Rechallenge Group Research Articles

Overall Survival, Treatment Duration, and Rechallenge Outcomes With ICI Therapy for Recurrent or Metastatic HNSCC

Immune checkpoint inhibition (ICI) is a frontline treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but questions remain surrounding optimal duration of therapy, benefits and risks of ICI rechallenge, and efficacy in first vs subsequent lines of therapy. To estimate survival in US patients receiving ICI-based treatment for R/M HNSCC, compare outcomes associated with treatment discontinuation vs continuation at 1 or 2 years, and assess outcomes after immunotherapy rechallenge. This retrospective, population-based cohort study included adult patients in the Flatiron Health nationwide oncology database treated with immunotherapy for R/M HNSCC from 2015 to 2023. Data cutoff was August 31, 2023; data analysis was conducted from December 2023 to February 2024. Treatment continuation vs discontinuation at 1 and 2 years; rechallenge with ICI after at least a 60-day period off ICI therapy without intervening systemic treatment (immediate rechallenge), or with intervening systemic treatment (delayed rechallenge). Overall survival (OS) from ICI initiation was analyzed using the Kaplan-Meier method. Cox multivariable regression was used to examine associations of key variables (line of therapy, human papillomavirus [HPV] status, Eastern Cooperative Oncology Group [ECOG] performance status) with survival. The cohort included 4549 patients with R/M HNSCC who received ICI-containing therapy (median [IQR] age, 66 [59-72] years; 3551 [78.1%] male; 56 [1.2%] Asian, 260 [5.7%] Black or African American, 3020 [66.4%] White, 1213 [26.7%] other or unknown race; 3226 [70.9%] ECOG performance status 0 or 1). There were 3000 patients (65.9%) who received ICI in frontline and 1207 (26.5%) in second line; 3478 patients (76.5%) received ICI monotherapy. Median (IQR) OS was 10.9 (4.1-29.1) months and was longer in patients who received ICI in frontline therapy (12.2 [4.8-32.0] vs 8.7 [3.2-22.4] months), had HPV-positive cancer (16.6 [6.5-43.9] vs 8.8 [3.5-24.0] months), and had ECOG performance status 0 or 1 (13.5 [5.2-33.9] vs 5.5 [2.0-13.7] months). There were no survival differences on adjusted analysis between patients who stopped vs those who continued ICI at 1 or 2 years. Median (IQR) OS after ICI rechallenge was 15.7 (13.7-21.9) months in the immediate rechallenge group and 9.9 (3.7-18.1) months in the delayed rechallenge group. In this large cohort study of patients with R/M HNSCC receiving ICI-based therapy, survival estimates closely mirrored clinical trial results, both in frontline and later-line settings. Discontinuation of ICI in long-term responders at 1 or 2 years may be a reasonable strategy that does not appear to compromise survival. ICI rechallenge was associated with clinical benefit in a subset of patients.

Efficacy and safety analysis of immune checkpoint inhibitor rechallenge therapy in locally advanced and advanced non-small cell lung cancer: a retrospective study.

Immune checkpoint inhibitors (ICIs) have dramatically changed the first-line treatment pattern of non-small cell lung cancer (NSCLC) without driver gene alterations. However, the optimal choice for second-line treatment after initial treatment with ICIs is unclear. This study aimed to clarify the efficacy and safety of ICI rechallenge therapy in locally advanced and advanced NSCLC. We retrospectively analyzed the histories of 224 patients with locally advanced or advanced NSCLC treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy and/or antiangiogenic therapy in first-line treatment. Progression-free survival 2 (PFS2) was the time from the first defined progress disease (PD) to the second disease progression or death. Efficacy evaluation was performed directly in accordance with RECIST v1.1 criteria. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Survival data were estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test in overall cohort and other subgroups. There were no significant differences in objective response rate (ORR) and median PFS2 (mPFS2) between the ICI rechallenge group and non-rechallenge group (ORR: 10.3% vs. 15.3%, P=0.308; mPFS2: 5.33 vs. 4.40 months, P=0.715). And the ICI rechallenge group showed no new safety signals compared with non-rechallenge group. In ICI rechallenge group, patients resistant to first-line immunotherapy had a lower ORR and shorter PFS2 compared with those who responded to initial ICIs treatment (ORR: 7.0% vs. 17.6%, P=0.038; mPFS2: 3.68 vs. 5.91 months, P=0.014). No significant difference in mPFS2 was observed among different second-line treatment groups (P=0.362). Radiotherapy in second-line treatment and ICI rechallenge therapy were not the main factors affecting PFS2. ICI rechallenge therapy beyond disease progression did not improve clinical outcomes in patients with NSCLC, but no new safety signals emerged. However, patients with favorable response to initial ICIs treatment still showed significant efficacy of subsequent ICI rechallenge therapy.

