Patients Experienced Disease Progression Research Articles

Expression of programmed cell death-ligand 1 in primary testicular diffuse large B cell lymphoma: A retrospective study.

The present study evaluated programmed cell death-ligand 1 (PD-L1) expression in tumor cells and in the tumor microenvironment (TME) and its association with clinical data in primary testicular diffuse large B cell lymphoma (DLBCL). PD-L1 was determined by immunohistochemistry in 30 patients with primary testicular DLBCL and assessed for associations with clinical characteristics, progression-free survival (PFS) and overall survival (OS). The mean patient age was 62.2 years. Overall, 10 (33.3%) patients had advanced-stage (stage III/IV) disease and 14 (46.7%) patients had an International Prognostic Index (IPI) of ≥3. The median follow-up time following orchiectomy was 23.5 months. During this time, 10 (33.3%) patients experienced disease progression and 11 (36.7%) patients succumbed. PD-L1 expression in tumor cells and in the TME was detected in 20 (66.7%) and 13 (43.3%) patients, respectively. PD-L1 expression on tumor cells and in the TME was higher in those at an early stage compared with patients with an advanced stage of disease (P=0.045 and 0.017, respectively). In addition, PD-L1 expression in tumor cells was higher in patients with a low IPI compared with those with a high IPI (P=0.019). A Kaplan-Meier analysis identified no association of PD-L1 expression on tumor cells with PFS (P=0.763) or OS (P=0.531), or of PD-L1 expression in the TME with PFS (P=0.572) or OS (P=0.934). The present study demonstrated that PD-L1 expression in tumor cells and in the TME was higher in patients at an early stage of disease compared with those at an advanced stage, and that PD-L1 expression on tumor cells was higher in patients with a low IPI than in those with a high IPI. Furthermore, PD-L1 expression in tumor cells and in the TME was not associated with PFS or OS.

Role of heat shock proteins in bladder cancer: potential biomarkers for treatment response and oncological prognosis

Transurethral resection of bladder tumor (TURBT) and BCG intravesical instillation have been the gold standard for non-muscle invasive bladder cancer (NMIBC) treatment in patients with intermediate and high-risk disease (1,2). However, patients with T1 high grade (T1HG) disease still have relatively poor outcomes with 11.4 and 19.8% of patients experiencing disease progression at 1 and 5 years, respectively and disease specific mortality rates of 4.8% and 11.2%, respectively (3). The identification of biomarkers that could appropriately select patients who will benefit from BCG therapy would be greatly beneficial for optimizing outcomes and minimizing overtreatment.

S875 SUBCUTANEOUS DARATUMUMAB + CYCLOPHOSPHAMIDE, BORTEZOMIB, AND DEXAMETHASONE (CYBORD) IN PATIENTS WITH NEWLY DIAGNOSED AMYLOID LIGHT CHAIN (AL) AMYLOIDOSIS: UPDATED SAFETY RUN‐IN RESULTS OF ANDROMEDA

Background:The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab‐based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis.Aims:We present the 1‐year follow up on safety and efficacy data for the 28 patients enrolled in the safety run‐in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis.Methods:Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT‐ProBNP ≤8,500 ng/L. In the safety run‐in, patients received DARA (1,800 mg in 15 mL) co‐formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m2 PO or IV, Bor 1.3 mg/m2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter.Results:Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow‐up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (>6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow‐up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1.Summary/Conclusion:DARA‐CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well‐tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.

S876 GILTERITINIB SIGNIFICANTLY PROLONGS OVERALL SURVIVAL IN PATIENTS WITH FLT3-MUTATED (FLT3MUT+) RELAPSED/REFRACTORY (R/R) ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE PHASE 3 ADMIRAL TRIAL

Background: The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab-based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis. Aims: We present the 1-year follow up on safety and efficacy data for the 28 patients enrolled in the safety run-in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis. Methods: Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT-ProBNP ≤8,500 ng/L. In the safety run-in, patients received DARA (1,800 mg in 15 mL) co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m2 PO or IV, Bor 1.3 mg/m2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter. Results: Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow-up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (>6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow-up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1. Summary/Conclusion: DARA-CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well-tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.

