Advanced Melanoma Pts Research Articles

Phase 3 study (PIVOTAL) of neoadjuvant intralesional daromun vs. immediate surgery in fully resectable melanoma with regional skin and/or nodal metastases.

LBA9501 Background: PIVOTAL (NCT02938299) is an open label, randomized, multicenter, phase 3 trial evaluating Daromun as a neoadjuvant intralesional therapy for resectable, locally advanced Stage III melanoma. Daromun, a combination of two antibody-cytokine fusions (L19IL2 and L19TNF) showed efficacy in a phase 2 study (NCT02076633) in unresectable melanoma patients (pts). Methods: PIVOTAL was run at 22 sites in 4 EU countries. Pts were 1:1 randomly assigned to receive up to 4 weekly intratumoral injections of Daromun followed by surgery (week 5 to 8; treatment arm) or surgery alone within 4 weeks from randomization (control arm). Each weekly administration of Daromun (13 Mio IU of L19IL2 and 400 μg of L19TNF) was distributed among all injectable tumor lesions. Cutaneous melanoma pts with skin and/or LN metastases amenable to complete surgical resection were eligible. Prior anti-tumor treatments including surgery, radiation therapy (RT) and systemic therapies were allowed. Any approved adjuvant treatment post-surgery during follow-up was equally allowed. Pts with uveal or mucosal melanoma, metastatic melanoma with unknown primary, or distant metastases at screening (ruled out by PET/CT) were not eligible. Results: From 07/2016 to 08/2023, 127 pts were randomized to the treatment and 129 to the control arm. Most pts had received previous treatments, including surgery, systemic therapy or RT (Table). The study’s primary endpoint was relapse-free survival (RFS), assessed by investigators and confirmed by retrospective Blinded Independent Central Review (BICR) of PET/CT scans. The primary outcome analysis shows an HR between the RFS of the treatment and control arm of 0.59 [95% CI 0.41-0.86; log-rank p=0.005] as per BICR assessment and 0.61 [0.41-0.92; p=0.018] as per investigator assessment (power = 85%; two-sided α = 0.05). Median RFS was 16.7 mo. in the treatment and 6.9 mo. in the control arm as per BICR. Moreover, distant metastasis-free survival (DMFS) was significantly improved by the neoadjuvant treatment, with an HR of 0.60 [0.37-0.95; p=0.029]. Complete pathological responses (pCR) after surgery were recorded in 21% of treatment arm pts. The safety profile of Daromun was characterized mostly by low-grade, local adverse events (14% grade 3 TEAEs). Systemic AEs were limited and of low grade (no autoimmune TEAEs and no drug-related death recorded). Conclusions: The analysis of the primary efficacy endpoint RFS and of secondary endpoints DMFS, pCR and safety show that neoadjuvant Daromun is an effective and safe therapeutic option for resectable, locally advanced melanoma pts. Clinical trial information: NCT02938299 . [Table: see text]

Updated results from an ongoing phase 1/2a study of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, administered via IT injection as monotherapy or combined with pembrolizumab in advanced solid tumors.

9535 Background: T3011 is a recombinant HSV-1 oncolytic virus expressing both IL-12 and anti-human PD-1 antibody. Upon injection, locally produced IL-12 induces IFN-γ production, enhances the oncolytic activity of NK cells and cytotoxic T lymphocytes, promotes anti-angiogenesis and inhibits tumor growth. PD-1 antibodies act as immune checkpoint inhibitors to augment tumor-killing activity of T-cells. Here we report the updated results from an open-label, dose escalation and expansion study of T3011 administered via intratumoral injection as monotherapy or in combination with intravenous pembrolizumab. Methods: Pts with pathologically confirmed recurrent or metastatic malignancy after failure of SOC were enrolled and received T3011 monotherapy (1*106-5*107 PFU/mL Q2W) or in combination with pembrolizumab (Lead-in T3011 1*106 PFU/mL Q2W monotherapy for 2 cycles followed by combination therapy Q3W). Pts with documented progression on T3011 monotherapy may cross over to receive combination therapy at the discretion of the investigator. The primary endpoints were safety and tolerability. Key secondary endpoints included confirmed ORR, DCR, DOR, PFS by investigator per RECIST1.1; OS; PD and PK. Results: As of 17 Jan 2023, 29 pts received T3011 alone or in combination with pembrolizumab, the median follow-up was 14.1 (1.2-27.6) months. No DLTs were reported. Any treatment-related adverse events (TRAEs) occurred in 75.9% (22/29) of pts (≥G3 in 10.3%). Treatment-related SAEs occurred in 3.4% (1/29). Most frequent TRAEs (≥10%) were pyrexia (27.6%), fatigue (20.7%) and chills, injection site pain, arthralgia, nausea, headache (10.3% each). No additional safety signals were observed with combination therapy. 12 advanced melanoma pts failing prior PD-1 or PD-1/CTLA-4 combination treatment received 5*107 PFU/mL of T3011 monotherapy. The confirmed ORR and DCR were 25.0% (3/12) and 33.3% (4/12), respectively. 12-month PFS rate was 36.4%. 6 of these pts were re-challenged with immunotherapy with T3011 (5*107 PFU/mL) combined with pembrolizumab after progressing on T3011 monotherapy, 1 pt achieved PR after 4 months lasting > 8 months at data cutoff. 15 pts had tumor tissues for PD analysis. Increased CD8+ cells were observed in 46.7% (7/15) of all pts and 50% (5/10) of melanoma pts. It appeared to be more pronounced in pts with PR and SD, 66.7% (6/9) in all pts and 80% (4/5) in melanoma pts, respectively. Notably, the increment of CT8+ cells in 2 melanoma pts with PR was over 15 folds. Conclusions: Both T3011 IT monotherapy and combination therapy with pembrolizumab were safe and tolerable. The efficacy of T3011 in immune-resistant melanoma was encouraging. Our data suggest T3011 may modify the tumor microenvironment and overcome immune resistance. Clinical trial information: NCT04370587 .

