Collichio, Frances A.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor. Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 10 6 plaque-forming units (PFU)/mL in week 1, followed by 10 8 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported. At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297 .

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

10029 Background: This is the first randomized trial testing the addition of an oncolytic virus to an immune checkpoint inhibitor for advanced melanoma. At the 3-year (yr) follow-up, the combination (combo) of T-VEC and ipi demonstrated durable and statistically superior objective response rate (ORR) over ipi alone (36.7% vs. 16.0%; odds ratio, 3.0; 95% Cl, 1.6–6.0; P = 0.002). Complete response (CR) rate was 21.4% with the combo and 6.0% with ipi. Median overall survival (OS) was not reached in either arm. In this post hoc analysis, we utilized the 3-yr landmark data to explore the relationship between CR and OS in the combo arm. Methods: Pts with unresectable, stage IIIB-IV melanoma were randomized 1:1 to receive combo or ipi alone. T-VEC was administered intratumorally on day 1 of week (wk) 1 at 106 plaque-forming units (PFU)/mL followed by subsequent doses at 108 PFU/mL on day 1 of wk 4, and every 2 wks thereafter. Ipi (3 mg/kg) was given every 3 wks starting on day 1 of wk 6 for up to 4 doses. Response was assessed by investigators per immune-related response criteria every 12 wks until disease progression. The primary endpoint was ORR; key secondary endpoints were OS, progression-free survival, and safety. Results: 198 pts were randomized (98 to combo; 100 to ipi). As of February 25, 2019, the median follow-up time was 40.0 mos (range: 0.2–63.7) for the combo arm. Among 98 pts who received combo, 21 (21.4%) had a best overall response of CR including 8 who converted from an initial partial response (PR), 15 (15.3%) had PR, 19 (19.4%) had stable disease, 30 (30.6%) had progressive disease, and 13 (13.2%) were unevaluable. Of 21 pts achieving CR, 17 (81%) had ECOG status of 0, 16 (76.2%) had stage IIIB-IVM1a disease, and 16 (76.2%) had no visceral metastases. Median duration of CR was not reached (range: 5.4[+]–58.2[+] mos); 19 of 21 CRs lasted more than 6 months. The baseline tumor burden was lower in pts with CR than in those with non-CR. Median OS was not reached in pts with CR (range: 25.1[+]–63.7[+] mos) and was 47.6 mos (range: 0.2[+]– 63.7[+] mos) in pts with non-CR (Log-rank P = 0.0005). The Kaplan–Meier estimated 3-year OS rate was 100.0% for patients with CR and 52.3% for those with non-CR. Conclusions: CR rate was higher with T-VEC plus ipi than with ipi alone in pts with advanced melanoma (21.4% vs. 6.0%). In the combo arm, CR was associated with prolonged OS, and pts with CR tended to have better ECOG performance status, earlier-stage disease, and lower baseline tumor burden, as compared with those with non-CR. Clinical trial information: NCT01740297.

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 6 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 8 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Purpose To evaluate the career plans, professional expectations, and well-being of oncology fellows compared with actual experiences of practicing oncologists. Methods US oncology fellows taking the 2013 Medical Oncology In-Training Examination (MedOnc ITE) were invited to participate in an optional postexamination survey. The survey evaluated fellows' career plans and professional expectations and measured burnout, quality of life (QOL), fatigue, and satisfaction with work-life balance (WLB) using standardized instruments. Fellows' professional expectations and well-being were compared with actual experiences of US oncologists assessed simultaneously. Results Of the 1,637 oncology fellows in the United States, 1,373 (83.9%) took the 2013 MedOnc ITE. Among these, 1,345 (97.9%) completed the postexamination survey. The frequency of burnout among fellows decreased from 43.3% in year 1 to 31.7% in year 2 and 28.1% in year 3 (P < .001). Overall, the rate of burnout among fellows and practicing oncologists was similar (34.1% v 33.7%; P = .86). With respect to other dimensions of well-being, practicing oncologists had lower fatigue (P < .001) and better overall QOL scores (P < .001) than fellows but were less satisfied with WLB (P = .0031) and specialty choice (P < .001). Fellows' expectations regarding future work hours were 5 to 6 hours per week fewer than oncologists' actual reported work hours. Levels of burnout (P = .02) and educational debt (P ≤ .004) were inversely associated with ITE scores. Fellows with greater educational debt were more likely to pursue private practice and less likely to plan an academic career. Conclusion Oncology fellows entering practice trade one set of challenges for another. Unrealized expectations regarding work hours may contribute to future professional dissatisfaction, burnout, and challenges with WLB.