Phase II study of avelumab in multiple relapsed/refractory testicular germ cell cancer.

e16045 Background: Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. PD-L1 expression is significantly higher in germ cell tumors (GCTs) in comparison to normal testicular tissue and high PD-L1 expression is associated with inferior progression-free and overall survival compared to patients with low PD-L1 expression. This study aimed to determine the efficacy and toxicity of PD-L1 antagonist, Avelumab, in patients with refractory GCTs. Methods: From November 2017 to January 2018, 8 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies (median 5, range 2 – 6); 5 tumors (62.5%) were absolutely refractory to cisplatin and 5 patients (62.5%) had visceral non-pulmonary metastases. Avelumab was administered at a dose of 10mg/kg biweekly until progression or unacceptable toxicity. The primary end point was 12-weeks progression-free survival (PFS). If < 8 responses to study therapy will be observed among the first 15 patients, the study will be terminated. Results: Median age was 29 years (range: 22 – 52 years). During a median follow-up period of 2.6 months (range: 0.3 - 14.4), 7 (87.5%) patients experienced disease progression and 6 patients (80.0%) died. Twelve-week PFS was 0%, median PFS was 1.4 months, 95%CI (0.9 – 1.4) and median OS was 2.7 months, 95% CI (1.0 – 3.3). No objective response was observed. Avelumab was well tolerated, no severe adverse event was observed. Conclusions: This study failed to achieve its primary end point and our data suggest lack of Avelumab efficacy in unselected multiple relapsed/refractory TGCTs. Clinical trial information: NCT03403777.

A phase III, randomized, open label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SOC) chemotherapy and durvalumab in combination with tremelimumab and SOC chemotherapy versus SOC chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC).

TPS4590 Background: Despite high response rates to 1L SoC for locally advanced or metastatic UC chemotherapy (gemcitabine + cisplatin or gemcitabine + carboplatin for patients who are cisplatin-ineligible [poor performance status, impaired renal function, comorbidities]), most patients experience disease progression. Novel strategies such as combining chemotherapy and immunotherapy offer hope for improving clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a human IgG2 mAb directed against CTLA-4. The mechanisms of action of PD-1 and CTLA-4 are nonredundant, so targeting both checkpoint pathways may have additive or synergistic efficacy compared with monotherapy. Studies of platinum-based chemotherapy combined with checkpoint blockade in other tumor types have yielded improved efficacy with acceptable safety and support exploration of this approach for 1L locally advanced or metastatic UC. Methods: NILE (NCT03682068) is a randomized, open-label, multicenter, global trial that will enroll approximately 1265 patients with histologically or cytologically documented, unresectable, locally advanced, or metastatic transitional cell carcinoma of the urothelium. Patients will be randomized (1:1:1) to durvalumab + SoC chemotherapy, durvalumab + tremelimumab + SoC chemotherapy, or SoC chemotherapy as 1L therapy. Primary endpoints are progression-free survival using blinded independent central review assessments per RECIST 1.1 and overall survival (OS). Secondary endpoints include objective response rate, OS at 24 months, proportion of patients alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, and health-related quality of life. Safety, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. The study opened for enrollment in September 2018. 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 Genitourinary Cancers Symposium. Clinical trial information: NCT03682068.

Predictors of Overall and Disease-Free Survival in Metastatic Castration-Resistant Prostate Cancer Patients Receiving 225Ac-PSMA-617 Radioligand Therapy.

Metastatic prostate carcinoma overexpresses prostate-specific membrane antigen (PSMA), making this antigen a suitable target for radioligand therapy of the disease. Here we report on our experience with a series of 73 castration-resistant prostate carcinoma patients treated with 225Ac-PSMA-617, identifying variables predictive for overall survival (OS) and progression-free survival (PFS) after 225Ac-PSMA-617 treatment. Methods:225Ac-PSMA-617 was administered to patients who had metastatic castration-resistant prostate carcinoma and who had exhausted available therapy options for their disease. Full blood count, glomerular filtration rate, and liver function test were obtained at baseline and on follow-up for evaluation of toxicity. 68Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle, and on follow-up for selection of patients for treatment, to determine the activity of the treatment agent to be administered, and for response assessment. Serial prostate-specific antigen (PSA) was obtained for PSA response assessment. Results: Seventy-three men (mean age, 69 y; range, 45-85 y) with metastatic castration-resistant prostate carcinoma were treated with 210 cycles of 225Ac-PSMA-617. In 70% of patients, a PSA decline of greater than or equal to 50% was obtained; 82% of patients had any PSA decline. In 29% of patients, all lesions on 68Ga-PSMA PET resolved in response to treatment. During follow-up, 23 patients experienced disease progression, whereas 13 patients died from their disease. The estimated median PFS and OS were 15.2 mo (95% CI, 13.1-17.4) and 18 mo (95% CI, 16.2-19.9), respectively. In univariate analyses, factors such as baseline PSA, any PSA decline, PSA decline of greater than or equal to 50%, prior chemotherapy, prior radiation therapy, and baseline hemoglobin level were associated with longer PFS and OS (all Ps < 0.05). In multivariate analyses, there was a negative association between prior 177Lu-PSMA therapy and PFS, and a positive association between PSA decline of greater or equal to 50% and PFS. Only a PSA decline of greater than or equal to 50% remained significantly associated with OS on multivariate analyses. Xerostomia was seen in 85% of patients but was not severe enough to warrant discontinuing treatment. Anemia was seen in 27 patients; no patients had grade IV bone marrow toxicity. Renal failure of grade III or IV was seen in 5 patients with baseline renal impairment. Conclusion: In this study, a PSA decline of greater than or equal to 50% after treatment with 225Ac-PSMA-617 was proven by multivariate analyses to be significantly associated with OS and PFS. Furthermore, previous 177Lu-PSMA treatment was negatively associated with PFS in both univariate and multivariate analyses.