Trifluridine/tipiracil (TAS-102) in combination with anti-EGFR re-challenge versus TAS-102 plus anti-VEGF in patients with mCRC who experienced first-line anti-EGFR-based chemotherapy.

120 Background: TAS-102 is one of the standard treatments for refractory metastatic colorectal cancer (mCRC). Add-on bevacizumab to TAS-102 has been proved to improve progression-free survival (PFS) and overall survival (OS). However, the two strategies of combination with anti-EGFR or anti-VEGF in RAS/RAF wild-type mCRC patients have not been compared. Methods: We retrospectively collected mCRC patients who received TAS-102 treatment from December 2018 to March 2023 at National Taiwan University Hospital. The key inclusion criteria included RAS/RAF wild-type, first-line treatment with anti-EGFR therapy, and TAS-102 in combination with anti-EGFR re-challenge, or with anti-VEGF therapy. Concurrent use of other chemotherapies was allowed. The patients with combination duration less than 4 weeks were excluded. Results: A total of 30 patients were enrolled. There were 20 patients who received TAS-102 plus anti-EGFR re-challenge, and 10 were treated with TAS-102 plus anti-VEGF. The median treatment line of TAS-102 combined with targeted therapies was 5 (Range 3-11). There was no significant difference in baseline characteristics between the two groups (Table). For TAS-102 plus anti-EGFR vs VEGF, the ORR was 30.0% vs 0%, and the DCR was 70.0% vs 30.0%, respectively. The median PFS was 4.0 vs 2.3 (p=0.389) months, respectively. The median OS was 12.67 vs 9.93 (p=0.722) months, respectively. Conclusions: TAS-102 plus anti-EGFR re-challenge showed a higher ORR than TAS-102 plus anti-VEGF. The PFS and OS were comparable in both arm and numerically longer in the TAS-102 plus anti-EGFR re-challenge group.[Table: see text]

Comparing the efficacy of regorafenib and 5-fluorouracil-based rechallenge chemotherapy in the third-line treatment of metastatic colorectal cancer

BackgroundThe optimal treatment for metastatic colorectal cancer (mCRC) after the second line is still controversial. Regorafenib has been the standard of care in this setting as it improved overall survival (OS) compared to placebo. In real-world practice chemotherapy rechallenge is also a preferred option even though supporting evidence is not enough. We aim to compare the efficacy of regorafenib and 5-fluorouracil-based (5-FU) rechallenge treatment in the third line setting of mCRC.MethodsIn this retrospective multi-institutional trial, mCRC patients from 21 oncology centers who progressed after 2 lines of chemotherapy were analyzed. Patients who were treated with regorafenib or rechallenge therapy in the third-line setting were eligible. Rechallenge chemotherapy was identified as the re-use of the 5-FU based regimen which was administered in one of the previous treatment lines. OS, disease control rate (DCR), progression free survival (PFS) and toxicity were analyzed.ResultsThree hundred ninety-four mCRC patients were included in the study. 128 (32.5%) were in the rechallenge, and 266 (67.5%) were in the regorafenib group. Median PFS was 5.82 months in rechallenge and 4 months in regorafenib arms (hazard ratio:1.45,95% CI, p = 0.167). DCR was higher in the rechallenge group than regorafenib (77% vs 49.5%, respectively, p = < 0.001). Median OS after the third-line treatment was 11.99 (95% CI, 9.49–14.49) and 8.08 months (95% CI, 6.88–9.29) for rechallenge and regorafenib groups, respectively (hazard ratio:1.51, 95% CI, p < 0.001). More adverse effects and discontinuation were seen with regorafenib treatment.ConclusionOur study revealed that higher disease control and OS rates were achieved with rechallenge treatment compared to regorafenib, especially in patients who achieved disease control in one of the first two lines of therapy.

