There is no consensus on the optimal treatment duration of anti‐PD‐1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti‐PD‐1 discontinuation, the association of ...treatment duration with progression and anti‐PD‐1 re‐treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first‐line anti‐PD‐1 monotherapy in the absence of progressive disease (n = 324). Survival was estimated after anti‐PD‐1 discontinuation and with a Cox model the association of treatment duration with progression was assessed. At the time of anti‐PD‐1 discontinuation, 90 (28%) patients had a complete response (CR), 190 (59%) a partial response (PR) and 44 (14%) stable disease (SD). Median treatment duration for patients with CR, PR and SD was 11.2, 11.5 and 7.2 months, respectively. The 24‐month progression‐free survival and overall survival probabilities for patients with a CR, PR and SD were, respectively, 64% and 88%, 53% and 82%, 31% and 64%. Survival outcomes of patients with a PR and CR were similar when anti‐PD‐1 discontinuation was not due to adverse events. Having a PR at anti‐PD‐1 discontinuation and longer time to first response were associated with progression hazard ratio (HR) = 1.81 (95% confidence interval, CI = 1.11‐2.97) and HR = 1.10 (95% CI = 1.02‐1.19; per month increase). In 17 of the 27 anti‐PD‐1 re‐treated patients (63%), a response was observed. Advanced melanoma patients can have durable remissions after (elective) anti‐PD‐1 discontinuation.
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Reasons for discontinuing treatment with the anti‐PD‐1 antibodies nivolumab and pembrolizumab can vary significantly among melanoma patients. Moreover, the optimal treatment duration for these drugs remains unclear. In this observational study on anti‐PD‐1 discontinuation, most patients with advanced melanoma who had complete or partial response at anti‐PD‐1 discontinuation experienced ongoing response, with potential survival benefits. Shorter time to first response of anti‐PD‐1 monotherapy and partial response at discontinuation were associated with later progression of disease. Elective discontinuation, by contrast, was linked to a reduced likelihood of subsequent progression. Anti‐PD‐1 retreatment exhibited clinical activity against melanoma, warranting further investigation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We conducted a population-based study to establish the incidence, treatment and overall survival over time of patients with small bowel adenocarcinoma.
All patients diagnosed with small bowel ...adenocarcinoma in the Netherlands between 1999 and 2013 were included (n = 1775). Age-standardized incidence rates were calculated per 100 000 person-years using the European standardized population rate. The influence of patient and tumor characteristics on the administration of chemotherapy was analyzed by means of a multivariable logistic regression analysis. The Cochran-Armitage trend test was conducted to evaluate trends in treatment and survival and the Cox proportional hazards model was used to identify prognostic factors of overall survival.
The incidence of small bowel adenocarcinomas increased, mainly due to an almost twofold increase of duodenal adenocarcinomas. Patients with locoregional duodenal tumors were less likely to undergo surgery (58%), towards 95% of the locoregional jejunal and ileal tumors (p < 0.0001). The use of chemotherapy doubled for adjuvant (7-15%) and palliative chemotherapy (19-37%). Median overall survival of patients with locoregional disease increased from 19 to 34 months (p = 0.0006), whereas median overall survival of patients with metastatic disease remained 4-5 months. Favorable prognostic factors for prolonged survival in locoregional disease, identified by multivariable survival analysis, included age <60 years, tumor stage I or II, diagnosis in 2009-2013, surgical treatment and chemotherapy. Favorable prognostic factors for prolonged survival in metastatic disease were age <50 years, jejunal tumors, surgical treatment and chemotherapy.
Small bowel adenocarcinomas are rare tumors with an increasing incidence. The administration of adjuvant and palliative chemotherapy doubled, but median overall survival only increased for patients with locoregional disease. Given the rarity and dismal prognosis, it is important to develop international studies to determine the optimal treatment for these patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cutaneous melanoma is a common type of cancer in Adolescents and Young Adults (AYAs, 15–39 years of age). However, AYAs are underrepresented in clinical trials investigating new therapies and the ...outcomes from these therapies for AYAs are therefore unclear. Using prospectively collected nation-wide data from the Dutch Melanoma Treatment Registry (DMTR), we compared baseline characteristics, mutational profiles, treatment strategies, grade 3–4 adverse events (AEs), responses and outcomes in AYAs (n = 210) and older adults (n = 3775) who were diagnosed with advanced melanoma between July 2013 and July 2018. Compared to older adults, AYAs were more frequently female (51% versus 40%, p = 0.001), and had a better Eastern Cooperative Oncology Group performance status (ECOG 0 in 54% versus 45%, p = 0.004). BRAF and NRAS mutations were age dependent, with more BRAF V600 mutations in AYAs (68% versus 46%) and more NRAS mutations in older adults (13% versus 21%), p < 0.001. This finding translated in distinct first-line treatment patterns, where AYAs received more initial targeted therapy. Overall, grade 3–4 AE percentages following first-line systemic treatment were similar for AYAs and older adults; anti-PD-1 (7% versus 14%, p = 0.25), anti-CTLA-4 (16% versus 33%, p = 0.12), anti-PD-1 + anti-CTLA-4 (67% versus 56%, p = 0.34) and BRAF/MEK-inhibition (14% versus 23%, p = 0.06). Following anti-CTLA-4 treatment, no AYAs experienced a grade 3–4 colitis, while 17% of the older adults did (p = 0.046). There was no difference in response to treatment between AYAs and older adults. The longer overall survival observed in AYAs (hazard ratio (HR) 0.7; 95% CI 0.6–0.8) was explained by the increased cumulative incidence of non-melanoma related deaths in older adults (sub-distribution HR 2.8; 95% CI 1.5–4.9), calculated by competing risk analysis. The results of our national cohort study show that baseline characteristics and mutational profiles differ between AYAs and older adults with advanced melanoma, leading to different treatment choices made in daily practice. Once treatment is initiated, AYAs and older adults show similar tumor responses and melanoma-specific survival.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
OBJECTIVES:To investigate the effect of preoperative chemoradiotherapy on surgical complications in patients after pancreatic resection for (borderline-)resectable pancreatic cancer.