Pretreatment financial toxicity predicts progression-free survival following concurrent chemoradiotherapy for locally advanced non-small-cell lung cancer.

Aim: Financial toxicity (FT) describes patients' burden from out-of-pocket medical treatment costs. We studied associations between patient-reported pretreatment FT, socioeconomic status and clinical outcomes for locally advanced non-small-cell lung cancer (LA-NSCLC) patients. Methods: Patients received chemoradiotherapy for locally advanced non-small-cell lung cancer and completed the European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) quality of life assessment before treatment. One question asks whether patients experience 'financial difficulties'. We tested FT and socioeconomic status (SES) as predictors of progression-free survival (PFS) and overall survival (OS). Results: A total of 43 patients were included. Median follow-up for surviving patients was 15 months. A total of 19 patients (44%) experienced disease progression and 17 patients (40%) died. Increasing FT was associated with shorter PFS (p=0.011). FT did not predict overall survival (p=0.67). Conclusion: Higher pretreatment FT is associated with shorter PFS.

Expectations and Experience: Optimising Efficacy and Maintaining Quality of Life in Follicular Lymphoma

Prof Salles provided an update on the ongoing first-line follicular lymphoma (FL) studies, demonstrating how analysis of the GALLIUM study data regarding the use of different chemotherapy backbones consistently showed the benefits of obinutuzumab (G) chemotherapy (G-chemo) versus rituximab (R) chemotherapy (R-chemo) in FL patients. An update from the PRIMA study showed that 10-year progression-free survival (PFS) was improved following the use of R maintenance compared with observation following induction. Prof Salles also provided an overview of the RELEVANCE study data, which showed that R plus lenalidomide was not superior to standard R-chemo for the treatment of first-line FL. Prof Seymour presented data showing that two-thirds of premature FL deaths occur in patients experiencing disease progression within 2 years of treatment, highlighting the need to identify patients at early risk of progression. Prof Seymour explored various prognostic and predictive tools that could be used to identify patients at high risk of death, but he noted that until these prognostic tools are available in the clinic, the high-risk population remains unidentifiable. Furthermore, the accuracy of these prognostic indices needs to be improved. Data analysis from the GALLIUM study showed that G-chemo decreased the risk of a disease progression event in the first 2 years by 46% compared to R-chemo. Prof Trotman explored the use of PET imaging and detection of minimal residual disease (MRD) to assess treatment outcomes. Prof Trotman showed that PET status at the end of induction is highly prognostic of the outcome. An exploratory analysis of the GALLIUM data showed that the application of the Lugano 2014 response criteria showed a rapid, deep separation of the PFS curves of patients achieving a complete metabolic response (CMR) versus those who did not. There was almost a 5-fold increase in risk of progression and in risk of death in patients failing to achieve CMR. An exploratory analysis of the MRD status of GALLIUM patients showed that a greater proportion of patients in the G-chemo arm achieved MRD-negative status at the end of induction (EOI). Interestingly, patients achieved similar MRD outcomes with G-chemo, regardless of chemotherapy backbone. Both PET and MRD status after induction were independently predictive of PFS. Dr Pettengell and Mr Bouguet discussed FL from both the clinician’s and the patient’s perspective, with a focus on health-related quality of life (HRQoL). They demonstrated how a marked decrease in HRQoL at progression highlights the importance of extending remission for FL patients. Dr Pettengell presented data from GALLIUM showing comparable quality of life for patients treated with either G-chemo or R-chemo. They also presented patient surveys showing that FL has a substantial physical and psychological impact on patients that both lasts beyond treatment and persists even during long-term remission.