Platinum resistance and sensitivity in recurrent/metastatic head and neck squamous cell carcinoma

ObjectiveFor patients with recurrent/metastatic head and neck squamous cell carcinoma (R/MHNSCC), platinum-free interval (PFI)-based differences in the effectiveness of rechallenge with platinum-based chemotherapy (PBCT) remain unknown. We aimed to evaluate the difference in platinum sensitivity based on PFI in R/MHNSCC. MethodsWe retrospectively examined 80 patients with R/MHNSCC who underwent PBCT between 2001 and 2020. Treatment efficacy was compared between patients with prior PBCT for treatment of recurrence/metastasis or concurrent chemoradiotherapy during radical treatment (rechallenge group) and those without (control group). Patients with prior PBCT (rechallenge group) were stratified by PFI. PFI was defined as the period from the last dosing date with the previous platinum agent to rechallenge with PBCT. ResultsOf 80 patients, 55 had been with prior PBCT (rechallenge group) and 25 had been without prior PBCT (control group).The rechallenge group was divided into three groups: PFI <6 months (10), PFI 6-11 months (17), and PFI ≥12 months (28). The PFI <6-month group had shorter overall survival (p=0.047, the log-rank test) and lower disease control rate (p=0.02, Fisher's exact test) than the control group. The PFI 6–11- and ≥12-month group outcomes did not significantly differ from those of the control group. ConclusionsPatients with PFI <6 months tend to have a poorer prognosis after rechallenge with PBCT than patients without prior PBCT, suggesting that PFI 6 months may be considered as a threshold of platinum resistance and rechallenge with PBCT may be a valid option in PFI ≥6 months.

Results of a retrospective multicenter study comparing the effectiveness of regorafenib and the rechallenge of chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).

e15561 Background: Regorafenib is considered the standard third-line therapy of mCRC. However, the modest efficacy and significant toxicity of regorafenib urges the search for new therapeutic approaches. In various countries, the re-challenge of the previously effective treatment regimens is being considered. We compared the effectiveness of various variants of systemic therapy in the third and subsequent lines of the treatment. Methods: We analyzed the prospective database of pts with mCRC from two clinics of the Russian Federation. The statistical hypothesis implied the equivalence of the 6-month overall survival on the repeated chemotherapy (CT) and targeted therapy with the third line regorafenib therapy, provided the equivalence boundaries from 0.8 to 1.25. With α = 0.05, the study power is 80% with 178 patients, 89 people in each group. We conducted statistical analysis with the SPSS statistical software package (v. 20, IBM). Results: In the database, we identified 215 patients with morphologically confirmed metastatic colon cancer who received two or more lines of antitumor drug therapy from 2010 to 2021. Of them, we selected 132 patients with a history of regorafenib therapy, and 83 patients with the re-challenge of CT as the third line of the therapy. Overall survival (OS) in the re-challenge and regorafenib groups did not differ (hazard ratio [HR] 1.01 with 95%CI 0.7-1.45; p = 0.9) and the 6-month OS was 74 and 70%, respectively. Progression-free survival was significantly higher in the re-challenge group (HR 1.94 with 95%CI 1.3-2.7; p &lt; 0.001); In the multifactorial analysis, the re-challenge of previous treatment regimens kept its independent positive effect on progression-free survival (HR 1.9 with 95%CI 1.3-2.8; p = 0.0001) also as index T &lt; 3 (HR 0.7, 95CI 0.55-0,94); ECOG ≥1 a (HR 1.5 with 95%CI 1.16-2.05; p &lt; 0.01) affected PFS negatively. The reduction of the regorafenib dose did not affect PFS (HR 0.9 with 95% CI from 0.9 to 1.0; p = 0.1), its starting dose (HR 0.9 with 95 CI from 0.9 to 1.0; p = 0.2), and a break in the regorafenib treatment (HR 0.9 with 95% CI from 0.5 to 1.8; p = 0.9). Conclusions: Regorafenib and the re-challenge of previously effective CT in the third-line of mCRP therapy show the similar 6-mon. OS. However, progression-free survival is significantly higher in the re-challenge group in third line therapy.

Efficacy, prognosis and safety analysis of anti-PD-1/PD-L1 inhibitor rechallenge in advanced lung cancer patients: a cohort study.

