. The survival outcomes of patients stratified by subsequent systemic treatments suggested the tendency that those who received TKI or ICI showed better survival outcomes, although a small number of patients hindered statistical comparisons.ConclusionsWe describe the outcomes of patients with NSCLC who underwent surgical resection of BrM, revealing that younger patients were more likely to anticipate improvement in PS, and patients who received TKI or ICI after BrM resection tended to exhibit a more preferable prognosis.

Outcomes With Postrecurrence Systemic Therapy Following Adjuvant Checkpoint Inhibitor Treatment for Resected Melanoma in CheckMate 238.

In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy. Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Patients with recurrence in each group were assessed for PFS and OS from subsequent systemic therapy (SST) initiation per recurrence timing (≤12 months [early] v >12 months [late] from initial therapy). Recurrences occurred in 198 (44%) of 453 nivolumab-treated patients (122 early, 76 late) and 232 (51%) of 453 ipilimumab-treated patients (160 early, 72 late). Median PFS on next-line systemic therapy for nivolumab-treated patients recurring early versus late was 4.7 versus 12.4 months (24-month rates, 16% v 31%); median OS was 19.8 versus 42.8 months (24-month rates: 37% v 73%). In response to subsequent therapy, patients on nivolumab with late versus early recurrence were more likely to benefit from anti-PD-1 monotherapy. Nivolumab-treated patients with either an early or late recurrence benefitted from an ipilimumab-based therapy or targeted therapy, each with similar OS. Postrecurrence survival was longer for patients who recurred >12 months. Patients on nivolumab who recurred early benefitted from SST but had better survival with ipilimumab-based regimens or targeted therapy compared with anti-PD-1 monotherapy.

8 Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: 8-year follow-up with analyses in favorable risk patients from the phase 3 CheckMate 214 trial

Abstract Background First-line nivolumab plus ipilimumab (NIVO+IPI) has provided substantial long-term survival benefits over sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC) in CheckMate 214. With a median follow-up of 8 years, the longest follow-up to date for any phase 3 trial of immune checkpoint inhibitor combination therapy in patients with aRCC, we report survival, response per independent radiology review committee (IRRC), and safety in all randomized patients (intent-to-treat [ITT] population) and in patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable risk. Methods Patients with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W×4 doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN 50 mg once daily for 4 weeks on, 2 weeks off. Key study endpoints included overall survival (OS), IRRC-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (primary), ITT (secondary), and favorable-risk (exploratory) patients. Cancer-specific survival was evaluated in ITT patients by censoring all causes of death other than RCC. Post hoc exploratory analyses in patients with favorable risk were performed. Results With 8 years (99.1 months) median follow-up, OS with NIVO+IPI versus SUN remained superior in ITT patients (hazard ratio [HR], 0.72; Table). The HR for PFS with NIVO+IPI versus SUN was 0.88. ORR was higher with NIVO+IPI versus SUN (Table), with more complete responses (12% vs 3%) and a longer median duration of response (DOR) in the combination arm versus SUN. In patients with favorable risk, OS benefits were similar between arms (HR, 0.82; Table). The HR for PFS favored SUN (HR, 1.76). ORR was lower with NIVO+IPI versus SUN, yet more patients achieved complete responses (13% vs 6%, respectively) and median DOR was longer with NIVO+IPI. Median cancer-specific survival (95% CI) in ITT patients was 73.7 (62.8-91.2) months with NIVO+IPI versus 45.1 (37.8-53.3) months with SUN (HR, 0.69; 95% CI 0.59-0.82). In exploratory post hoc analyses of patients with favorable risk, 75/125 (60.0%) patients in the NIVO+IPI arm and 85/124 (68.5%) patients in the SUN arm died over 8 years of follow-up. Of these patients, 31 in the NIVO+IPI arm and 27 in the SUN arm died within 3 years of randomization; the primary reason for death was disease in either arm (71.0% and 85.2%, respectively). Furthermore, among 27 patients in the NIVO+IPI arm with favorable risk who died after disease progression within 3 years, 12 patients did not receive second-line systemic therapy. Beyond 3 years, only 2 of 43 patients who died after disease progression did not receive subsequent systemic therapy. Among all treated patients, incidence of any-grade and grade 3-4 treatment-related adverse events remained largely unchanged. No new drug-related deaths occurred in either arm since the previous database lock. Table Conclusions With a median follow-up up of 8 years, NIVO+IPI continues to demonstrate sustained survival and more durable response benefits versus SUN in the ITT population, including a further reduction in the risk of death with NIVO+IPI as measured by cancer-specific survival. Long-term exploratory data in patients with favorable risk have shown a steady improvement in the HR for OS, and a marked improvement in median DOR and complete response rates with NIVO+IPI versus SUN, thus contributing to the survival and response benefits reported in the ITT population. Furthermore, the disproportionate number of patients with favorable risk who died within 3 years of randomization after documented progression without receiving subsequent therapy may have affected the HR for OS in this patient population early on. NIVO+IPI offers the potential for positive long-term outcomes, regardless of IMDC risk, and with no emergence of new safety signals.