Prognostic utility of pre- and post-treatment FDG-PET parameters in anal squamous cell carcinoma

Background and purposeWe prospectively assessed the contributions of PET to initial staging, early detection of treatment failures, and prognostication in patients with anal squamous cell carcinoma (ASCC). Materials and methodsConsecutive patients with ASCC referred for radical chemoradiotherapy (CRT) consented to undergo FDG-PET imaging pre-treatment and at 3 and 6 months post-treatment. Clinicopathologic data were collected and CT and PET imaging reviewed for contribution to staging and recurrence detection. Maximum standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were assessed for association with progression-free survival (PFS), cause-specific survival (CSS), and overall survival (OS) using the Kaplan–Meier and Cox regression models. ResultsBetween 2009 and 2016, 73 patients with clinical stages I-IIIB ASCC completed curative-intent CRT. Median follow-up was 48 months. 14 patients died and 18 patients experienced disease progression. 4-year PFS, CSS, and OS were 73%, 87%, and 84%, respectively. A pre-treatment MTV >35 cm3 predicted for worse PFS (p = 0.011) and CSS (p = 0.024) on univariate and multivariate analyses, employing an MTV definition of voxels ≥25% of SUVmax. Higher 6-month post-treatment SUVmax and SUVpeak predicted for worse PFS and OS (p ≤ 0.011). Pre-treatment SUVmax, SUVpeak, and TLG, and 3-month post-treatment SUVmax and SUVpeak did not significantly correlate with survival outcomes. ConclusionsOur findings support that pre-treatment MTV provides meaningful prognostic information, with suggestion that an MTV delineation threshold of voxels ≥25% of SUVmax is appropriate in the anal region. Post treatment, the combination of clinical examination and PET effectively detected all treatment failures. Higher 6-month post-treatment SUVmax and SUVpeak predicted worse PFS and OS; however, the optimal timing of post-treatment PET imaging remains unclear.

Clinical characteristics of chronic myeloid leukemia with T315I mutation and the efficacy of ponatinib

To analyze the clinical features of chronic myeloid leukemia (CML) with T315 I mutation (CML-T315I) and compare the effectiveness of different treatments. We retrospectively analyzed the clinical data and outcomes of 19 patients with CML-T315I receiving different treatments. The T315 I mutations in these patients were detected by examination of BCR-ABL kinase domain (KD) mutation by RTQ-PCR and Sanger sequencing. The relapse following the treatments, defined as hematological, cytogenetic and molecular biological recurrences, were analyzed in these patients. Of the 19 patients with CML-T315I, 14 (73.7%) were in CML-CP stage at the initial diagnosis, and 13 (81.2%) were high-risk patients based on the Sokal scores. All the 19 patients were treated with TKI after the initial diagnosis, and during the treatment, 15 (78.9%) patients were found to have additional chromosomal aberrations, and 10 (52.6%) had multiple mutations; 13 (68.4%) of the patients experienced disease progression (accelerated phase/blast crisis) before the detection of T315I mutation, with a median time of 40 months (5-120 months) from the initial diagnosis to the mutation detection. After detection of the mutation, 12 patients were treated with ponatinib and 7 were managed with the conventional chemotherapy regimen, and their overall survival rates at 3 years were 83.3% and 14.2%, respectively (P &lt; 0.001). CML patients resistant to TKI are more likely to have T315I mutations, whose detection rate is significantly higher in the progressive phase than in the chronic phase. These patients often have additional chromosomal aberrations and multiple gene mutations with poor prognoses and a high recurrence rate even after hematopoietic stem cell transplantation. Long-term maintenance therapy with ponatinib may improve the prognosis and prolong the survival time of the patients.

Plasma ctDNA monitoring during epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment in patients with EGFR-mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib, a third generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is active against EGFR-mutant non-small cell lung cancer (NSCLC) resistant to first-/second-generation EGFR-TKIs with the T790M mutation. T790M monitoring in plasma circulating tumor DNA (ctDNA) in patients receiving EGFR-TKIs is less invasive than re-biopsy and could provide valuable clinical information. Patients with advanced or postoperative recurrent NSCLC with sensitizing EGFR mutations who were planned to receive or were receiving first-/second-generation EGFR-TKI treatment without disease progression were eligible for enrollment. Plasma samples at baseline and every 1-2 months thereafter were analyzed for EGFR mutation status using the cobas®EGFR Mutation Test v2. Between September 2016 and March 2017, 122 patients at 15 Japanese institutions were enrolled. In August 2018, 1291 plasma samples from 121 patients were analyzed for EGFR mutation status. At baseline, a sensitizing EGFR mutation was detected in 29 (23.9%) of 121 patients and T790M mutation was detected in three (2.5%). At follow-up, 66 (54.5%) patients experienced disease progression and 64 (52.9%) discontinued first-line EGFR-TKI treatment. Twenty-two (18.2%) patients showed T790M in plasma ctDNA, of which 15(68.2%) received osimertinib. Although 31 patients received re-biopsy to examine EGFR status at disease progression, T790M was detected in only nine (22.0%) patients, of which 7 (77.8%) received osimertinib. ctDNA monitoring during EGFR-TKI treatment is useful for detecting T790M mutation. The efficacy of osimertinib treatment based on T790M status in plasma ctDNA remains to be established, warranting further research.