BackgroundThe rechallenge of immune checkpoint inhibitors (ICI) is now an optional strategy for patients who discontinued ICI due to immune-related adverse events (irAEs) or disease progression. However, little data is available for the prognosis and prognostic factors of patients receiving ICI rechallenge treatment in advanced lung cancer patients. Our study aimed to explore the efficacy, prognosis and safety of patients who received anti-programmed cell death-1/programmed cell death ligand 1 (anti-PD-1/PD-L1) inhibitor rechallenge.MethodsIn our retrospective cohort study, data of advanced lung cancer patients who received anti-PD-1/PD-L1 inhibitor and discontinued due to irAEs or disease progression were collected from December 2016 to August 2021. Enrolled patients were categorized into two groups: rechallenge group (R group) and non-rechallenge group (NR group). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety data were analyzed. Cox model and subgroup analysis were analyzed according to baseline characteristics, ICI type, the reason for discontinuing ICI, etc. According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), evaluation was performed routinely every 6–8 weeks after initiating treatment with the PD-1/PD-L1 inhibitor. The last follow-up in the study was on September 20, 2021.ResultsEighty-one patients who met our inclusion criteria were enrolled. In the whole cohort, the R group achieved better OS than the NR group [hazard ratio (HR) =0.176; 95% confidence interval (CI): 0.065–0.477; P=0.001). In the irAEs group, the survival analyses showed a trend toward improved OS in the rechallenge subgroup (HR =0.287; 95% CI: 0.081–1.025; P=0.055), and a promising DCR of 75% after an ICI rechallenge. Additionally, the exploration of safety outcomes indicated an acceptable recurrence rate (22.5%) of irAEs and an early onset of irAEs after an ICI rechallenge. In the disease progression group, the rechallenge subgroup did not improve OS (HR =0.214; 95% CI: 0.027–1.695; P=0.144), and the DCR of the rechallenge subgroup was 40% after ICI rechallenge.ConclusionsICI rechallenge might be an attractive option for patients who discontinue treatment due to irAEs. For patients with disease progression, further research should be conducted. The recurrence of irAEs and their early onset during the second round of ICI should be considered.

Clinical Outcomes after Clozapine Discontinuation in Patients with Schizophrenia: A Systematic Review.

Clozapine is the gold standard of treatment for patients with treatment-resistant schizophrenia. However, approximately 60% of those patients do not respond to clozapine; moreover, clinical outcomes after clozapine discontinuation are unclear so far. Therefore, we conducted a systematic review to clarify the outcomes after clozapine discontinuation. A systematic literature search was conducted, using MEDLINE and Embase with the following keywords: (clozapine AND (cessation* OR cease* OR withdraw* OR discontinu* OR halt* OR stop* OR switch*) AND (schizophreni* OR schizoaffective)). A total of 28 clinical studies from 27 articles were identified and included in this systematic review. Three randomized controlled trials reported worsening of psychiatric symptoms. In 10 single-arm studies, the results of worsening and improving psychiatric symptoms were inconsistent. In one large retrospective cohort study, clozapine rechallenge, olanzapine, and antipsychotic polypharmacy had lower rehospitalization rates compared to no medication after clozapine discontinuation. In the other 14 retrospective studies, the vast majority showed worsening of clinical status after clozapine discontinuation. Among five studies on clinical outcomes after clozapine rechallenge, four reported improvements in clinical status in more than half of patients who rechallenged clozapine. The remaining study reported that the clozapine discontinuation-rechallenge group had a worse remission assessment score than the clozapine discontinuation-no rechallenge group. Clinical outcomes generally worsen after clozapine discontinuation. Clozapine rechallenge and olanzapine may be considered following clozapine discontinuation. The outcomes after clozapine discontinuation in clozapine non-responders remain inconclusive; therefore, well-designed studies are warranted.

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma

BackgroundIn the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I–V and of grade III–V immune-related adverse events (irAEs) was 37% and 7%, respectively. MethodsPatients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. ResultsAt the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over (‘crossover’). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 (‘rechallenge’).In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7–15.2) and the 3-year PFS rate was 32% (95% CI 25–40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48–83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6–NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I–IV irAE and 11 (6%) had a grade III–IV irAE. ConclusionsPembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.

Docetaxel Rechallenge Improves Survival in Patients With Metastatic Castration-resistant Prostate Cancer: A Retrospective Study.

Docetaxel has been widely used in metastatic Castration-resistant Prostate Cancer (mCRPC) patients for decades. The purpose of the study was to evaluate the efficacy of docetaxel rechallenge in patients with mCRPC. We retrospectively compared patients who had received either first-line docetaxel and rechallenge after Androgen Receptor-axis Targeted therapies (ARAT), to those without rechallenge docetaxel. Multivariate cox-regression analysis was used to evaluate survival. Out of the 204 patients with mCRPC enrolled in the study, 24 patients received docetaxel rechallenge and 180 did not. The median overall survival was 50.11 months in the rechallenge group, as compared to 26.36 months in the non-rechallenge group (p of log rank=0.044). In the multivariate model, doxetaxel rechallenge was an independent risk factor for overall survival [hazard ratio (HR)=0.59, 95% confidence interval (CI)=0.32-0.99], together with the performance status score 2 (HR=2.46, 95%CI=1.32-4.58), hormone-sensitive state duration (HR=0.99, 95%CI=0.99-0.999), liver (HR=1.90, 95%CI=1.04-3.47) and brain metastases (HR=2.23, 95%CI=1.26-5.46). The advantage of rechallenge was addressed in the androgen receptor-axis-targeted (ARAT) non-responsive patients (HR=0.36, 95%CI=0.17-0.78). Adverse events were at 29.17% with Grade 3/4 neutropenia and at 20.83% with Grade 1/2 neutropenia in the docetaxel rechallenge group. The docetaxel rechallenge improved survival in patients with mCRPC failure of first-line docetaxel and subsequent abiraterone acetate or enzalutamide. Independent predictive factors for overall survival included i) the performance status, ii) hormone-sensitive state duration, iii) liver and iv) brain metastases. Patients non-responsive to ARATs will benefit from docetaxel rechallenge with regards to overall survival.