Spontaneously ruptured hepatocellular carcinoma on non-cirrhotic liver: A prospective case series

Background and aimsSpontaneous ruptured hepatocellular carcinoma is an uncommon complication, and there are scarce data about non-cirrhotic patients. Tumor treatment is not standardized and the risk of peritoneal dissemination is unclear. Aim: we analyzed the treatment and survival in patients with rHCC on non-cirrhotic liver. MethodsOne hundred and forty-one non-cirrhotic patients with hepatocellular carcinoma diagnosed by histology were included in a multicenter prospective registry (2018–2022). Seven of them (5%) presented with hemoperitoneum due to spontaneous rupture. ResultsLiver disease was associated in three patients (42.9%). A single nodule was detected in three cases (42.9%). One patient had vascular invasion and none extrahepatic spread.Initial hemostatic therapy and sequential treatment was individualized. Patients with single nodule were treated: resection (one case) with recurrence at 4 months treated with TACE and sorafenib. TACE/TAE followed by surgery (two cases) one in remission 43 months later, the other had liver recurrence at 18 months and was transplanted. Patients with multiple lesions were treated: TAE/emergency surgery and subsequent systemic therapy (two cases), one received lenvatinib (1-year survival) and the other sorafenib (5-month survival). TAE and surgery with subsequent systemic therapy (one case). Initial hemostatic surgery, dying on admission (one case).No patient developed intraperitoneal metastasis. All patients with multiple lesions died by tumor. The 3-year survival rate was 42.9%. ConclusionsInitial hemostasis was achieved in all patients by TAE/TACE or surgery. Subsequent treatment was individualized, based on tumor characteristics, regardless of rupture. Long-time remission could be achieved in single nodule patients.

Treatment-free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5-year update of CheckMate 214

BackgroundImmunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of...

Clinical features associated with NeoRAS wild-type metastatic colorectal cancer A SCRUM-Japan GOZILA substudy

“NeoRAS WT” refers to the loss of RAS mutations (MTs) following first-line treatment in metastatic colorectal cancer (mCRC). We evaluate the incidence and clinicopathological characteristics of NeoRAS WT mCRC using next-generation sequencing of plasma circulating tumor DNA. Patients with mCRC enrolled in the GOZILA study initially diagnosed with tissue RAS MT mCRC and received subsequent systemic therapy are eligible. NeoRAS WT is defined as the absence of detectable RAS MT in plasma and assessed in all eligible patients (Group A) and in a subgroup with at least one somatic alteration detected in plasma (Group B). Overall, 478 patients are included. NeoRAS WT prevalence is 19.0% (91/478) in Group A and 9.8% (42/429) in Group B. Absence of liver or lymph node metastasis and tissue RAS MTs other than KRAS exon 2 MTs are significantly associated with NeoRAS WT emergence. Overall, 1/6 and 2/6 patients with NeoRAS WT treated with anti-EGFR monoclonal antibodies (mAbs) show partial response and stable disease for ≥6 months, respectively. NeoRAS WT mCRC is observed at a meaningful prevalence, and anti-EGFR mAb-based therapy may be effective.

Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): Overall survival (OS) and melanoma-specific survival (MSS) outcomes at 3 years.

9524 Background: NIVO + RELA as a fixed-dose combination (FDC) demonstrated a statistically significant progression-free survival (PFS) benefit vs NIVO in RELATIVITY-047 (NCT03470922), with a clinically meaningful, but not statistically significant, improvement in OS and a numerically higher objective response rate (ORR), resulting in regulatory approval of the FDC. Here we report updated descriptive analyses with 3 years of follow-up. Methods: Patients (pts) were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg FDC or NIVO 480 mg Q4W. PFS per RECIST v1.1 was assessed by blinded independent central review (BICR); secondary endpoints included OS and ORR per BICR. Exploratory analyses included MSS (death due to melanoma, with censoring of deaths due to other causes), CNS metastasis-free survival in specified populations, and efficacy on subsequent systemic therapy. Results: At database lock (19 Oct 2023), median follow-up was 33.8 months (mo; range, 0.3–64.2). NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS (Table). NIVO + RELA was also favored over NIVO across the majority of key subgroups. Subsequent systemic therapy was received by 135 pts (38%) on NIVO + RELA and 141 pts (39%) on NIVO. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 78 pts (22%) on NIVO + RELA and 43 pts (12%) on NIVO; TRAEs (any grade) led to treatment discontinuation in 63 pts (18%) and 35 pts (10%), respectively. No new treatment-related deaths were reported since the last analysis. Conclusions: At 3 years of follow-up, NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS. OS and MSS demonstrated sustained improvement, with the OS HR 95% CI upper bound &lt; 1. Efficacy results also continued to favor NIVO + RELA vs NIVO across the majority of prespecified subgroups. Safety of NIVO + RELA remained consistent with previous reports, with no new or unexpected safety signals. CNS metastasis-free survival and efficacy outcomes on subsequent systemic therapy will be presented. Clinical trial information: NCT03470922 . [Table: see text]

Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Expanded efficacy analysis from CheckMate 8HW.

3503 Background: NIVO + IPI demonstrated superior progression-free survival (PFS) vs chemo in patients (pts) with previously untreated MSI-H/dMMR mCRC in the randomized phase 3 CheckMate 8HW study (NCT04008030). We report expanded efficacy analysis from the prespecified interim analysis of NIVO + IPI vs chemo in the 1L setting. Methods: Pts with unresectable or mCRC and MSI-H/dMMR status by local testing were enrolled across different lines of therapy and randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms) or for up to 2 years (NIVO ± IPI arms). In pts with blinded independent central review (BICR)–documented progression with chemo, crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) was a key exploratory endpoint. Results: Among 303 pts randomized to NIVO + IPI (n = 202) or chemo (n = 101), 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR. At 31.5-months (mo) median follow-up (range 6.1–48.4), NIVO + IPI demonstrated superior PFS vs chemo (HR 0.21; 97.91% CI 0.13–0.35; P &lt; 0.0001). Subsequent systemic therapy was received by 20 (12%) and 57 (68%) pts in the NIVO + IPI and chemo arms, respectively. In the chemo arm, 56 (67%) pts received subsequent immunotherapy (39 [46%] crossed over to NIVO + IPI on study; 17 [20%] received non-study immunotherapy). Median PFS2 was not reached (NR) with NIVO + IPI and 29.9 mo with chemo (HR 0.27; 95% CI 0.17–0.44; Table). Any grade and grade 3/4 treatment-related adverse events (TRAEs) are presented (Table). Treatment-related deaths were reported for 2 pts in the NIVO + IPI arm. Conclusions: Clinical benefit with 1L NIVO + IPI vs chemo was maintained after subsequent therapy, as shown by improved PFS2 in pts with centrally confirmed MSI-H/dMMR mCRC. No new safety concerns were identified with NIVO + IPI. These results further support NIVO + IPI as a standard-of-care 1L treatment option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . [Table: see text]