Single institution experience of split course radiotherapy in patients with desmoid tumors.

PurposeThis study aimed to assess the feasibility of split course radiotherapy (SCRT) and reports long-term outcomes in patients with desmoid tumors (DT).Patients and methodsBetween 2001 and 2004, 31 patients with recurrent (n=19) or primary large desmoid fibromatosis (≥10 cm) (n=12) who were treated with SCRT were retrospectively analyzed. All patients were treated with two phases of radiotherapy with a median interval time of 99 days (range: 81–122 days) and a median total dose of 6,399 cGy (range: 5,013–7,039 cGy). The median dose for the first phase was 3,969 cGy/22 Fx (range: 2,999–4,305 cGy), and 2,495 cGy/14 Fx (range: 1,982–3,039 cGy) for the second phase. Progression-free survival (PFS) in response to radiotherapy was evaluated using the Kaplan–Meier method and compared using the log-rank test. The prognostic factors associated with survival were evaluated by univariate and multivariate analyses.ResultsThe median age of all patients was 30 years (range, 7–58 years). With a median follow-up of 60.4 months (range, 2–187 months), eight patients experienced disease progression after treatment. The PFS rate at 3 and 5 years for the whole population was 90% and 71.3%, respectively. PFS for patients with split course of <100 days or ≥100 days interval was 100% vs 78.6% at 3 years, and 80.4% vs 62.9% at 5 years, respectively (P=0.189). In multivariate analysis, the radiotherapy (RT) interval time was an independent prognostic factor for PFS (≥100 days vs <100 days, HR 11.544, 95% CI 1.034–128.878, P=0.047). PFS was not significantly influenced by age, gender, surgery, tumor location, RT technology, or RT dose. Radiation-related acute complications occurred in nine (29%) patients after RT, and RT-related long-term complications occurred in three (9.7%) patients.ConclusionSCRT with an appropriate treatment interval (<100 days) is well tolerated by DT patients with favorable long-term outcomes.

A phase III, randomized, open-label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SoC) chemotherapy and durvalumab in combination with tremelimumab and soc chemotherapy versus soc chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC).

TPS499 Background: Despite high response rates to 1L SoC for locally advanced or metastatic UC chemotherapy (gemcitabine +cisplatin or gemcitabine + carboplatin for patients who are cisplatin-ineligible [poor performance status, impaired renal function, comorbidities]), most patients experience disease progression. Novel strategies like combining chemotherapy and immunotherapy offer hope for improving clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a human IgG2 mAb directed against CTLA-4. The mechanisms of action of PD-1 and CTLA-4 are nonredundant, so targeting both checkpoint pathways may have additive or synergistic efficacy compared to monotherapy. Studies in other tumor types of platinum-based chemotherapy combined with checkpoint blockade have yielded improved efficacy with acceptable safety and support exploration of this approach for 1L locally advanced or metastatic UC. Methods: NILE is a randomized, open-label, multicenter, global trial that will enroll approximately 1265 patients who will be randomized (1:1:1) to durvalumab + SoC chemotherapy, durvalumab + tremelimumab + SoC chemotherapy, or SoC chemotherapy as 1L-line therapy in patients with histologically or cytologically documented, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium. Primary endpoints are progression-free survival using blinded independent central review assessments per RECIST 1.1 and overall survival (OS). Secondary endpoints include objective response rate, OS at 24 months, proportion of patients alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, and HRQoL. Safety, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. The study opened for enrollment in September 2018. Clinical trial information: NCT03682068.

Abstract P6-17-19: What to do with trastuzumab therapy after achieving radiological complete remission (rCR) in HER2+ metastatic breast cancer (MBC)?