Is there a role for rechallenge and reintroduction of anti-EGFR plus chemotherapy in later lines of therapy for metastatic colorectal carcinoma? A retrospective analysis

BackgroundMechanisms of resistance have been described during disease progression (PD) for patients under treatment with anti-EGFR plus chemotherapy (CT). The aim of our study was to evaluate efficacy of anti-EGFR rechallenge (ReCH) and reintroduction (ReIn) in metastatic colorectal cancer (mCRC).Materials and methodsThis is a retrospective analysis of patients with mCRC that previously received anti-EGFR + CT and interrupted therapy due to PD in the ReCH group and other reasons in the ReIn group. We aimed to describe progression-free survival (PFS), overall survival (OS) and response rate (RR) after re-exposure and to evaluate prognostic factors associated with PFS.ResultsSixty-eight patients met the inclusion criteria. The median follow-up after re-exposure was 39.3 months. ReCH was adopted in 25% and ReIn in 75%. The median anti-EGFR free interval was at 10.5 months. At re-exposure, the main CT regimen was FOLFIRI in 58.8%. Cetuximab and Panitumumab were used in 59 and 9 patients, respectively. mPFS for ReCH and ReIn was 3.3 × 8.4 months, respectively (p 0.001). The objective response rate for ReCH and ReIn was 18% and 52%, respectively. In univariate analysis, adverse prognostic factors related to PFS were: stable disease or PD at first anti-EGFR exposure (HR: 2.12, CI:1.20–3.74; p = 0.009); ReCH (HR: 3.44, CI:1.88–6.29, p < 0.0001); rechallenge at fourth or later lines (HR: 2.51, CI:1.49–4.23, p = 0.001); panitumumab use (HR: 2.26 CI:1.18–5.54, p = 0.017). In the multivariate model, only ReCH remained statistically significant (HR = 2.63, CI: 1.14–6.03, p = 0.022).ConclusionIn our analysis, ReCH resulted in short PFS and low RR. However, reintroduction of anti-EGFR plus CT before complete resistance arose resulted in prolonged PFS. These data could be clinically useful to guide a treatment break due to side effects or patient decisions. Our data should be confirmed by larger and prospective trials.

Retreatment With Anti-EGFR Antibodies in Metastatic Colorectal Cancer Patients: A Multi-institutional Analysis

BackgroundOn the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti–epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice. Patients and MethodsA real-life database of 5530 patients treated at 6 institutions was queried. Included were patients who were retreated with anti-EGFRs, who had RAS/BRAF wild-type–status tissue samples, who had received a first-line anti-EGFR–based regimen with at least stable disease as best response, and who had received at least one further line of therapy before anti-EGFR retreatment. The association with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of variables potentially related to anti-EGFR sensitivity was investigated. ResultsA total of 86 patients were identified. The ORR during anti-EGFR retreatment was 19.8%; median PFS and OS were 3.8 and 10.2 months, respectively. No significant association of clinical features of anti-EGFR sensitivity with ORR, PFS, and OS was observed. Among the 56 patients with a time from the last anti-EGFR administration to first-line progressive disease of < 3 months (rechallenge group), > 2 prior therapy lines and a longer anti-EGFR–free interval were associated with higher ORR, but not with longer PFS or OS. ConclusionClinical features we deemed surrogates of anti-EGFR sensitivity were not reliable predictors of benefit from anti-EGFR retreatment.