Efficacy and safety of sequencing with vemurafenib (V) plus cobimetinib (C) followed by atezolizumab (Atezo) in patients (pts) with advanced BRAFV600-positive melanoma: Interim analysis of the ImmunoCobiVem study.

9548 Background: Immunotherapies (ICI) and targeted therapies (TT) have improved PFS and OS in BRAFV600-mutated advanced melanoma pts, but evidence regarding their optimal sequence is limited. The randomized phase 2 ImmunoCobiVem study evaluated efficacy and safety of an early switch to Atezo after initial treatment with V + C. Interim results are reported. Methods: Pts with previously untreated BRAFV600-mutated advanced melanoma received a 3-mo run-in with V (960 mg twice daily) + C (60 mg once daily for 21/28 days). Pts without PD/treatment interruption due to AEs during run-in were then randomized 1:1 to continue V + C (Arm A) or switch to Atezo (1200 mg every 3 wks; Arm B) until first documented PD (PD1), followed by crossover to the alternate treatment until second documented PD (PD2). End points were PFS1 (time from start of run-in until PD1 or death from any cause), PFS2 (time from start of run-in until PD2 or death from any cause), PFS3 (time from PD1 until PD2 or death from any cause), DCR, ORR, OS, and safety. Results: 185 pts were enrolled between Nov 2016 and Dec 2019 (63% male; median age 58 y); 135 pts completed run-in and were randomized to Arm A (n=69) or Arm B (n=66). At data cutoff, median follow-up for all pts was 19.0 mo. In Arm A, 36/69 pts (52%) discontinued V + C due to PD and 21/36 (58%) crossed over to Atezo; in Arm B, 49/66 pts (74%) discontinued Atezo due to PD and 35/49 (71%) crossed over to V + C. Median PFS1 was significantly longer in Arm A vs Arm B (HR 0.55; 95% CI 0.37–0.84; P=0.001), while median PFS3 was significantly shorter in Arm A vs Arm B (HR 2.24; 95% CI 1.17–4.30; P=0.013); median PFS2 was not significantly different between arms (HR 1.57; 95% CI 0.83–2.96; P=0.163) (Table). During the randomized phase, ORR and DCR were higher in Arm A before crossover and in Arm B after crossover (Table). OS was similar between arms (HR 1.22; 95% CI 0.69–2.16; P=0.389). Median (range) treatment duration across treatment phases was 11.2 mo (2.3–56.1) for Arm A and 10.7 mo (2.8–56.7) for Arm B. Grade 3/4 AEs occurred in 55% of pts in Arm A and 64% in Arm B; AEs led to discontinuation in 10% and 12%, respectively. Conclusions: Early switch from V + C to Atezo is feasible and safe, but tumor control achieved in run-in is maintained in only a subset of pts on subsequent ICI monotherapy. Crossover to ICI monotherapy at PD results in low response, while response to TT re-exposure is frequent. Clinical trial information: NCT02902029. [Table: see text]

Treatment beyond progression with immune checkpoint inhibitors in advanced melanoma.

e21541 Background: Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST defined progression (PD). Clinical concept of treating of selected patients (pts) beyond PD is supported by this pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond progression (TBP) in melanoma patients. Methods: We evaluated advanced melanoma pts who started anti-PD1 treatment between 12/2015 and 12/2018 and identified pts who received TBP and had subsequent imaging to evaluate the tumor burden. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Data cut-off was 02/2021. Results: Of 399 subsequent melanoma pts treated, 57 (14%) patients received TBP. Anti-PD1 was 1st line treatment in 61.4% and 2nd line - in 38.6% of patients. 71.9% patients were diagnosed with skin, 7.0% - mucosal and 21.1% with FPI melanoma and 47.4% were BRAF mutated, 56.1% were male and 12.3% had 3 or more metastatic sites at treatment initiation. In this cohort median time to 1st PD (TTFP) was 4.43 months(m), while to 2nd PD (TTSP) – 8.01 m. On TBP 26.3% pts achieved objective response (OR), and next 42.1% - SD. 1st PD was reported most often as increase in 3 or more targets or one new lesion – both 22.8%; and in 24.6% cases involved central nervous system. In 56.8% second PD was observed in the same targets as 1st PD. 61.4% patients received multimodal treatment of ITH combined with radiation therapy – in 49.1%, surgery - 5.3% and both - 7.0%. There was no correlation of TTSP with gender, ECOG, initial disease stage or TNM, BRAF mutation, number of metastatic sites or pattern of progression. Multimodal treatment resulted in 13.6 m TTSP, while ITH alone - 8.0 m (p = 0.056). 1st line OR correlated with DCR on TBP while TTFP > 6 m correlated with TTSP (HR = 0.53, 95%CI 0.28-0.99). Patients with 1st line CR – had median TTSP 16.4 m, with PR – 23.5 m, while those with PD – 5.1 m. Median OS after 1st PD was 26 months and correlated with OR on TBP. Conclusions: Selected clinically fit melanoma patients despite evidence of first radiographic progression may benefit from continued treatment with PD-1 inhibitors. Multidisciplinary treatment should be offered to these patients including radiosurgery or stereotactic radiotherapy of progressing loci. Molecular biomarkers of TTSP should be analyzed in prospective studies.