Characteristics, treatment, and outcomes of cutaneous mantle cell lymphoma: A decade-long study at MD Anderson Cancer Center.

e19037 Background: Mantle cell lymphoma (MCL) is a rare B cell neoplasm that accounts for 6% of all non-Hodgkin lymphomas and affects predominantly older Caucasian males. Cutaneous involvement is rare in MCL, but more commonly occurs in the advanced or terminal stages of the disease and lacks a standardized approach. Here we report our center’s experience with cutaneous MCL. Methods: We conducted a retrospective chart review of all MCL patients treated at the University of Texas MD Anderson Cancer Center from January 2013 to December 2023 and identified 20 MCL patients with cutaneous involvement. Demographic data, disease characteristics, imaging findings, therapies, and survival outcomes were collected. The study was performed in accordance with the guidelines of the institutional review board. Results: Among the 20 MCL patients with cutaneous involvement (Table), nearly all were Caucasian (n=19/20, 95%), and most were male (n=14/20, 70%). The median age at cutaneous MCL diagnosis was 63.5 years (range: 50-83). All patients had advanced stage disease. The median interval from MCL diagnosis to the emergence of cutaneous symptoms was 2.2 years (range 0-9.3). Most had relapsed/refractory disease (n=17/20, 85%). Most patients had blastoid (n=13/19) or pleomorphic (n=4/19) cytology with a Ki-67 proliferative index ≥50% (n=19/20, median 90%). Several patients had p53 expression (n=11/14) and/or TP53 aberrations (n=4/16). Immediate subsequent systemic therapy, most commonly immunochemotherapy (n=9/20), led to frequent responses (overall response rate: 61%). Most patients received low-dose radiotherapy (RT) for their cutaneous disease (n=19/20) achieving high rates of local control (n=16/18). Of those who are alive and in complete response (n=3) at data cutoff, 2 received chimeric antigen receptor (CAR) T cell therapy as their last MCL-directed treatment. The median survival time from MCL diagnosis to death was 6.83 years (95% confidence interval (CI):4.20-not estimable (NE)). The median survival time from the diagnosis of cutaneous involvement to death was 3.16 years (95%CI: 1.93-NE). The median follow-up duration from MCL diagnosis was 8.22 years. Conclusions: Cutaneous involvement in MCL is associated with aggressive disease biology and poor survival outcomes. Low-dose RT with concurrent immunochemotherapy should be considered the current standard therapeutic approach. CAR T cell therapy and/or bispecific T cell engagers may further improve outcomes in these high-risk patients. [Table: see text]

Partitioned overall survival: Comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC).