Immunotherapy rechallenge after nivolumab treatment in advanced non-small cell lung cancer in the real-world setting: A national data base analysis

ObjectivesNivolumab is now a reference treatment for patients with advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. Little data are available on treatment approaches following discontinuation of nivolumab and on the interest of a second course of immunotherapy after nivolumab discontinuation. The aims of this study were to describe treatment pathways following nivolumab discontinuation and to describe survival following retreatment with immunotherapy. Materials and methodsThe analysis includes all patients with NSCLC recorded in a national hospital database, starting nivolumab in 2015-2016. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Patients starting a second course of PD-1 inhibitor following nivolumab discontinuation were analysed according to the duration of their initial nivolumab treatment course. Results10,452 patients were included (71 % men; mean age: 63.8 ± 9.6 years; squamous histology: 44 %). Median nivolumab treatment duration was 2.8 months [IQR :1.4–6.9]. Median OS was 11.5 months [95 %CI: 11.1–11.9]; 5118 (53.4 %) patients received post nivolumab therapy lines: 1517 (29.6 %) of these received a second course of PD-1 inhibitor, either after a treatment-free interval (resumption: n = 1127) or after intervening chemotherapy (rechallenge: n = 390). Median OS after nivolumab discontinuation was 15.0 months [13.9–16.7] in the resumption group and 18.4 months [14.8–21.9] in the rechallenge group. Median OS was significantly longer in patients with an initial nivolumab treatment duration ≥3 months. ConclusionIn this real-world setting, outcome after retreatment with a PD-1 inhibitor following a first course of nivolumab was significantly better in patients with a longer duration of initial nivolumab treatment.

MA07.06 Immunotherapy Re-Challenge After Nivolumab Treatment in Advanced Non-Small Cell Lung Cancer in French Real-World Setting

Real-world evidence of nivolumab as treatment for advanced non-small cell lung cancer (aNSCLC) can complement evidence from clinical trials to optimize routine usage and personalization of care. Further, little is known about treatment options and outcomes after discontinuation of nivolumab. Based on the National hospitals database (PMSI), we built a retrospective cohort of all NSCLC patients (ICD code: C34*) starting nivolumab in 2015-2016 and followed them until Dec 2017. Information on patients’ baseline characteristics (demographics, comorbidities, treatment history) was retrieved. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Time to treatment discontinuation (TTD) and overall survival (OS) were estimated with Kaplan-Meier methodology. Re-challenged patients were analyzed according to their first nivolumab treatment duration i.e. <3; 3-6; ≥6 months. We identified 10,452 NSCLC patients initiating nivolumab during the inclusion period (male: 71%; mean age; 63.8±9.6 years; squamous histology: 44%; cerebral metastasis: 17.4%; median aNSCLC history: 12.5 months; previous curative surgery: 15.6%; median time since first chemotherapy: 10.5 months; mean dose of nivolumab: 213±54mg). Median TTD and OS were 2.8 months and 11.6 months. One-year and 2-year OS rates were 48.8% and 27.4%. Overall, 5118 (53.4%) patients received subsequent systemic therapy after nivolumab discontinuation. Among them, 1517 patients (29.6%) were re-treated with anti-PD1 agents (nivolumab: 98.8%) either after a therapeutic break (‘immunotherapy resumption group’: n=1127; mTTD: 4.1 months; mOS: 14.9 months from second initiation) or after chemotherapy (‘immunotherapy re-challenge group’: n=390; mTTD: 3.0 months; mOS: 18.2 months from second initiation). The Figure presents OS curves of the ‘re-challenge group’ according to first nivolumab treatment duration. After nivolumab discontinuation, around 30% of patients received immunotherapy again, either as a resumption or as a re-challenge following non-immunotherapy treatment. The influence of the first nivolumab treatment duration on re-challenged patients' OS should be further investigated.

FOLFOX rechallenge versus regorafenib in patients with metastatic colorectal cancer refractory to standard chemotherapy: A retrospective analysis.

669 Background: Nowadays the optimal treatment for mCRC beyond second line is still questioned. During last years, regorafenib and TAS-102 showed to improve survival compared to best supportive care in pts with refractory mCRC. Recently, some retrospective analyses compared the efficacy and safety of regorafenib and TAS-102 reporting no significant differences in survival and response outcomes. In real-world clinical practice, chemotherapy (CT) rechallenge is often considered for refractory mCRC. However, evidences regarding CT rechallenge is limited and no study has previously compared such approach with the recently approved antineoplastic agents in late lines. The aim of this study was to compare the efficacy between CT rechallenge and regorafenib in pts with refractory mCRC. Methods: This is a mono-institutional retrospective study. We compared the efficacy of FOLFOX rechallenge and regorafenib in pts with mCRC refractory to at least 2 lines of standard CT, treated at Fondazione Policlinico Universitario “A. Gemelli”-IRCCS between Jan-10 and Jan-18. The primary endpoint was OS. Secondary endpoints were RR and PFS. Results: One hundred thirty-one pts received regorafenib and 43 FOLFOX rechallenge. OS was significantly higher with FOLFOX rechallenge than it was with regorafenib (13 vs. 6 months; HR 0.67, 95% CI 0.33-0.66; p = 0.0002). PFS was significantly higher in the FOLFOX rechallenge group compared to the regorafenib group (5 vs. 3 months; HR 0.64, 95% CI 0.46-0.89; p = 0.0073). Accordingly, RR was better in pts receiving FOLFOX rechallenge compared to regorafenib (25 vs. 3%; Chi-square p &lt; 0.0001). Conclusions: Our study, although retrospective and small-sized, compared for the first time to our knowledge the efficacy of CT rechallenge to regorafenib in refractory mCRC. In our analysis, CT rechallenge with FOLFOX proved to be superior compared to regorafenib, with a survival and response benefit in pretreated mCRC. The survival benefit observed for rechallenge might be explained by the significantly higher tumor shrinkage achieved with CT rechallenge compared to regorafenib. Our results warrant further confirmation in wider and/or prospective analyses.