A process mining approach to real-world advanced melanoma treatments.

e22040 Background: Process Mining (PM) is an emerging discipline with promising potential in oncology, which offers a time-oriented perspective on the clinical events that define the patient’s (pts) path of care, from diagnosis to follow-up. PM enables us to 1) build unsupervised models that automatically discover frequent patterns and detect unexpected behaviors, and 2) show the pts flow through predefined models, allowing quantitative assessments of conformance/divergence between reality and expected behaviors or medical guidelines. Methods: We explored the potential of PM to analyze treatments in a real-world melanoma cohort of 212 advanced melanoma pts treated with tyrosine kinase inhibitors (TKI), chemotherapy, or immunotherapy (IO) since 2010. 44% of pts are BRAF mutated, 24% NRAS mutated, and 16% WT. Using PM, we characterize the sequences of treatment according to type of drugs, order and timing of consecutive lines. We use kernel density estimations, Fisher or Wilcoxon tests to assess differences between groups. As main endpoint we assess the overall survival (OS) with respect to specific patterns of care followed by the pts using Kaplan-Meier analysis with log-rank test. Results: This approach provides important self-consistency checks for data and reveals the most frequent treatment sequences, and the associated outcome. The 324 administered treatments, characterized in terms of type and occurrence, are: TKI (23%), antiCTLA4 + antiPD1 (22%), antiPD1 (21%), and antiCTLA4 (20%). The overall 3-year OS is 56.9% (95% CI: 49.2 – 65.8). We identified 50 distinct patterns, which can be further aggregated into relevant cohorts to provide real-world answers to medical questions. Among others, we probed the influence of treatment order: IO single (any BRAF status), IO → TKI, TKI → IO (see table). Preliminary results suggest that pts treated with TKI → IO had shorter OS despite balance prognostic factors to IO → TKI group. IO → TKI provides short-term benefits with 1.5-year OS similar to IO alone, but degraded 3-year OS. Conclusions: The PM approach enables fast and efficient visual inspection of the data, emphasizing treatment sequences over time and allowing stratification at different levels. More population attributes and outcomes will be included to further characterize treatment sequences and provide real-world insights into future personalized care options. [Table: see text]

Baseline biomarkers correlated with outcome in advanced melanoma treated with pembrolizumab monotherapy.

e22041 Background: Pembrolizumab (PEMBRO) improves survival in advanced melanoma (MEL). This research investigates baseline (BL) biomarkers that predict long-term benefit on PEMBRO monotherapy. Methods: Outcome data on patients (pts) with advanced cutaneous/mucosal MEL treated with PEMBRO in our institution were collected after pt consent. Responses were evaluated using the immune-related response criteria. Total metabolic tumor volume (TMTV), assessed by 18-fluorodeoxyglucose positron emission tomography/computed tomography, was calculated as the sum of all tumor-associated voxels with a standardized uptake value (SUV) above the mean SUV measured in a reference region in normal liver tissue plus 3 standard deviations using Syngo.via software (Siemens Healthcare). The NanoString PanCancer IO360 panel was used for gene expression profiling (GEP). Results: A total of 196 pts was included in this analysis (median age 60; cutaneous 86%, mucosal 3%, unknown primary 12%; stage III 14%, IV-M1a/b/c 60%, IV-M1d 26%; first-line 24%). Median progression-free survival (PFS) in the population was 20.4 w (95% CI 10.2-30.7); median overall survival (OS) was 143.6 w (95% CI NR-NR). BL WHO Performance Status (PS) > 0 (HR 1.63 [95% CI 1.13-2.37]), C-reactive protein (CRP) > ULN (HR 1.92 [95% CI 1.33-2.77]), absolute lymphocyte count (ALC) < 750/mm³ (HR 2.45 [95% CI 1.32-4.55]) and > 1 metastatic site (HR 1.84 [95% CI 1.23-2.77]) were associated (P≤0.01) with worse PFS in multivariate analysis (Cox regression); BL WHO PS > 0 (HR 2.77 [95% CI 1.82-4.24]), lactate dehydrogenase (LDH) > ULN (HR 1.80 [95% CI 1.16-2.79]) and > 1 metastatic site (HR 1.95 [95% CI 1.16-3.25]) were associated with worse OS (P≤0.011). BL TMTV data were available in 118 pts (60%): BL CRP > ULN (HR 1.83 [95% CI 1.13-2.96]), ALC < 750/mm³ (HR 2.49 [95% CI 1.02-6.08]), > 1 metastatic site (HR 1.71 [95% CI 1.04-2.82]) and BL corticosteroid use (HR 4.62 [95% CI 1.38-15.45]) were associated with worse PFS (P < 0.05). BL WHO PS > 0 (HR 2.82 [95% CI 1.57-5.08]), ALC < 750/mm³ (HR 2.62 [95% CI 1.06-6.51]), history of brain metastases (HR 2.59 [95% CI 1.37-4.91]) and TMTV > 80 mL (HR 3.56 [95% CI 1.82-6.95]) were all associated with worse OS (P≤0.038). GEP data on a representative BL tumor sample were available in 27 pts (14%). Higher apoptosis signature scores were associated with increased probability of OS (HR 0.45 [95% CI 0.33-0.73], P < 0.01). Conclusions: BL TMTV > 80 mL identifies a subgroup of advanced MEL pts with worse outcome on PEMBRO. Increased apoptosis gene signature scores in a subset of patients predict increased OS.