SUMMARY OF ...BACKGROUND DATA:Preoperative chemoradiotherapy is increasingly used in patients with (borderline-)resectable pancreatic cancer. Concerns have been raised about the potential harmful effect of any preoperative therapy on the surgical complication rate after pancreatic resection.
METHODS:An observational analysis was performed within the multicenter randomized controlled PREOPANC trial (April 2013–July 2017). The trial randomly assigned (1:1) patients to preoperative chemoradiotherapy followed by surgery and the remaining adjuvant chemotherapy or to immediate surgery, followed by adjuvant chemotherapy. The main analysis consisted of a per-protocol approach. The endpoints of the present analyses were the rate of postoperative complications.
RESULTS:This study included 246 patients from 16 centers, of whom 66 patients underwent resection after preoperative therapy and 98 patients after immediate surgery. No differences were found regarding major complications (37.9% vs 30.6%, P = 0.400), postpancreatectomy hemorrhage (9.1% vs 5.1%, P = 0.352), delayed gastric emptying (21.2% vs 22.4%, P = 0.930), bile leakage (4.5% vs 3.1%, P = 0.686), intra-abdominal infections (12.1% vs 10.2%, P = 0.800), and mortality (3.0% vs 4.1%, P = 1.000). There was a significant lower incidence of postoperative pancreatic fistula in patients who received preoperative chemoradiotherapy (0% vs 9.2%, P = 0.011).
CONCLUSIONS:Preoperative chemoradiotherapy did not increase the incidence of surgical complications or mortality and reduced the rate of postoperative pancreatic fistula after resection in patients with (borderline-)resectable pancreatic cancer.
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Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study to evaluate pembrolizumab (pembro) in mCRPC. A previous analysis of patients with RECIST-measurable (cohort 4 ...C4) or bone-predominant nonmeasurable (cohort 5 C5) disease who were chemotherapy-naive and had progression while on enzalutamide (enza) found that pembro + enza showed antitumor activity and manageable safety. Long-term outcomes are of interest with immunotherapy; hence, updated efficacy and safety data after an additional 1 year of follow-up are presented. Methods: Pts were eligible if they had resistance to enza after prior response. Prior treatment with abiraterone was allowed. Pts received pembro 200 mg Q3W for up to 35 cycles + enza QD until progression, unacceptable toxicity, or withdrawal. Primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR) in C4. Secondary end points were DOR (C4), and DCR, rPFS, OS and safety (both cohorts). Results: 126 pts (C4, 81; C5, 45) were treated. Median age was 72 years (range 43-92), 32.5% had visceral disease and 87.3% previously received ≥6 mo of enzalutamide; 121 pts (96.0%) discontinued, most because of progressive disease. Median (range) time from enrollment to data cutoff was 31.7 mo (23.1-37.1) in C4 and 35.5 mo (22.9-37.3) in C5. In C4, confirmed ORR was 12.3% (95% CI 6.1-21.5) (2 CRs, 8 PRs); median (range) DOR was 8.1 mo (2.5+ to 15.2), and 62.5% had a response ≥6 mo (Kaplan-Meier estimate). Additional efficacy analyses are outlined in the table. A total of 27.2% and 28.9% of pts in C4 and C5, respectively, experienced grade ≥3 treatment-related adverse events. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any-grade (34.1%) and grade 3 or 4 (5.6%) rash, regardless of relatedness to treatment, was higher than previously reported for individual agents but manageable with standard-of-care treatments; 2 pts discontinued because of rash. Conclusions: After an additional 1 year of follow-up, pembro + enza continued to show antitumor activity and a manageable safety profile in pts with mCRPC who became resistant to enza. The treatment combination is being further evaluated in the ongoing phase 3 KEYNOTE-641 trial (NCT03834493). Clinical trial information: NCT02787005. Table: see text
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