4507 Background: Immunotherapy regimens can be associated with prolonged disease control after treatment discontinuation without the need for further anticancer therapy. An integrated, comprehensive partitioned survival analysis describes how patients spend overall survival (OS) time, on/off treatment, with/without toxicity. Previous analysis of first-line (1L) nivolumab (NIVO) + ipilimumab (IPI) for aRCC in CheckMate 214 showed treatment-free survival (TFS) twice as long vs sunitinib (SUN). TFS and survival states for immune checkpoint inhibitor plus tyrosine kinase inhibitor (TKI) combination are of interest. Methods: Overall, 651 patients (pts) with aRCC were randomized to receive 1L NIVO + cabozantinib (CABO) or SUN in the CheckMate 9ER trial; treatment continued until progression or intolerance, NIVO for at most 24 months. Minimum follow-up was 4 years. We partitioned area under the Kaplan–Meier (KM) OS curve into 3 survival states, defined from randomization: time on 1L protocol therapy, TFS, and survival after subsequent systemic therapy (second line [2L]) initiation. TFS and protocol therapy were subdivided as mean times with/without reported grade 2+ treatment-related adverse events (TRAEs). Areas under and between KM curves were estimated by 48-month restricted mean times to event. Bootstrapped 95% CIs for between-group differences are reported. Results: At 4 years post randomization, KM estimates of OS were 49.2% vs 40.2% of pts assigned to NIVO+CABO vs SUN, respectively; 17.6% vs 4.7% of pts were surviving treatment-free, and 15.8% vs 8.2% were continuing on 1L protocol therapy. Over the 48-month period since randomization (Table), the mean TFS (95% CI) was 2.4 (0.8–3.9) months longer after treatment with NIVO+CABO than SUN. At least half of TFS was spent with toxicity in both treatment groups, resulting in difference in mean TFS (95% CI) without toxicity of 0.7 (−0.4 to 1.8) month. The NIVO+CABO group spent a mean (95% CI) of 8.5 (6.2–10.8) months more survival time on 1L protocol therapy, whereas the SUN group spent a mean (95% CI) of 6.5 (4.4–8.6) months more survival time after 2L therapy initiation. Conclusions: Over the 4-year period since initiation of 1L therapy for aRCC, the longer OS achieved with NIVO+CABO was accompanied by 1.5 times longer mean time surviving treatment-free before 2L therapy compared with SUN, a smaller difference than seen for NIVO + IPI vs SUN. [Table: see text]

Clinical outcomes after adjuvant anti-PD1 therapy for high-risk resectable melanoma and predictors of response.

e21502 Background: Adjuvant anti-PD1 is the standard of care for high-risk resectable melanoma but many still suffer recurrence. We report a single institution observational study of patients who received adjuvant anti-PD1 with a particular focus on those who recurred. Methods: Through an approved protocol by Huntsman Cancer Institute IRB, patients with resected high-risk melanoma who first received anti-PD1 in the adjuvant setting were consented and followed. Clinical outcomes were assessed per RECIST 1.1, progression free survival (PFS), and overall survival (OS). Results: 186 eligible patients were included, 105 male and 81 females, median age at C1D1 58 (22-93), 12/161/7 at stage II/III/IV and 5 unstageable. Subtypes included 79 (43%) superficial spreading, 50 (27%) nodular, 16 (9%) lentigo/nevoid, 13 (7%) non-acral skin (NOS), 10 (5%) acral, 4 (2%) mucosal, and 14 (7%) others. With median follow up of 708 days (23-9599), 66 (35.5%) had progressive disease (PD), including 33 (50%) early PD and 33 (50%) late PD. Statistically significant predictors of worse outcome included age &gt; 50 (OS p = 0.043), acral subtype (PFS p = 0.023), PD-L1 IHC &lt; = 1% (OS p = 0.052, PFS p = 0.002), duration of treatment &lt; 3 months (OS p = 0.005, PFS p = 1.8E-07), early PD (OS p = 0.003, PFS p = 1.5E-6) and distant recurrence (OS p = 0.002). Trends that were not significant included: male gender (worse OS), BRAF mutation (better PFS), NF1 mutation (better PFS). No correlation between outcomes and TMB, NRAS, TERT mutation, and primary location. In the early/late PD groups, median age was 57/55 (range 28-79 / 25-84), 64/61% male, 1/0, 29/31, 3/2 stage II, III, IV. 17/13 were superficial spreading, 6/10 nodular, 2/5 acral, 2/2 lentigo, 1/0 mucosal and 4/3 other non-acral skin. Primary site was 12/12 head/neck, 9/5 trunk, 4/7 upper limb, 8/9 lower limb. BRAF was 9/11 wildtype, 15/9 mutant and 9/13 unknown. PD-L1 &gt; = 1% by IHC was 4/2. TMB mut/mb &gt; 10 was 6/5. Sites of recurrence included 6/12 local, 7/7 regional LN, 20/14 distal (3/1 in brain) relapses. For unresectable PD (13/13 early/late) response to next line systemic therapy is shown in Table 1. Conclusions: One third of patients developed PD after adjuvant anti-PD1 for high-risk melanoma. PD-L1 negativity and short duration of treatment was associated with worse outcome. Early PD corresponded to more distant metastasis, poorer OS and response to subsequent systemic therapy. Importantly most late PD can still have a favorable response by resuming anti-PD1 therapy. Further molecular study is ongoing to investigate mechanisms of resistance. [Table: see text]

