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Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. In the randomized, phase III OAK study of atezolizumab (anti–programmed death-ligand 1) versus docetaxel in advanced NSCLC, overall survival (OS) benefit with atezolizumab was observed in the overall patient population, without improvement in objective response rate (ORR) or progression-free survival (PFS). We examine the benefit-risk of atezolizumab treatment beyond progression (TBP).

Although programmed death-ligand 1–programmed death 1 (PD-L1–PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.

The efficacy and safety of atezolizumab versus the efficacy and safety of docetaxel as second- or third-line treatment in patients with advanced NSCLC in the primary (n = 850) and secondary (n = 1225) efficacy populations of the randomized phase III OAK study (respectively referred to as the intention-to-treat [ITT] 850 [ITT850] and ITT1225) at an updated data cutoff were assessed.

IMPORTANCE: Preclinical models and studies in the metastatic and neoadjuvant settings suggest that single nucleotide polymorphisms in FCGR3A and FCGR2A may be associated with differential response to trastuzumab in the treatment of ERBB2/HER2–positive breast cancer, by modulating antibody-dependent cell-mediated cytotoxic effects. OBJECTIVE: To evaluate the effect of FCGR2A and FCGR3A polymorphisms on trastuzumab efficacy in the adjuvant treatment of ERBB2/HER2–positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective analysis of patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, a phase 3 cooperative group study conducted between 2000 and 2005. The NSABP B-31 trial randomized 2119 women with surgically resected node-positive, ERBB2/HER2–positive breast cancer to treatment with doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab. Patients were accrued at cooperative group sites across the United States and Canada. This analysis was performed between 2013 and 2016. INTERVENTIONS: Doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab. MAIN OUTCOMES AND MEASURES: Disease-free survival. RESULTS: The genotyped cohort (N = 1251) resembled the entire B-31 cohort based on clinical variables and the degree of benefit from trastuzumab. Median follow-up time was 8.2 years in the genotyped samples. The disease-free survival probability at 3, 5, and 8 years was 74% (95% CI, 71%-79%), 66% (95% CI, 62%-71%), and 58% (95% CI, 54%-63%) in patients who received ACT and 86% (95% CI, 83%-89%), 82% (95% CI, 79%-85%), and 78% (95% CI, 74%-81%) in patients who received ACTH. Addition of trastuzumab significantly improved patient outcome (hazard ratio [HR], 0.46; 95% CI, 0.37-0.57; P < .001). The expected trend for interaction between polymorphisms and trastuzumab was observed for both genes, but only FCGR3A-158 polymorphism reached statistical significance for interaction (P < .001). As hypothesized, patients with genotypes FCB3A-158V/V or FCB3A-158V/F received greater benefit from trastuzumab (HR, 0.31; 95% CI, 0.22-0.43; P < .001) than patients who were homozygous for the low-affinity allele (HR, 0.71; 95% CI, 0.51-1.01; P = .05). CONCLUSIONS AND RELEVANCE: The FCGR3A-158 polymorphism is predictive of trastuzumab efficacy in this cohort of patients with early ERBB2/HER2–positive breast cancer. Patients who are homozygous for phenylalanine at this position represent a considerable proportion of the population and, in contrast to previously reported analyses from similarly designed trials, our results indicate that trastuzumab may be less efficacious in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00004067

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Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.

The NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ. This report assesses the effect of these drugs on quality of life and symptoms.

Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy.

The Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting. A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n= 220) were patients who died from breast cancer. Controls (n= 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score. After adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P= 0.003 and P= 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7–3.9%), 10.7% (95% CI 6.3–14.9%), and 15.5% (95% CI 7.6–22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5–7.9%), 17.8% (95% CI 11.8–23.3%), and 19.9% (95% CI 14.2–25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values. In this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients.