1344P - Outcomes of advanced melanoma patients who discontinued pembrolizumab (pembro) after complete response (CR) in the French early access program (EAP)

BackgroundInformation on outcomes after cessation of anti-PD-1 mAb for CR are scarce outside KN-001 & 006 trials. We investigated these outcomes in the French pembro EAP, where pts were less selected than in registration trials. MethodsA multicenter ambispective cohort of advanced melanoma pts initiating pembro between May 2014-Sept 2015 (CCTIRS, #15.640) was searched for pts who achieved CR. Overall and progression-free survivals with Log rank tests were used to compare curves. Results687 pts (159 with brain metastases) were included from 41 centers, which covered 75% of French pembro EAP. 79 pts (13%) achieved CR, among whom 68 (10%) stopped pembro for CR. Compared with the remaining 619 pts surveyed, these 68 pts had lower baseline serum LDH levels (54.5% vs 73.8%, respectively, were normal, p=0.016), lower ECOG PS (ECOG 0 for 298 (52.6%) and 54 (80.6%), respectively, p=0.001), and fewer metastatic sites (p=0.003). Of note, 10% of these 68 pts had >3 metastatic sites, 10% had brain metastases, 53% had 2010 AJCC stage M1c melanoma, and 67% had received previous treatment for advanced melanoma (mainly ipilimumab). Frequency of BRAFV600, NRAS, and c-kit mutation status was not different between pts who did or did not achieve CR. Median duration on pembro in these 68 pts was 21.2 m (range: 2.5-48.4, SD 10.0). Pembro was used alone to achieve CR in 79% of pts, while 4% received concurrent radiotherapy alone, 10% concurrent surgery alone, and 6% both treatments. At the cut-off date (13/09/2018), after a median follow-up since pembro initiation of 36.3 m and of 15.3 m since pembro cessation (2-31, SD 8.3), only 3% of pts experienced melanoma recurrence. Median recurrence-free survival was not achieved. These 2 pts received radiotherapy, with one partial response achieved. 5 pts died, with 2 deaths unrelated to melanoma (1 lymphoma, 1 chylothorax), 1 related to melanoma progression, and 2 of unknown causes. ConclusionsIn this large real-life cohort, 10% of pts reached CR and discontinued pembro. All but 3% were recurrence-free after a median 15.3 m of treatment, thus validating the discontinuation of anti-PD1 in complete responders. Clinical trial identificationCCTIRS, #15.640. Editorial acknowledgementRIC-Mel network and their team. Legal entity responsible for the studyMSD France. FundingMSD France. DisclosureP. Saiag: Honoraria (self), Advisory / Consultancy: MSD. L. Mortier: Honoraria (self), Advisory / Consultancy: MSD. C. Dutriaux: Honoraria (self), Advisory / Consultancy: MSD. L. Benmahammed: Full / Part-time employment: MSD. O. Morsli: Full / Part-time employment: MSD. C. Train: Full / Part-time employment: ClinSearch. A. Spampinato: Full / Part-time employment: MSD. M.T. Leccia: Honoraria (self), Advisory / Consultancy: MSD. N. Meyer: Advisory / Consultancy: MSD. J.J. Grob: Honoraria (self), Advisory / Consultancy: MSD.

Efficacy of hypofractionated radiotherapy (Rx) in melanoma patients who failed anti-PD-1 monotherapy: Assessing the abscopal effect.