Platinum rechallenge in second-line treatment for endometrial carcinoma

Objectives: Metastatic endometrial carcinoma (EC) has a poor prognosis. Systemic treatment (hormone therapy or chemotherapy) has been used in first line, however, the best therapy as second-line therapy is not known. The aim of this study is to evaluate the role of platinum-based chemotherapy rechallenge in second-line treatment for EC. Materials and Methods: Retrospective review of patients with recurrent EC who were treated with second-line systemic therapy from April 2007 to April 2015 at two cancer centers. Clinical data included: age, histology, tumor grade, tumor stage at diagnosis, site of disease progression, ECOG performance status, adjuvant chemotherapy, first-and second-line chemotherapy for recurrent disease and comorbidities. Results: A total of 84 patients were evaluated. Median age was 66.2 years; most patients had endometrioid histology (67.9%) and grade 2 tumors (45.8%). Twenty-nine patients (34.5%) were treated with platinum rechallenge at second line. Median overall survival (OS) was 9.7 months (7.1-12.3 months; 95% CI). Longer OS was observed in platinum rechallenge group compared to non-re-exposed (13.8 months vs. 7.9 months, p = 0.005). Only platinum rechallenge was significantly associated to a better OS on multivariate analysis (HR 0.43 [95%CI 0.21-0.87, p = 0.019]). Platinum rechallenge was also associated with a higher progression-free survival (PFS) (4.9 months vs. 3.4 months, p = 0.008). Conclusions: The present findings suggest a longer OS and PFS for patients treated with platinum rechallenge at second-line treatment for EC and add more evidence for adoption of this strategy in a scenario where there is little evidence of effective treatments.

Rechallenge treatment with a platinum-based regimen in patients with sensitive relapsed small-cell lung cancer.

Among patients with relapsed small-cell lung cancer (SCLC), those who relapse > 90days after first-line chemotherapy are classified sensitive relapse. Rechallenge with a first-line platinum-based regimen has been used in sensitive relapsed SCLC patients, but its importance is not known. We evaluated the outcome of rechallenge with platinum-based chemotherapy for sensitive relapse patients. We reviewed consecutive patients with sensitive relapsed SCLC who received second-line chemotherapy between January 1999 and December 2016. We evaluated the treatment outcomes of platinum-based rechallenge and non-rechallenge regimens for second-line chemotherapy in sensitive relapse patients. Of 245 patients, 81 sensitive relapse patients received second-line chemotherapy. Sixty-seven patients (82.7%) were treated with rechallenging platinum-based regimens ("rechallenge group") and 14 patients (17.3%) were treated with other regimens ("non-rechallenge group") as second-line chemotherapy. Median progression-free survival (PFS) was 5.1months in the rechallenge group and 3.5months in the non-rechallenge group, and median survival time was 10.8 and 8.2months, respectively. There were no significant differences in PFS or overall survival (OS) between the two groups. Sub-analyses of patients who received chemotherapy alone as first-line treatment showed that the rechallenge group had longer PFS than that of the non-rechallenge group (median 5.4 vs. 3.6months, p = 0.0038), and the rechallenge group had a tendency to have longer OS than non-rechallenge group. These data suggest that rechallenge treatment with a platinum-based regimen could be second-line chemotherapy in patients with sensitive relapsed SCLC, especially those treated with chemotherapy alone as first-line therapy.

Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?