To examine raloxifene use among women with a history of breast cancer.Kaiser Permanente tumor registry and membership files were used to identify women diagnosed with breast cancer after 1994 who were health plan members in 1998 or later, when raloxifene became available. Information on raloxifene treatment was obtained from computerized pharmacy records. Treatment patterns were examined and the characteristics of those who did and did not receive raloxifene were compared.Among the 17,968 women with a history of breast cancer, 711 (4.0%) had at least one prescription for raloxifene. Use among these women was more common than among similarly aged women in the health plan without a history of breast cancer, especially among those less than age 60 years. Among women with a history of breast cancer, raloxifene users were more than twice as likely as non-users to have had a bone mineral density test (60 versus 26%, p<0.0001) and, if tested, were more likely to have osteopenia or osteoporosis (80 versus 63%, p<0.0001). Compared to non-users, users had earlier stage breast cancer at diagnosis (80% versus 71% with local disease, p<0.0001). Raloxifene use was largely restricted to women whose initial breast cancer had not been treated with adjuvant tamoxifen or who had received less than 5 years of tamoxifen therapy.In this setting, raloxifene use among women with a history of breast cancer is related to stage at diagnosis and bone mineral density and is rare among women who have completed a 5-year course of adjuvant tamoxifen.

The effectiveness and superiority of sequential versus concurrent administration are unknown for regimens used in patients with operable, node-positive, early-stage breast cancer. There is evidence that the adjunctive use of ovarian ablation or suppression independent of chemotherapy may be associated with improved survival in premenopausal patients with hormone-receptor-positive breast cancer. The added benefit of ovarian suppression to chemotherapy outcomes in early-stage node-positive breast cancer is unclear.

Neoadjuvant chemotherapy can increase the rates of breast-conserving surgery in patients with operable breast cancer and is a reasonable alternative to adjuvant chemotherapy. Several trials have shown that adding bevacizumab (an antiangiogenic monoclonal antibody against vascular endothelial growth factor A) and the antimetabolites capecitabine and gemcitabine to taxanes can improve outcomes in patients with metastatic breast cancer.