Efficacy of immunotherapy retreatment in patients with non-small cell lung cancer receiving consolidative durvalumab.

8625 Background: The standard of care for patients with stage III, unresectable non-small cell lung cancer (NSCLC) is curative intent chemoradiation followed by durvalumab consolidation. However, most patients progress necessitating further treatment. Although immunotherapy (IO) is the cornerstone of treatment in advanced/metastatic disease, the benefit in patients who received prior durvalumab is unclear. Clinical trials excluded prior IO exposure and current guidelines do not provide specific recommendations. This study aims to characterize the efficacy of post-durvalumab IO treatment. Methods: This was a retrospective cohort study conducted at the University of North Carolina (UNC) Medical Center. Adult patients with unresectable NSCLC who received chemoradiation and consolidative durvalumab followed by subsequent systemic therapy for disease progression between February 2018 to May 2023 were included. Patients were excluded if they received targeted therapy as subsequent systemic treatment. The primary endpoint was real-world progression-free survival (rwPFS) of post-durvalumab treatment. Key secondary outcomes included physician assessed response, overall survival (OS), and subgroup analyses to identify biomarkers which may predict benefit from IO retreatment. Results: A total of 66 patients met inclusion criteria, of which 39 (59%) received subsequent chemotherapy alone and 27 (41%) received IO-containing therapy. Of those who received IO-containing treatments, 18 received chemotherapy plus IO (chemoIO) and 9 received IO alone. Durvalumab was discontinued for therapy completion (chemotherapy: 18%, IO: 26%), disease progression (chemotherapy: 54%, IO: 48%), or side effects (chemotherapy: 26%, IO: 19%). No significant difference was observed between median rwPFS of chemotherapy versus IO-containing therapy (7.0 months vs 5.8 months, respectively; p = 0.9419) or OS (13.0 months vs 12.6 months, respectively; p = 0.5769). Notably, patients in our cohort who received IO alone had a numerically longer rwPFS compared to chemoIO (12.6 months vs 5.8 months, respectively; p = 0.3951), as well as a numerically longer OS (12.6 months vs 6.4 months, respectively; p = 0.8885). Conclusions: This study found that there were no statistically significant differences in median rwPFS or OS between chemotherapy or IO-based regimens following the conclusion of durvalumab consolidation. Interestingly, we observed a numerically improved rwPFS and OS in those who received IO alone compared to chemoIO, which suggests there may be key clinical or molecular features that may help identify patients who benefit from IO therapy. We acknowledge the limitations of this small, retrospective study. The efficacy of IO-based regimens post-durvalumab warrants further investigation in a larger, prospective manner to assess the risks and benefits of IO retreatment.