Abstract Intro MBC is generally considered incurable, but patients with HER2+ disease treated with trastuzumab do relatively well and some have an exceptional durable response and survive over 10 years. We analyzed the clinical-pathological characteristics associated with long-term survival in patients with HER2+ MBC treated with trastuzumab. In addition, we studied the effect of stopping trastuzumab in case of rCR. Methods We included all patients with HER2+ MBC treated with first- or second-line trastuzumab-based palliative therapy between January 2000 and December 2014 in 8 Dutch hospitals (Netherlands Cancer Institute, Erasmus Medical Center, Albert Schweitzer Hospital, Reinier de Graaf Hospital, Amphia Hospital, St. Antonius Hospital, Ikazia Hospital, Haga Hospital). Patients were identified through the Netherlands Cancer Registry and linkage with the institutes' tumor registries. Data was collected from medical records using case record forms. Primary endpoint was overall survival (OS), defined as first-date of MBC until death due to any cause. Kaplan-Meier survival estimates were calculated and multivariable Cox-regression models used to identify prognostic factors for improved survival. Time to progression (TTP) after achieving rCR for patients who continued and stopped trastuzumab and breast cancer specific survival were secondary outcomes. Results We included 744 patients (median age 53, range 24-87). Median follow-up (FU) was 109 months (range 0-178). Clinical factors associated with improved survival in multivariable analyses were single-organ metastases, ER-positivity, no skin or liver metastases, no prior trastuzumab, local therapy of metastatic disease and achievement of rCR. In line with our first single center analyses1, achievement of rCR was the strongest predictor of improved survival (multivariable HR 0.30, 95%CI 0.20-0.46). RCR was observed in 71 patients (10%), of whom 60 had been treated with trastuzumab and chemotherapy, 9 with trastuzumab and hormonal therapy, and 2 with hormonal therapy. In patients with rCR the estimated 10-year OS was 53% versus 7% in patients who did not achieve rCR (p&amp;lt;0.001). Thirty patients stopped trastuzumab after achieving rCR. Median time between onset of rCR and last gift of trastuzumab in these patients was 6 months (0-132). Twenty-one patients (70%) remain in complete remission after a median FU of 75 months (range 54-90) since onset of rCR. Nine patients experienced disease progression after a median time of 14 months (range 9-62) since last gift of trastuzumab. Of these, 8 patients died due to MBC and one again achieved an ongoing rCR. Out of 39 patients who continued trastuzumab after achieving rCR, 12 are in ongoing remission after a median FU of 71 months (range 51-91). In this group median TTP was 14 months (range 5-23). Conclusion Achieving rCR is strongly associated with long-term survival in patients with HER2+ MBC. Seventy percent of patients who stopped trastuzumab after achieving rCR remained in remission, suggesting this can be an attractive approach in selected patients. External validation of these findings is required, however, as well as additional analyses to characterize the patients -and their tumors- who achieved rCR. 1 Steenbruggen, CancerRes 2017 Citation Format: Steenbruggen TG, Bouwer NI, Smorenburg CH, Rier HN, Jager A, Beelen KJ, ten Tije AJ, de Jong PC, Drooger JC, Holterhues C, Horlings HM, Sanders J, Levin M-D, Sonke GS. What to do with trastuzumab therapy after achieving radiological complete remission (rCR) in HER2+ metastatic breast cancer (MBC)? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-19.

Real-world outcomes in patients with unresected stage III non-small cell lung cancer

This study examined real-world clinical outcomes such as progression-free survival (PFS), time to metastasis (TTM), overall survival (OS), and health-related quality of life (HRQOL) in patients with unresected stage III non-small cell lung cancer (NSCLC) treated in the community setting. A retrospective review of medical records extracted from 10 US community oncology practices was conducted. Eligible patients were adults diagnosed with stage III NSCLC from 1/1/2011 to 3/1/2016 without evidence of surgical resection within 6 months after stage III NSCLC diagnosis (index date). PFS, OS, and TTM were assessed from the index date, and were analyzed using Kaplan–Meier and Cox regression analyses. HRQOL was assessed for a subset of patients using a patient-reported measure, the 86-item Patient Care Monitor (PCM). Linear mixed models (LMM) were used to assess the impact of patient characteristics and change in PCM scores associated with progression. Among the sample of 478 patients, median PFS (95% confidence interval) was 10 months (9–11), median OS was 20 months (17–22), and median TTM was 30 months (23–45). Most patients (58.2%) experienced disease progression, which the LMM showed to be associated with significant worsening of physical symptoms and psychological states (p < 0.001). This study documented PFS and OS consistent with published literature. The majority of patients experienced disease progression, which was associated with worsening of HRQOL. These findings highlighted the need for better therapeutic options in patients with unresected stage III NSCLC with potential to improve patient outcomes and HRQOL.

Efficacy, safety, and resistance profile of osimertinib in T790M mutation-positive non-small cell lung cancer in real-world practice.