9537 Background: Radiotherapy (Rx) and anti-PD-1 mAb are potentially synergistic. No study has tested this combination only in pts who failed on anti-PD-1 mAb, which allows to assess the abscopal effect. We evaluated this combination in a cohort of advanced melanoma pts after failure of anti-PD-1 monotherapy. Methods: Analysis of a prospective database in a referral center searching for advanced melanoma pts with confirmed (2 CT-scans) progressive (PD) or stable (SD) disease on anti-PD-1 monotherapy, who later received concurrent Rx without modification of anti-PD-1 mAb regimen. Radiologists performed independent tumor evaluations (RECIST 1.1) every 3 m, both on radiated and non-radiated lesions, with abscopal effect defined as a partial (PR) or complete (CR) response outside radiated fields. Results: 26 pts (21 achieving PD, 5 SD, 10 pt ≥3 involved organs), mean age 70 Y, were included. Anti-PD-1 mAb was first line in 50% of pts. Rx, consisting of hypofractionnated Rx (3-5 sessions, 26 Gy), standard palliative Rx, or gamma-knife in respectively 23, 2, and 1 pts, was begun on a single site in 73% of pts or on 2 sites after a median of 5 m after beginning anti-PD-1 mAb. Median follow-up after onset of anti-PD-1 mAb was 17 (7-35) m, with 65% of pts alive at last follow-up. Best response was 7 CR (27%, including CR in 4 pts with prior PD) 1 PR, 3 SD (12%), 15 PD (58%). Abscopal effect was seen in 10 pts (38%). No correlation between the occurrence of CR and BRAF/NRAS mutation status, number of metastatic sites, presence or absence of brain metastases, and LDH level was seen. Anti-PD-1 mAb could be discontinued in 6 pts with CR, without relapse to date. No unusual adverse event was recorded. Conclusions: In pts who have previously failed on anti-PD-1 mAb, obtaining with concurrent Rx and without modifying anti-PD-1 mAb, CR or PR in 30% of pts, median OS not achieved, and abscopal effect in > 1/3 of pts is probably not due only to late efficacy of anti-PD-1 mAb but suggests a synergy with RT. Release after radiation of tumor neoantigens may stimulate immune response. Hypo-fractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in melanoma pts who failed on anti-PD-1 mAb. Controlled studies are needed.

Continuous intravenous infusion Rh-endostatin in combination with dacarbazine and cisplatin as the first-line therapy for metastatic melanoma.

e21007 Background: Immunotherapy and targeted therapy have dramatically improved the survival of advanced melanoma patients (pts), but they show relative lower efficacy in Asian pts especially in acral and mucosal subtypes. Rh-Endostatin (endostar) is a potent endogenous inhibitor of angiogenesis. Previous studies have indicated that endostar combined with dacarbazine (DTIC) was effective in the treatment of metastatic melanoma. To further improve the effectiveness, this study was designed to observe the efficacy and safety of continuous infusion (CIV) of endostar combined with DTIC and cisplatin as the first line therapy for advanced melanoma pts. Methods: Pts with treatment naive, ECOG 0/1, and unresectable stage IIIC or IV melanoma were enrolled. DTIC (250 mg/m2, intravenous infusion, day 1-5), cisplatin (75 mg/m2, intravenous infusion, separated in 3 days) and endostar (15 mg/m2, CIV, day 1-14) were administered in a 28-day cycle until disease progression or intolerable toxicity. The primary endpoint was progression free survival (PFS). Secondary endpoints included disease control rate (DCR) and safety. Results: From January 2016 to May 2018, 64 pts were enrolled and 50 pts were evaluable. 26 pts were female. The median age was 50 years (range 28-71 years) old. 10/64 (15.6%) were primary mucosal and 21/64 (32.8%) were primary acral, 40 pts were at stage IV and 32% pts got BRAF mutation. At the last follow up of Dec 2018, 5 pts achieved partial response and 27 pts got stable disease. The objective response rate was 10%. The DCR was 64%. The median PFS was 6.0 months (95% CI 1.7-10.3 months). The median overall survival was not reached. The most common adverse events were nausea (56.25%), vomiting (31.25%) and leucopenia (29.7%). Grade 3-4 toxicity was few, one got intermittent palpitation and one got atrial fibrillation, which caused drug discontinuation and recovered to normal. Conclusions: Continuous infusion of endostar plus DTIC and cisplatin improved median PFS as the first line therapy for advanced melanoma. This combination therapy was well tolerated and might be recommended as the first line therapy for advanced melanoma. Clinical trial information: NCT03095079.

Prospective cardiac function monitoring in immunotherapy-treated patients.

e14157 Background: Immune checkpoint inhibitors (ICI) demonstrate activity and long-term benefit in melanoma and other cancers. While certain immune-related toxicities have been well described, cardiac toxicities remain poorly characterized. We sought to characterize changes in cardiac function in advanced melanoma patients (pts) starting ICI treatment. Methods: A prospective, observational, single institution trial was performed to monitor cardiac function in pts receiving ICI. Eligible pts were adults with stage III/IV melanoma and ECOG 0-1, determined safe to exercise and without unstable cardiac symptoms. Pts received PD-1 monotherapy or combination ipilimumab/pembrolizumab. Rest and exercise stress cardiac testing (EKG, echocardiography) was conducted at baseline, at 3 months (mo), and at 6 mo. Patient-reported surveys were administered at baseline and at 6 mo. Results: Between Feb 2018 to Jan 2019, we prospectively identified 8 pts who completed baseline cardiac testing. As of Feb 2019, 6 pts completed 3-mo testing, and 4 completed 6-mo testing. Mean age was 57 years (range 34-68). 5 pts received pembrolizumab or nivolumab monotherapy, and 3 received ipilimumab/pembrolizumab. Resting LVOT-VTI decreased from 23.1±2.8 cm at baseline to 20.7±2.8cm at 6 mo (p = 0.047). Maximum HR at peak exercise decreased over time from 149.7±13 bpm at baseline to 114±20.5 bpm at 6 mo (p = 0.085) with concurrent decrease in maximum BP. Enrollment is ongoing. Conclusions: These data suggest measurable changes in left ventricular cardiac function at rest over time, in a prospective cohort of ICI-treated advanced melanoma pts. Further, we observe progressive loss of chronotropic and blood pressure response to exercise. These data have important implications for cancer survivorship in the era of immunotherapy. Updated data to be presented at the meeting include correlation with patient-reported symptoms. [Table: see text]

Relationship between clinical efficacy and AEs of IMCgp100, a novel bispecific TCR–anti-CD3, in patients with advanced melanoma.