BackgroundStatin-associated muscle symptoms (SAMS) are common. Rechallenge with the same statin (same-statin rechallenge) has recently been included as part of a proposed scoring index for diagnosing SAMS, but data regarding tolerability and efficacy of same-statin rechallenge, compared with other strategies, is minimal. In this study we evaluated the tolerability, percent change in low-density lipoprotein cholesterol (LDL-C), and proportion of patients achieving their LDL-C targets among 3 common management strategies—same-statin rechallenge, switching to a different statin (statin switch), and use of nonstatin medications only. MethodsWe performed a retrospective analysis of 118 patients referred to our tertiary care centre for management of SAMS, defined as development of muscle-related symptoms with 2 or more statins. Baseline and last follow-up lipid parameters were documented. Patients were classified as tolerant of a strategy if, at their last follow-up, they remained on that strategy. ResultsAfter a median follow-up of 17 months, most (n = 79; 67%) patients were able to tolerate a statin. Tolerability was similar among the 3 treatment strategies (71% same-statin rechallenge vs 53% statin switch vs 57% for nonstatin therapy only; P = 0.11). Those in the same-statin rechallenge and statin switch groups achieved greater LDL-C reductions compared with those who only tolerated nonstatins (−38.8 ± 3.4% vs −36.4 ± 2.9% vs −17.3 ± 4.5%; P = 0.0007). A greater proportion of patients in the same-statin rechallenge group achieved their target LDL-C compared with those in the nonstatin therapy only group (50% vs 15%; odds ratio, 6.8; 95% confidence interval, 1.5-40.7; P = 0.04). ConclusionsAmong individuals with a history of SAMS, most will tolerate statin therapy. Same-statin rechallenge was highly tolerable and efficacious. Thus, same-statin rechallenge might warrant increased utilization.

Characterization of Mucosal Immune Responses to Enterotoxigenic Escherichia coli Vaccine Antigens in a Human Challenge Model: Response Profiles after Primary Infection and Homologous Rechallenge with Strain H10407.

Enterotoxigenic Escherichia coli (ETEC) bacteria are the most common bacterial cause of diarrhea in children in resource-poor settings as well as in travelers. Although there are several approaches to develop an effective vaccine for ETEC, no licensed vaccines are currently available. A significant challenge to successful vaccine development is our poor understanding of the immune responses that correlate best with protection against ETEC illness. In this study, ETEC-specific mucosal immune responses were characterized and compared in subjects challenged with ETEC strain H10407 and in subjects rechallenged with the homologous organism. IgA responses to lipopolysaccharide (LPS), heat-labile toxin B subunit (LTB), and colonization factor antigen I (CFA/I) in antibody in lymphocyte supernatant (ALS), feces, lavage fluid, and saliva samples were evaluated. In all assay comparisons, ALS was the most sensitive indicator of a local immune response, but serum IgA was also a useful indirect marker of immune response to oral antigens. Volunteers challenged and then rechallenged with strain H10407 were protected from illness following rechallenge. Comparing mucosal antibody responses after primary and homologous rechallenge, protection against disease was reflected in reduced antibody responses to key ETEC antigens and in reduced fecal shedding of the H10407 challenge strain. Subjects challenged with strain H10407 mounted stronger antibody responses to LPS and LTB than subjects in the rechallenge group, while responses to CFA/I in the rechallenge group were higher than in the challenge group. We anticipate that this study will help provide an immunological benchmark for the evaluation of ETEC vaccines and immunization regimens in the future.

Efficacy of Rechallenge Chemotherapy in Patients With Sensitive Relapsed Small Cell Lung Cancer

To evaluate the efficacy of rechallenge with current induction regimens for sensitive-relapse small cell lung cancer (SCLC) patients. We defined sensitive relapse as treatment-free interval (TFI≥90 d). Sensitive-relapse SCLC patients who received second-line chemotherapy were separated into those treated with rechallenge chemotherapy (rechallenge group) and those treated with other regimens (other group). The endpoints were overall survival (OS), progression-free survival, and toxicity. Sixty-five patients (19 rechallenge group and 46 other group) were assessable for efficacy and safety evaluation. No significant differences in age, sex, ECOG performance status at relapse, disease extent at diagnosis, or response to first-line treatment were found between the 2 groups, but TFI was significantly longer in the rechallenge group. Twenty-one patients of the other group received amrubicin. There was no significant difference in OS between the 2 groups (median survival time [MST]: rechallenge group, 14.4 mo; other group, 13.1 mo; P=0.51). In the patients treated with amrubicin, MST was 12.6 months. Comparing the rechallenge group with the patients treated with amrubicin, there was also no significant difference in OS (P=0.38). Both the rechallenge and other group included 11 patients with ex-sensitive relapse (TFI≥180 d). There was no significant difference in OS between the 2 groups (MST 15.7 vs. 26.9 mo, P=0.46). Rechallenge chemotherapy did not prove superior to other chemotherapies, suggesting that monotherapy, such as amrubicin, might be reasonable as second-line chemotherapy for sensitive-relapse SCLC patients.