The efficacy and safety of osimertinib were demonstrated in clinical trials; however, real-world clinical data, particularly the resistance profile, are limited. Here, we investigated the efficacy, safety, and resistance profile of osimertinib in real-world practice. We reviewed medical records of T790M mutation-positive lung cancer patients who started osimertinib between February 2016 and June 2017. Molecular pathologic data of biopsy samples obtained after acquisition of resistance to osimertinib were also analyzed. The study included 23 patients with a median age of 59 years. The median follow-up duration was 11.9 months (IQR, 4.7–15.8). Objective response was achieved in 17 (73.9%) patients, and the disease was controlled in 22 (95.7%) patients. Median progression-free survival (PFS) was 7.4 months (95% CI, 3.6–11.0). Adverse events were minimal except for one case of pneumonitis. Of 14 patients experiencing disease progression, 10 underwent re-biopsy. The T790M mutation disappeared in seven patients (70%), and one showed wild-type conversion. PFS was shorter in the T790M-loss group than in the T790M-persistent group (4.4 vs. 7.7 months). Two patients with small cell transformation responded well to subsequent chemotherapy. One patient developed a C797S mutation that became undetectable after two cycles of gemcitabine and cisplatin followed by six cycles of pembrolizumab, after which the patient responded well to osimertinib. In conclusion, osimertinib showed favorable efficacy and safety in real-world practice comparable to those observed in clinical trials. Repeat biopsy after the acquisition of resistance to osimertinib is helpful to direct further treatment strategies.

Treatment burden and long-term health deficits of patients with low-grade gliomas or glioneuronal tumors diagnosed during the first year of life.

Low-grade gliomas (LGGs) and low-grade glioneuronal tumors (LGGNTs) diagnosed during the first year of life carry unique clinical characteristics and challenges in management. However, data on the treatment burden, outcomes, and morbidities are lacking. A retrospective study of LGGs and LGGNTs diagnosed in patients younger than 12 months at St. Jude Children's Research Hospital (1986-2015) was conducted. For the 51 patients (including 31 males), the mean age at diagnosis was 6.47 months (range, 0.17-11.76 months), and the mean follow-up period was 11.8 years (range, 0.21-29.19 years). Tumor locations were hypothalamic/optic pathway (61%), hemispheric (12%), brainstem (12%), cerebellar (8%), and spinal (8%). There were 41 patients with histological diagnoses: 28 had World Health Organization grade 1 tumors, 6 had grade 2 tumors, and 7 had an LGG/LGGNT not definitively graded. Forty-one patients required an active intervention at diagnosis. Throughout their treatment course, 41 patients eventually underwent tumor-directed surgeries (median, 2 surgeries; range, 1-6), 39 received chemotherapy (median, 2 regimens; range, 1-13), and 21 received radiotherapy. Forty patients experienced disease progression (median, 2 progressions; range, 1-18). Ten patients died of progression (n=5), malignant transformation (n=2), a second cancer (n=2), or a shunt infection (n=1). The 10-year overall survival, progression-free survival, and radiation-free survival rates were 85% ± 5.3%, 16.9% ± 5.3%, and 51.2% ± 7.5%, respectively. Forty-nine patients experienced health deficits (eg, endocrinopathies, obesity, seizures, visual/hearing impairments, neurocognitive impairments, and cerebrovascular disease). Predictors of progression and toxicities were defined. Infantile LGG/LGGNT is a chronic, progressive disease universally associated with long-term morbidities and requires multidisciplinary intervention.

Tumor Budding is a Valuable Diagnostic Parameter in Prediction of Disease Progression of Endometrial Endometrioid Carcinoma.

Recently, tumor budding (TB) found at the invasive margin has been related to lymph node involvement (LNI), local recurrence, and poor prognosis in various cancers. We assessed the presence of TB in endometrial endometrioid carcinoma (EEC), and examined the immunohistochemical (IHC) profiles to define its clinicopathological significance. Ninety-six EECs were obtained from 2008 to 2013. During the follow-up, ten patients experienced disease progression; of these, three patients succumbed to the disease. All hematoxylin and eosin-stained slides were scrutinized for the presence of TB. IHC stainings for estrogen receptor (ER), progesterone receptor (PR), β-catenin, and E-cadherin were performed. All cases were grouped as FIGO grade (G) 1 (47.9%), G2 (29.2%), and G3 (22.9%). The distribution for depth of invasion (DOI) was 68.5% with a DOI of less than half and 31.5% with a DOI of more than half. Myometrial invasion was characterized as infiltrating pattern (52.1%), adenomyosis-like (20.8%), microcystic, elongated, and fragmented (17.7%), or expansile (9.4%). TB was identified in 63 cases (65.6%). Lymphovascular invasion (LVI) and LNI were identified in 47 and 37 cases, respectively. TB was associated with deep DOI (p = 0.001), higher FIGO grade (p = 0.006), LVI (p < 0.0001), and LNI (p < 0.0001). TB showed loss of ER (p < 0.0001) and PR (p < 0.0001), reduced E-cadherin (p < 0.0001) expression, and aberrant β-catenin expression (p = 0.042). In EECs, TB was associated with deep DOI, less-differentiated histology, frequent LVI, and LNI; furthermore, TB was closely related to epithelial-mesenchymal transition phenotype and downregulation of hormonal receptors. Therefore, TB might be a determinant histologic clue for prediction of disease progression in EECs.