9530 Background: Bispecific antibodies have shown activity in hematologic (heme) but not solid tumors. ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeted against melanocyte-associated lineage antigen gp100, has shown monotherapy responses in advanced melanoma with associated immune changes. IMCgp100 causes rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. We explored clinical and biological characteristics of pts associated with treatment benefit. Methods: 84 HLA-A2 positive advanced melanoma pts received IMCgp100 on study IMCgp100-01 in 13 dose escalation cohorts. Efficacy was assessed by Kaplan–Meier survival and treatment related AEs (TRAE) reported by CTCAE v4.0. Serum samples evaluated changes in cytokines. A multivariate analysis investigated the relationship between efficacy and safety variables. Results: Demographics: 73% cutaneous (CM), 23% uveal (UM) primaries; 51% LDH > ULN; 25% received prior anti-PD(L)1. 83 (99%) pts had ≥1 TRAE; most commonly in skin (rash 82%, pruritus 69%) or cytokine-mediated (pyrexia 57%); the majority were Grade 1–2 and occurred and resolved within first 3 doses. The 2 most frequent Grade ≥3 TRAEs were rash (26%) and lymphopenia (13%). IMCgp100 induced transient increases in peripheral cytokines (peaking Day 1–2) that attenuated with subsequent doses; cytokine-mediated AE had similar kinetics.1-yr OS was 65% (95% CI: 48–78). In multivariate analysis, longer OS was associated with: LDH ≤ULN (p = 0.002) and any-grade rash occurring within 21 days (p = 0.003); melanoma primary site and prior anti-PD-(L)1 did not significantly affect outcome. In exploratory analyses, longer OS associated with lower baseline serum IL-6 (n = 43) or TNFα (n = 44). Conclusions: IMCgp100 is a first-in-class, TCR-based bispecific with monotherapy efficacy in advanced melanoma. AEs were manageable and consistent with MoA. Association between IMCgp100 efficacy and on-target TRAEs, previously reported for bispecifics to heme lineage antigens, is now recognized for solid tumor lineage antigens. Pivotal studies in UM are ongoing. Clinical trial information: NCT01211262.

Sustainable responses in metastatic melanoma patients with/without brain metastases after immunotherapy induced CR.

e21042 Background: Immunotherapy (IT) has demonstrated an improved overall survival (OS) in advanced melanoma with 15% complete responses (CR) in treatment-naïve patients (pts) with brain metastases (met) in the anti-PD1/anti-CTLA4 combination. However, data on brain-met pts who discontinue treatment (EoT) after achieving a CR are lacking. Methods: Disease characteristics and clinical outcome were retrospectively collected from 6 centers on advanced melanoma pts treated with anti-PD1 or anti-PD1/anti-CTLA4. Pts were followed for at least 10 weeks (10.8 – 242). Off-treatment survival (OTS) was defined as time between last IT dose to disease progression or death. Results: Out of 890 pts, 62 achieved a CR; 40 pts stopped treatment due to CR, while 22 due to an adverse event (AE) (n = 19) or investigator decision (n = 3) with subsequent CR. 14 were treated with anti-PD1/anti-CTLA4 and 48 with anti-PD1. 24 had a BRAF mutation, of which 10 had previously received targeted therapy (TT). The median time to first CR was 31 weeks (6 – 138), median duration of response and OTS was 91.1 and 60.7 (10.6 – 242) weeks respectively. OTS was numerically longer for those pts with EoT after AE (85 weeks, 13-242) versus those with EoT due to CR (60 weeks, 11-130). Median OS was not reached. 6/62 (3%) progressed after EoT; 4 locoregionally while 2 were subsequently treated with IT. All pts were alive at last follow-up. 19 pts had brain mets. 8 were BRAF mutated. 10 were treatment naïve, 6 received previously anti-CTLA4, 1 chemotherapy and only 2 TT. Data on reasons for EoT and responses in brain mets are seen in the table. Conclusions: Early data suggest that OTS is numerically longer in patients with EoT due to AE with subsequent CR. EoT due to sustained CR is a feasible option also in brain mets. EoT due to AE with subsequent CR was a more frequent event in the combination treatment. [Table: see text]

Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.

9571 Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR≥2 to NLR≥5) with NLR≥5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR≥1 (ORR 64%), NLR≥2 (ORR 61%), NLR≥3 (ORR 52%), NLR≥4 (ORR 43%), NLR≥5 (ORR 43%). Elevated NLR ( < 5 vs. ≥5) was associated with poorer PFS (median 21.5 mths vs. 5.2 mos; p = 0.00041) and OS (median 35.4 os vs. 10.6 mos; p < 0.0001). In a multivariate model, elevated NLR ( < 5 vs. ≥5) was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR≥3 to NLR≥5), although NLR≥5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade.