The efficacy and safety of tositumomab and iodine I 131 tositumomab (TST/I-131-TST), the Bexxar® Therapeutic Regimen, were evaluated in 60 patients (pts) with chemotherapy-refractory low-grade (LG) or transformed B-cell non-Hodgkin's lymphoma (B-NHL) who had received at least 2 chemotherapy regimens and had either not responded to (72%) or had progressed within 6 months of their last regimen (28%) (J Clin Onc 2001; 19:3918 and Blood 2004; Abstract 2631). The primary efficacy endpoint was comparison of the number of pts who had a longer duration of response to TST/I-131-TST with the number of pts with a longer duration of response to their last qualifying chemotherapy (LQC). Thirty-nine (65%) pts, including 20% who attained a complete response (CR), responded to TST/I-131-TST, compared to 17 (28%) pts, including 3% CR, after their LQC (p<0.001). Seventy-four percent of pts had a longer response duration after TST/I-131TST compared to the LQC. Four pts developed myelodysplasia (MDS), and 5 pts developed human anti-mouse antibodies (HAMA). We report final results of long term follow-up of these 60 pts.Pts were enrolled from 22 November 1996 to 06 March 1998. Pts alive at the last report date (1 March 2004) were followed for long-term safety and survival, and pts in remission at the last report date were followed for continued response.Sixty pts received the dosimetric dose, and 58 of 60 pts received both the dosimetric and therapeutic doses of TST/I-131-TST. The median number of prior chemotherapies was 4 (range, 2–13). Fifty-nine of 60 (98%) pts had stage III/IV disease, 56% had bone marrow (BM) involvement, and 88% had ≥ two IPI risk factors at study entry. Thirty-six pts had LG B-NHL, 23 pts had a history of transformed B-NHL, and 1 pt had mantle cell NHL (MCL). Forty-eight (80%) pts have died, of whom 77% died due to lymphoma progression. Twelve pts were alive, and 6 pts were in CR at last follow-up. One pt withdrew consent for further follow-up but was in CR at 5.0 years, and the other 5 pts (4 LG, 1 transformed B-NHL) were in CR of ≥ 10 years' duration. The pts who continued in CR had received a median of 3 different prior chemotherapy regimens (range, 2–5), and no pts had received prior rituximab. For all 12 pts who attained CR, the median duration of response was 9.9 years (range, 0.7–11.7 years). Long-term toxicity included 7 pts who developed hypothyroidism. Secondary cancers included 1 lung adenocarincoma, 1 colon cancer, and 7 skin cancers which were reported previously. In addition, 1 developed a myeloproliferative disorder (MPD). No cases of MDS beyond the 4 previously reported were observed.A single course of TST/I-131-TST achieved durable remissions in chemotherapy-refractory LG and transformed B-NHL pts, with 5 of the 12 pts who achieved CR still in remission ≥ 10 years later. No additional cases of MDS were observed, but 1 pt developed a MPD since the last report. Thus, the final results of this study demonstrate that TST/I-131-TST is able to attain long-lasting durable CRs, with an acceptable toxicity profile, in a subset of pts with chemotherapy-refractory LG and transformed B-NHL.Kaminski: GlaxoSmithKline: Patents & Royalties, Research Funding. Zelenetz:GlaxoSmithKline: Research Funding. Press:GlaxoSmithKline: Research Funding; Spectrum Pharmaceuticals: Honoraria; Roche/Genentech: Honoraria. Saleh:GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Leonard:GlaxoSmithKline: Consultancy. Lister:GlaxoSmithKline: Chairman of Safety Monitoring Board for GSK. Horner:GlaxoSmithKline: Employment. Williams:GlaxoSmithKline: Employment. Lin:GlaxoSmithKline: Consultancy, Employment. Vleisides:GlaxoSmithKline: Employment. Knox:GlaxoSmithKline: Research Funding. Wahl:GlaxoSmithKline: Consultancy, Patents & Royalties; Nihon Medi Physics: Consultancy; Spectrum Pharmaceuticals: Consultancy; Naviscan PET systems: Consultancy; Threshold Pharmaceuticals: Equity Ownership. Vose:GlaxoSmithKline: Research Funding.

Abstract 3960

The addition of rituximab (R) therapy significantly improves PFS in patients with relapsedl/refractory disease responding after CHOP as well as responders after R-CHOP induction (van Oers, 2005). The aim of this study was to assess, in patients with previously untreated indolent NHL, the safety, efficacy and PK of additional R therapy in responders to R-CHOP induction. Between 10/01 and 08/06, 102 patients aged 28–84 (mean 57 yr) yrs with Ann Arbor Stage III (28.4%) or IV (71.6%) indolent NHL were treated on this Phase II single-arm, open-label, multi-center, community-based trial. Baseline LDH and β2 microglobulin were above normal in 20.6% and 66.3% of patients, respectively. Treatment consisted of 6 cycles of R-CHOP (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, and doxorubicin 50 mg/m2 all IV on Day 1 of each 21-day cycle; prednisone 100 mg/d po Days 1–5; and R 375 mg/m2 IV 2–3 days prior to first dose of CHOP and thereafter on Day 1 of each cycle). Patients with ongoing response (CR/CRu or PR) received R 375 mg/m2 weekly x 4, repeated every 6 months x 2 yrs, for a total of up to 16 R doses, within 28 days after completion of R-CHOP. Median follow-up was 39 mos. ORR after R-CHOP was 86.3% (95% CI: 78.3, 92.1), with CR/CRu 48% (95% CI: 38.0, 58.2). As measured from initiation of R-CHOP, PFS at 2 and 3 yrs was 75.2% (95% CI: 64.0, 83.3) and 67.3% (95% CI: 54.6, 77.2), respectively. OS at 2 and 3 yrs was 92.9% (95% CI: 85.7, 96.6) and 89.4% (95% CI: 81.2, 94.2), respectively. Infusion-related toxicity with R given after R-CHOP was less frequent than seen with R-CHOP in this study. The overall incidence of serious adverse events during R therapy given after R-CHOP was 8.5%, including 3 NCI-CTC grade 3/4 events: viral encephalitis (n=1), patellar fracture (n=1) & development of colon cancer (n=1). Serum R concentrations were collected over serial timepoints from 12 patients. Both pre- and end of infusion serum R concentrations were similar across cycles 2–4 of R therapy given after R-CHOP. R concentration was higher just prior to infusion of the first R dose given after R-CHOP due to residual concentration from the R-CHOP treatment. Concentrations were very low (< 10 ug/mL) just prior to initiation of the subsequent R cycles. During R therapy given after R-CHOP, serum R concentrations were similar to those previously reported during R monotherapy treatment (Berinstein, 1998). In summary, this study demonstrated that R therapy given after R-CHOP to be generally well-tolerated, and associated with 75.2% PFS and 92.9% OS at 2 yrs, and 67.3% PFS and 89.4% OS at 3 yrs. Moreover, the current study demonstrates that PK data from R induction can be extrapolated to R given after R-CHOP. The benefit of adding additional R therapy to responders to R-chemotherapy will be addressed in the analysis of the ongoing Phase III PRIMA study, wherein patients with advanced follicular lymphoma who respond to R-chemotherapy induction are randomized to receive further R therapy vs. observation.