Low-Dose Lenalidomide Maintenance after Induction Therapy in Older Patients with Primary CNS Lymphoma

Introduction The challenges posed by the increasing incidence of hematologic malignancies in older patients are significant and while during the past 20 years there has been a dramatic expansion in the therapeutic armamentarium against hematologic malignancies, there is a need for data to guide treatment decisions for older adults, particularly with respect to the use of novel targeted or immunotherapeutic agents. To a large extent, this is a consequence of the under-representation of this growing demographic in cancer-related clinical trials.Management of primary CNS lymphoma (PCNSL) in patients age ≥ 70 years represents a significant problem. While it is established that older PCNSL patients benefit from high-dose methotrexate-based induction regimens, whole brain irradiation consolidation is not a favored option because of excessive neurotoxicity. While there is evidence that high‐dose chemotherapy improves outcomes in patients age < 70, dose‐intensive chemotherapy is not an option for most older PCNSL patients. Given that the median age of PCNSL at diagnosis is ~ 60 years, determination of the optimal consolidative approach for older patients is an important question. This problem is particularly significant given that the incidence of PCNSL continues to rise in this older age group.While PCNSL increasingly appears to be a curable brain tumor, outcomes for patients age > 60 remain poor, with 1-year progression-free survival (PFS) of ~ 40% and median overall survival of 14-30 months. Population-based registry data suggests a median overall survival for PCNSL patients age > 70 of approximately 7 months over the past decade. New therapeutic approaches are needed for the particularly vulnerable older PCNSL patient population.Given the evidence for activity of low-dose lenalidomide in relapsed primary and secondary CNS lymphoma, in 2011, we began using low-dose lenalidomide as maintenance in consecutive older PCNSL patients (age ≥ 70 years, HIV negative) following standard methotrexate/rituximab-based induction, in lieu of surveillance, whole brain irradiation or high-dose chemotherapeutic consolidation. Here we report on the characteristics, outcomes, toxicities, progression-free and overall survival of the first 11 PCNSL patients, age ≥ 70, to receive lenalidomide maintenance after high-dose methotrexate-based induction at our institution.Results Eleven patients age > 70 received low-dose lenalidomide maintenance 5-10 mg/d on a 21-d cycle after induction therapy for PCNSL.Median age of the cohort is 77 years (range 70-86). Median Karnofsky performance status (KPS) is 60 (range 50-80); median IELSG prognostic risk score is 4 (range 3-5). The median methotrexate dose administered was 2.5 grams/m2 (range 0.5 - 8). With overall median follow-up of 30 months, median time on lenalidomide maintenance is 14.8 months (range 0.9 - 65.2). Two patients received lenalidomide plus maintenance rituximab, every 6 months. Median PFS is 48 months (range 16.8 - 84.8). Median OS has not been reached, and there have been no deaths (Figure 1). Four patients experienced disease progression on lenalidomide; 3 of them continued maintenance lenalidomide after salvage and 1 received maintenance pomalidomide. Lenalidomide maintenance has generally been well-tolerated. However, 5 toxicities potentially related to therapy have mandated cessation of lenalidomide: 1 grade 2 arthralgia, 1 subdural hematoma, 1 pneumonia, 1 grade 3 fatigue, 1 deep vein thrombosis.Conclusions These encouraging preliminary results of prolonged PFS and OS with low-dose lenalidomide illustrate the feasibility and challenges, as well as suggest a potential benefit of maintenance therapy with low-dose lenalidomide in older patients with PCNSL. Nine of 11 patients were able to complete at least 8 months of lenalidomide maintenance after induction therapy. Toxicities were manageable and strikingly, there have been no deaths. Recently, lenalidomide has been shown to enhance the proliferation, survival, and chemotactic responses in T-cells isolated from older subjects. This suggests a potential mechanistic basis by which low-dose lenalidomide may improve immunity in the elderly and potentiate response to chemotherapy. Future studies are needed to prospectively test the benefit and mechanisms of lenalidomide maintenance in older patients with PCNSL. [Display omitted] DisclosuresRubenstein:Genentech: Research Funding; Celgene: Research Funding. Mannis:AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity's Board of Directors or advisory committees.