Immunological impact of canerpaturev (C-REV, formerly HF10), an oncolytic viral immunotherapy, with or without ipilimumab (Ipi) for advanced solid tumor patients (pts).

2610 Background: C-REV, an oncolytic, spontaneous mutant of Herpes Simplex Virus type 1 (HSV-1), is a cancer immunotherapy agent that combine direct tumor cell killing with immune modulation. A phase I study for solid tumors with cutaneous and/or superficial lesions treated with C-REV monotherapy and a phase II study for unresectable or metastatic melanoma treated with C-REV and Ipi combination therapy were conducted. Immune status of cancer pts before and after administration of C-REV with/without Ipi has been unclear. Methods: A phase I study (n = 6) included solid tumor pts with cutaneous and/or superficial lesions treated with C-REV monotherapy (1 x 106 and 1 x 107 TCID50/mL/dose; 4 injections q2-4wk). In phase II study (n = 28), C-REV (1 x 107 TCID50/mL/dose; 4 injections q1wk; then up to 15 injections q3wk) was injected into each tumor for advanced melanoma pts. Four Ipi infusions (3 mg/kg) were administered at q3wk. Immune-monitoring was conducted before and after treatment in tumor microenvironment usingpaired biopsy samples by multiplex immunohistochemistry (mIHC) and in peripheral blood by flow cytometry (FCM). Results: In the phase I study, significant infiltrations of CD8+and CD4+ T cells were observed at tumor local site statistically in three pts (60%) among five pts. In the phase II study, FCM of peripheral blood (n = 10) showed that the responders (irSD, n = 7, 70%) tend to express the higher levels of ICOS on CD4+ T cells as a pharmacodynamic biomarker of ipi monotherapy reported previously (Ng Tang D, et al. Cancer Immunol Res. 2013) and lower levels of PD-L1 on monocyte after two months of treatment. Moreover, mIHC analysis of paired tumor biopsy samples (n = 11) revealed that five pts (45%) among 11 pts were confirmed persistent infection of C-REV at the injected site by qPCR. Disease control rate of pts with the virus DNA detected on Days 85/169 was higher than that without it (100% [n = 5, irPR; 1, irSD; 4] vs. 33% [n = 6, irSD; 2, irPD; 4]). Furthermore, median OS of pts with or without the DNA detected was 342 or 251 days respectively. Conclusions: Our results suggest C-REV injection in the tumor local site have potential to enhance systemic immune response of Ipi. Clinical trial information: NCT03153085.

Palbociclib (P) in advanced acral lentiginous melanoma (ALM) with CDK4 pathway gene aberrations.

9528 Background: Genetic Aberrations in the CDK4 Pathway occur in 82% of the ALM pts (Clin Cancer Res,2017, 23(22):6946-6957), which is predominant subtype in China. This study is to evaluate the anti-tumor activity of palbociclib, a CDK4/6 inhibitor, in advanced ALM pts with CDK pathway gene aberrations. Methods: In this phase II trial, patients with advanced ALM with CDK pathway gene aberrations (CDK4 or/and CCND1 amplification or/and CDKN2A loss) were treated with palbociclib 125 mg po, d1-21 of 28 day cycles. According to the study design, this trial will be closed if less than 2 patients yield objective response (OR) or stable disease (SD) at a preset 8-week landmark analysis. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Fifteen pts were enrolled from April to Nov 2018. All pts are included in the data analysis for demographics, safety, ORR, PFS and OS. Median age was 54 y (range, 25-74y), 6(40%) were males,5( 33.3%) had the primary sites of subungual, 4(26.7%) were of stage III. Median numbers of prior therapies: 2 (range: 0-5). Three (20.0%) pts achieved tumor shrinkage at 8 wks, including 1 confirmed partial responses (PR). Two pts had treatment ongoing at the data cutoff (January 2019). Median PFS was 2.5m (range, 1.5-8.8m), estimated mean OS was 8.1m (range, 6.7-9.4m). Four pts deceased due to disease progression. The most common treatment related adverse events (TRAEs) were leukopenia/neutropenia (87%; G3, 33%), thrombocytopenia (27%; G3, 7%), anemia (40%; G3, 7%). Conclusions: Monotherapy with palbociclib demonstrated preliminary activities in advanced melanoma pts with CDK pathway gene aberrations. Therefore, the study met its primary endpoint. Palbociclib had an acceptable safety profile as previous studies. Combination of CDK4/6 inhibitor with other agents is under consideration. Clinical trial information: NCT03454919.

Association of baseline body mass index (BMI) with response and survival in patients (Pts) with advanced melanoma (MEL) receiving PD-1 inhibitors.