The addition of rituximab (R) therapy significantly improves PFS in patients with relapsedl/refractorydisease responding after CHOP as well as responders after R-CHOP induction (van Oers, 2005). The aim of this study was to assess, in patients with previously untreatedindolent NHL, the safety, efficacy and PK of additional R therapy in responders to R-CHOP induction. Between 10/01 and 08/06, 102 patients aged 28–84 (mean 57 yr) yrs with Ann Arbor Stage III (28.4%) or IV (71.6%) indolent NHL were treated on this Phase II single-arm, open-label, multi-center, community-based trial. Baseline LDH and β2microglobulin were above normal in 20.6% and 66.3% of patients, respectively. Treatment consisted of 6 cycles of R-CHOP (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, and doxorubicin 50 mg/m2all IV on Day 1 of each 21-day cycle; prednisone 100 mg/d po Days 1–5; and R 375 mg/m2IV 2–3 days prior to first dose of CHOP and thereafter on Day 1 of each cycle). Patients with ongoing response (CR/CRu or PR) received R 375 mg/m2weekly x 4, repeated every 6 months x 2 yrs, for a total of up to 16 R doses, within 28 days after completion of R-CHOP. Median follow-up was 39 mos. ORR after R-CHOP was 86.3% (95% CI: 78.3, 92.1), with CR/CRu 48% (95% CI: 38.0, 58.2). As measured from initiation of R-CHOP, PFS at 2 and 3 yrs was 75.2% (95% CI: 64.0, 83.3) and 67.3% (95% CI: 54.6, 77.2), respectively. OS at 2 and 3 yrs was 92.9% (95% CI: 85.7, 96.6) and 89.4% (95% CI: 81.2, 94.2), respectively. Infusion-related toxicity with R given after R-CHOP was less frequent than seen with R-CHOP in this study. The overall incidence of serious adverse events during R therapy given after R-CHOP was 8.5%, including 3 NCI-CTC grade 3/4 events: viral encephalitis (n=1), patellar fracture (n=1) & development of colon cancer (n=1). Serum R concentrations were collected over serial timepoints from 12 patients. Both pre- and end of infusion serum R concentrations were similar across cycles 2–4 of R therapy given after R-CHOP. R concentration was higher just prior to infusion of the first R dose given after R-CHOP due to residual concentration from the R-CHOP treatment. Concentrations were very low (< 10 ug/mL) just prior to initiation of the subsequent R cycles. During R therapy given after R-CHOP, serum R concentrations were similar to those previously reported during R monotherapy treatment (Berinstein, 1998). In summary, this study demonstrated that R therapy given after R-CHOP to be generally well-tolerated, and associated with 75.2% PFS and 92.9% OS at 2 yrs, and 67.3% PFS and 89.4% OS at 3 yrs. Moreover, the current study demonstrates that PK data from R induction can be extrapolated to R given after R-CHOP. The benefit of adding additional R therapy to responders to R-chemotherapy will be addressed in the analysis of the ongoing Phase III PRIMA study, wherein patients with advanced follicular lymphoma who respond to R-chemotherapy induction are randomized to receive further R therapy vs. observation.