Use of FOLFOXIRI Plus Bevacizumab and Subsequent Therapies in Metastatic Colorectal Cancer: An Age-Stratified Analysis

BackgroundTreatment recommendations for metastatic colorectal cancer (mCRC) do not differ by age group; nevertheless, aggressive multiagent chemotherapy comprising FOLFOXIRI+bevacizumab (triplet+bev) is routinely administered in younger patients. This study analyzed real-world data on index triplet+bev use and subsequent systemic therapies. Materials and MethodsThis retrospective, observational cohort study was conducted in patients aged ≥ 18 years with mCRC, who were initiated on triplet+bev. Data were derived from the Optum de-identified electronic health record dataset. ResultsOf 36,056 patients, 14%, 36%, and 50% were aged 18-49, 50-64, and ≥ 65 years, respectively. During the study period (2010-2021), triplet+bev use increased in patients aged 18-49 years (1%-4%) but remained at approximately 3% and 1% in patients aged 50-64 and ≥ 65 years, respectively. Patient demographics and clinical characteristics varied slightly; of patients receiving triplet+bev (n = 921) versus nontriplet+bev (n = 35,132) most were male (57% vs. 52%), resided in the Midwest (54% vs. 49%) and Northeast (18% vs. 14%) US regions, and had secondary malignancies (86% vs. 73%). Following triplet+bev, most patients received subsequent therapies (including continued triplet component therapies; 97%) or subsequent “new” therapies (therapies that did not include any agents comprising triplet+bev; 57%), most frequently EGFR inhibitors (28%) and regorafenib (21%), with a similar trend among all age groups. ConclusionsOverall, this study shows that younger patients with mCRC are more likely to receive first-line triplet+bev. These results also reveal that nonchemotherapy options are often used beyond first-line triplet chemotherapy for patients with mCRC.

Abstract PO5-18-04: Effect of Digoxin on clusters of circulating tumor cells in patients with metastatic breast cancer (DICCT)

Abstract Background: The presence of circulating tumor cell (CTC) clusters is associated with tumor progression and with a bad prognosis in various cancer types1,2. In breast cancer, a pre-clinical model demonstrated that Na/K-ATPase inhibitors such as digoxin could dissolve CTC clusters and reduce metastasis3. DICCT is a single-arm, therapeutic exploratory phase I study aimed to examine whether digoxin can disrupt CTC clusters in metastatic breast cancer patients (NCT03928210). Material and methods: Metastatic breast cancer patients in whom clusters of CTCs have been detected were eligible. Patients with concomitant heart disease were excluded. After progressive disease in any line of therapy, a window of opportunity before initiation of subsequent systemic therapy was used to administer digoxin treatment for seven (7) days. For CTC detection, blood samples were processed with the FDA-cleared Parsortix system (ANGLE plc, UK). Captured CTCs were stained for EPCAM, HER2, EGFR (positive CTC selection) and CD45 (exclusion marker). To gain insight into the cluster-dissolution ability of digoxin, the primary endpoint was size of CTC clusters (i.e. number of cells within each cluster) under digoxin therapy. The cumulative effect of digoxin treatment on the primary endpoint was assessed by a linear regression model. Results: Nine (9) patients with CTC clusters detected at baseline were enrolled. A target level of digoxin above 0.7 ng/ml could be confirmed at day 7 for all patients. For quantitative and qualitative analysis of CTC clusters, 5.5 to 27 ml of blood were analyzed at baseline, at day 0 pre-treatment, and post 2 hours, 3 days and 7 days of digoxin treatment. The average cluster size ranged between 2 and 11.8 cells (median 2.9) considering all samples from all patients. Digoxin treatment reduced cluster size in 8 patients (88.9%) to different extents, and the proportion of CTC cluster over single CTCs was also reduced in 6 patients (66.7%). The effect of digoxin was evident in both homotypic (cancer cells only) and heterotypic (aggregates of CTCs and white blood cells) clusters. The treatment was well tolerated, and no adverse events related to the study treatment occurred. All patients completed the treatment according to the protocol. Conclusion: DICCT provides the first-in-human proof-of-principle that digoxin induces a partial dissolution of CTC clusters in patients with metastatic breast cancer at drug levels that are safe and well tolerated. Conceptualization of follow-up trials including Na/K-ATPase inhibitors and patient outcome endpoints are underway.