9579 Background: Obesity promotes PD-1–mediated T cell dysfunction but also improves tumor response to PD-1 blockade. Obesity has been linked with positive outcomes in pts treated with PD-1 blockade. To evaluate the prognostic utility of BMI, we performed a retrospective evaluation of BMI and other covariates in 172 pts with stage IV cutaneous MEL. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. BMI was defined based on values at the first treatment date and dichotomized into two groups: ≥30 vs. < 30. Fisher exact test was used to evaluate the correlation between BMI group and ORR. Kaplan Meier method and Cox proportional hazard models were performed to analyzed the time-to-event outcomes (OS and PFS). Results: 172 pts with advanced MEL were evaluated. Greater BMI was associated with greater ORR, PFS and OS across various BMI cutoffs (BMI≥28, BMI≥30 and BMI≥35) although this effect was most obvious at BMI≥30. Pts with BMI≥30 achieved higher ORR than those with BMI < 30 (74% vs. 58%, p-value = 0.04). Concordantly, pts with BMI≥30 had improved PFS and OS: median PFS (BMI≥30 21.1 mos vs. BMI < 30 10.7 mos) and median OS (BMI≥30 35.4 mos vs. BMI < 30 22.8 mos). Higher BMI was independently associated with improved OS (p = 0.018) and PFS (p = 0.047) adjusting for age, Breslow thickness and sex. No significant interaction was observed between the effects of BMI and that of age, sex, or Breslow thickness. Conclusions: Increased BMI was associated with greater ORR in addition to previously reported associations with PFS/OS in a large retrospective series of advanced MEL pts treated with PD-1 blockade. This data was independent of other prognostic factors and underscore the “inflammaging” effects of obesity and age in relation to anti PD-1 therapy in advanced cancer.

Association of medication (Med) and antibiotic (Abx) use with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.

9572 Background: Retrospective studies suggest that various med could dichotomous effects in regards to immunotherapy. These include adverse (antibiotics) and positive (aspirin, beta-blockers) influences. To evaluate potential additive or detrimental effects of various med in patients (pts) receiving PD-1 immunotherapy, we performed a retrospective evaluation of med intake in 172 pts with stage IV cutaneous MEL focusing on aspirin (asp), antacid (ant), antibiotic (abx), bisphosphonate (bisp), metformin (met) and statin (stat) intake. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Med intake was documented based on chart review in all pts. Intake was confirmed by analyzing at least one other note from a non-oncological provider. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how categorical variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mths). Results: 172 pts with advanced MEL were evaluated. Asp, ant, abx, bisp, met and stat use was documented in 62, 82, 29, 4, 15 and 57 pts respectively. ORR was not significantly related to intake of asp, ant, bisp, met and stat use; although ORR was lower in pts who received abx (p=0.0328). There was no significant difference in PFS and OS in pts who received asp, ant, bisp, met and stat. In patients who received abx compared to those who did not, median PFS (16.6 mths vs. 19.8 mths) and median OS (23.8 mths vs. 35.4) were both lower. Abx use did not interact with other meds. Conclusions: In this retrospective series of advanced MEL pts treated with PD-1 blockade, abx use was adversely associated with response to PD-1 blockade. Abx use was also associated with poorer PFS and OS. Conversely, neither a positive nor negative association with ORR, PFS and/or OS was seen with asp, ant, bisp, met and stat use. These results validate prior studies suggesting that abx use is associated with worse outcomes in pts receiving PD-1 blockade possibly by mediating intestinal dysbiosis.

Efficacy and genetic analysis for a phase II multicenter trial of HF10, a replication-competent HSV-1 oncolytic immunotherapy, and ipilimumab combination treatment in patients with stage IIIb-IV unresectable or metastatic melanoma.

9541 Background: HF10, a bioselected replication-competent oncolytic virus derived from HSV-1, has been evaluated in combination with ipilimumab (ipi) in a Phase II trial (NCT02272855) in unresectable/unresected Stage IIIB-IV melanoma pts. Herein we report the recent efficacy and gene expression findings correlating with responders. Methods: HF10 injected into single or multiple tumors (1 x 107 TCID50/mL/dose, up to 5mL depending on tumor size and numbers); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Evaluation of correlative studies (nCounter PanCancer Immune Profiling Panel) including tumor biopsy was performed at baseline and on Days 85 and 169. Results: 46 pts were enrolled and treated: 59% men, median age 67 yrs (range 28 to 91); disease stage 20% IIIB, 43% IIIC and 37% IV; 57% were treatment naïve and 43% with ≥ 1 prior cancer therapy for unresectable/metastatic melanoma. HF10+ipi combination was well tolerated. HF10 adverse event (AE) profile was similar in combination with ipi as in HF10 monotherapy. 28.3% pts had treatment-related ≥G3 AEs, and the majority of ≥G3 AEs were due to ipi. Of the 44 efficacy evaluable pts, irRC BORR at 24 weeks was 41% (18% irCR and 23% irPR); disease stability rate was 68% (27% irSD). As of Feb 07, 2018, median PFS was 19 months and median overall survival was 26 months. Responding tumors exhibited an activation of the adaptive immune response with increased total tumor infiltrating lymphocytes and CD8+ T-cells, and decreased CD4+ T-cells. Conclusions: The combination HF10 and ipilimumab treatment demonstrated a favorable benefit/risk profile and encouraging antitumor activity in advanced melanoma pts by inducing immune-cell infiltration in the tumor microenvironment. Clinical trial information: NCT02272855.

Discontinuation of anti-PD-1 mAb after complete response in advanced melanoma pts.

e21549Background: Anti-PD-1 mAb represent a backbone of advanced melanoma therapy, but information on their duration and outcomes after cessation are scarce outside the KEYNOTE-001 pembrolizumab (P...

Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.

3014 Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 108 TCID50CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. Clinical trial information: NCT02307149.