The selective estrogen receptor modulator (SERM) tamoxifen has long been used to treat both early and advanced breast cancer. Raloxifene is a second-generation SERM that, in addition to combatting osteoporosis, may also lessen the risk of invasive breast cancer in postmenopausal women. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Study of Tamoxifen and Raloxifene (STAR) is a prospective, randomized, double-blind trial conducted at nearly 200 clinical centers throughout North America. Participating were 19,747 postmenopausal women whose mean age was 58.5 years and whose 5-year breast cancer risk was increased at 4.03%. The minimal 5-year risk for entering the trial was 1.66%. The women received either 20 mg tamoxifen or 60 mg raloxifene daily for 5 years.

Introduction The Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting.Methods A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score.Results After adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7–3.9%), 10.7% (95% CI 6.3–14.9%), and 15.5% (95% CI 7.6–22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5–7.9%), 17.8% (95% CI 11.8–23.3%), and 19.9% (95% CI 14.2–25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values.Conclusion In this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients.

Background: This study was designed to investigate the activity and safety of rituximab (Rituxan®, R) plus CHOP induction therapy followed by maintenance R in patients with previously untreated advanced stage indolent NHL. The initial results of R-CHOP induction treatment are reported here. Methods: 102 patients with Ann Arbor Stage III or IV indolent NHL (follicle center/follicular grade I/II or nodal marginal zone B-cell by REAL; Type B or C by IWF) were enrolled into this open-label, multi-center, community-based, Phase II, single-arm trial. Patients received 6 cycles of standard R-CHOP induction therapy (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, doxorubicin 50 mg/m2 all IV on Day 1; prednisone 100 mg/day Days 1–5). R 375 mg/m2 was given on Day 1 of each cycle except for cycle 1, when it was administered 2–3 days prior to CHOP chemotherapy. Subjects with an ongoing response (CR/CRu or PR) after induction receive maintenance R (4 weekly infusions) within 28 days after the completion of induction and repeated every 6 months for 2 years for a total of 16 maintenance R doses. The primary endpoints were CR/CRu after 6 cycles of induction and the incidence of R infusion-related toxicity during induction and maintenance therapy. Secondary endpoints included overall response rates (ORR), infusion times, serious adverse events (SAE) in induction and maintenance, and rituximab pharmacokinetics in maintenance therapy. Results: Baseline characteristics were: median age 57y (33.3% ≥60y); 40.2% female; ECOG performance status 0: 70.6%; Ann Arbor stage III: 28.4% and IV: 71.6%. Serum β2-microglobulin and LDH at baseline were above normal in 66.3% and 20.6%, respectively. CR/CRu at the end of induction in 102 patients was 51.0% (ORR 86.3%). 1% had progressive disease (PD) during induction. 2 subjects died during the induction period, both due to SAEs (probable pulmonary embolus, acute respiratory distress). SAEs occurred in 22.5% of subjects during induction with the most common event being febrile neutropenia (7.8%). Grade 3–4 R infusion-related toxicity occurred in 4.9% of patients in cycle 1; this decreased to 1% by cycle 2 of induction. Two subjects discontinued R for infusion-related toxicity. 44% of patients were able to receive their R dose within 3 hrs at cycle 2 and 69.2% of patients at cycle 6. Conclusion: Patients with advanced stage indolent NHL treated in the community setting with R-CHOP induction tolerate therapy well and have an excellent response rate. The outcomes of maintenance therapy and rituximab pharmacokinetics in maintenance await further follow-up.

Introduction: In 2001, we reported results of a pivotal study using BEXXAR in 60 patients (pts) with chemotherapy-refractory NHL who had been previously treated with a minimum of 2 protocol-specified chemotherapy regimens and had either not responded (72%) or had progressed within 6 mos of their last regimen (28%) (JCO. 2001;19:3918). Enrollment occurred between Nov 1996 and Mar 1998, with a data cutoff for the initial report of 31 Jan 2001. Thirty-six pts had low-grade (LG) NHL, 23 pts had transformed LG NHL, and 1 pt had mantle cell NHL. The median number of prior chemotherapies was 4 (range, 2–13). The overall response rate was 65%. Twelve (20%) of 60 pts achieved a CR; median duration of CR was not reached with 47 mos’ follow-up. At the initial data cutoff, an independent review panel verified that 9 (75%) of 12 CR pts had ongoing responses, without further therapy, ranging from 2.7–4.0 yrs. Methods: These 9 pts continue to be followed annually for investigator-assessed response. In addition, all 25 pts alive at the time of the last report continue to be followed for long-term safety (hypothyroidism, secondary cancers) for 10 yrs or until death. With a data cut-off of 1 Mar 2004, the minimum follow-up is now 5 yrs. Results: Of the 9 pts, 3 were >60 yrs of age, 5 had no response to their last chemotherapy; 3 had transformed to a higher histology, 2 had an IPI score ≥3; 4 had BM involvement; 2 had elevated LDH, and 6 had tumors ≥5 cm in diameter. Of the 9 ongoing responders, 7 are still being followed for efficacy and safety. One pt relapsed at 6.9 yrs and continues to be followed for safety. One pt was noncompliant with clinical assessments and was withdrawn from study at 5.0 yrs (still in CR at last follow-up). The remaining 7 pts (~60% of complete responders) remain in continuous CR from 5.0–7.2 yrs. With an additional 37 mos’ follow-up, none of the 25 pts developed an elevated TSH level. The rate of hypothyroidism remains at 4.2%. Six pts developed 8 secondary malignancies (7 skin cancers, 1 GI carcinoma). With 3 yrs’ longer follow-up, no additional cases of MDS have been reported. The annualized incidence of MDS is 2.4%/yr. Conclusions: In this pivotal study of BEXXAR, durable remissions of ≥5 yrs were achieved following only 1 wk of therapy in 9 heavily pretreated patients with LG, follicular, or transformed NHL who had many poor prognostic features for their disease. With 3 more yrs’ follow-up, long-term safety data remain basically unchanged, with no further reported cases of hypothyroidism or MDS.

Background:This study was designed to investigate the activity and safety of rituximab (Rituxan®, R) plus CHOP induction therapy followed by maintenance R in patients with previously untreated advanced stage indolent NHL. The initial results of R-CHOP induction treatment are reported here.

Introduction:In 2001, we reported results of a pivotal study using BEXXAR in 60 patients (pts) with chemotherapy-refractory NHL who had been previously treated with a minimum of 2 protocol-specified chemotherapy regimens and had either not responded (72%) or had progressed within 6 mos of their last regimen (28%) (JCO . 2001; 19:3918). Enrollment occurred between Nov 1996 and Mar 1998, with a data cutoff for the initial report of 31 Jan 2001. Thirty-six pts had low-grade (LG) NHL, 23 pts had transformed LG NHL, and 1 pt had mantle cell NHL. The median number of prior chemotherapies was 4 (range, 2–13). The overall response rate was 65%. Twelve (20%) of 60 pts achieved a CR; median duration of CR was not reached with 47 mos' follow-up. At the initial data cutoff, an independent review panel verified that 9 (75%) of 12 CR pts had ongoing responses, without further therapy, ranging from 2.7–4.0 yrs.