Type Of Prior Therapy Research Articles

Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL).

LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. Methods: A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. Results: 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and >75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. Conclusions: MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. Clinical trial information: NCT01295827. [Table: see text]

Chronic lymphocytic leukemia: treatment of relapse.

Despite significant advances in the frontline treatment of chronic lymphocytic leukemia (CLL), patients eventually experience disease progression. Treatment selection of relapsed disease depends upon a variety of factors, including patient age, performance status, duration of response to initial therapy, type of prior therapy, disease-related manifestations and genetic abnormalities within the CLL cells. This presentation offers synthetic overview of the options in this field.

Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy

Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

Prolonged treatment with lenalidomide in relapsed and refractory multiple myeloma

The medical treatment of multiple myeloma has significantly improved over the last few years. Lenalidomide is an immunomodulatory agent approved, in combination with dexamethasone, to treat this disease. The agent is well tolerated and results in disease improvement in 60% of treated patients. The overall outcome of patients who achieve a response is better than those who do not. However, attaining a response can take several months. Prolonged treatment has been associated with induction of responses of better quality and maintenance of responses, leading to better long-term outcomes. The clinical cases presented here illustrate how continued long-term administration of lenalidomide in combination with dexamethasone: 1) is effective for patients who are resistant to thalidomide, regardless of the type of prior therapy; 2) is suitable for patients with neuropathy and renal impairment: and finally 3) leads to a long lasting, clinically meaningful outcome when treatment is adapted to the best tolerated dose.

The relationship between the responses to prior systemic therapies and the efficacy of subsequent pemetrexed (Pem) therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC)

8061 Background: Pem has been used for pts with previously treated advanced NSCLC. We tried to examine whether the response to prior systemic therapy regimen could predict the efficacy of subsequent Pem therapy. Methods: The medical record of clinical stage IIIB or IV NSCLC pts who received Pem as the second-line or further-line treatment were analyzed retrospectively. Prior systemic therapies were divided into 4 types [gemcitabine based (G), paclitaxel based (P), docetaxel based (D), and EGFR tyrosine kinase inhibitors (I)]. Along with that, patients were classified into two response groups, either responders (partial responses or stable disease for 4 months or more) or non-responders to each type of the prior therapy. Response rate (RR) and progression free survival (PFS) for Pem therapy were analyzed according to the response groups for each type of prior therapies. Results: A total of 247 pts received Pem therapy, and their median PFS was 2.3 months. The number of pts who previously received G, P, D and I, was 159, 120, 110, and 139, respectively. The RR for Pem was higher in responders to G therapy than in non-responders to G (15.0% vs 4.3%, p = 0.02). In addition, median PFS after Pem therapy was longer in responders to G therapy than in non-responders (3.0 vs 1.7 months, p = 0.007). However, the responses to prior P, D, I therapies had no impact on the efficacy of subsequent Pem therapy. By univariate analyses, the variables of the responders to G therapy, female, never-smoker, ECOG performance status 0–1 were good predictive factors for Pem therapy in terms of PFS. By multivariate analysis, only the responders to G therapy had a statistical significance (Hazard ratio = 0.55; 95% CI, 0.37–0.82). Conclusions: The response to the prior gemcitabine based therapy was a predictive factor for subsequent pemetrexed therapy for advanced NSCLC. No significant financial relationships to disclose.

Management of early and advanced colorectal cancer: Therapeutic issues

The staging of colorectal cancer, therapeutic decision making in the management of early and advanced colorectal cancer, and dilemmas posed by drug-related toxicity are discussed. Staging of colorectal cancer occurs after surgery and is based on the extent of disease invasiveness and dissemination. Surgery is the primary treatment for stage I disease. Adjuvant chemotherapy is recommended after resection in selected high-risk patients with stage II disease and in all patients with stage III disease. Convenience of administration, tolerability, and patient factors not necessarily age may be considerations in decisions about adjuvant therapy after resection. Treatment of stage IV colorectal cancer is based on the type of prior therapy and patient-specific factors. Recently, significant improvements in survival have been achieved through the use of combination chemotherapy and monoclonal antibody regimens. Bevacizumab in combination with chemotherapy is first-line therapy for stage IV disease. Age alone should not preclude the use of chemotherapy in stage IV colorectal cancer, although the ability to tolerate drug-related toxicity may be a consideration. The optimal duration of chemotherapy in patients with early and metastatic colorectal cancer is unclear. The optimal approach to the treatment of colorectal cancer depends on several considerations, including patient-specific factors.

Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib

To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

Development of neuropathy in patients (pts) with multiple myeloma (MM) treated with thalidomide (thal)—Patterns of occurrence and the role of electrophysiologic monitoring

7618 Background: Given new treatment options for pts with MM, physicians are faced with the dilemma of how best to sequence these drugs in order to optimize efficacy and toxicity. Peripheral neuropathy frequently limits the duration of treatment (Rx) with thal. In this study we assessed the utility of serial nerve electrophysiological studies (NES) to detect the onset of neuropathy, and assessed the time course of occurrence and possible clinical and Rx-related predictive factors. Methods: 75 pts with relapsed/refractory MM were enrolled in a multi-centre trial of thal. In addition to clinical assessment, pts underwent sensory and motor NES at baseline and every 3 months in order to identify neuropathy. We examined the value of baseline and serial NES for development of neuropathy, with time to development of neuropathy according to clinical or NES criteria compared using Kaplan-Meier analysis. Differences between pt and Rx-related variables were compared using a Mann-Whitney U-test or a Fisher’s exact test. Results: Thirty nine percent had some NES abnormalities at baseline. Pts were treated with thal at a median dose intensity of 373 mg/day and followed for a median of 18 months (range 6–26). Thirty-one of the 75 pts (41%) developed neuropathy during thal Rx, with 11 (15%) ceasing thal due to neuropathy. The actuarial incidence of any neuropathy increased from 38% at 6 months to 73% at 12 months with 81% of responding pts developing this complication. The use of NES did not reliably predict the imminent development of clinical neuropathy requiring cessation of thal. Nor were pt age, gender or type of prior therapy (ie vincristine) predictive. Development of neuropathy was related to duration of thal exposure with a median time of 268 days thal in those who developed neuropathy compared to 89 days in those who did not (p = 0.0001). Cumulative dose or dose intensity received were not predictive. Conclusions: The majority of pts will develop peripheral neuropathy given sufficient length of thal Rx and to minimize the risk of neurotoxicity, therapy should be limited to less than six months. NES monitoring provides no clear benefit over careful clinical evaluation for the development of clinically significant neuropathy. [Table: see text]

Lenalidomide (Len) in combination with dexamethasone (Dex) is more effective than Dex alone at first relapse and provides better outcomes when used early rather than as later salvage therapy in relapsed multiple myeloma (MM)

7600 Background: High-dose Dex remains a standard therapy for relapsed or refractory MM. Lenalidomide is a novel, oral, immunomodulatory drug (IMiD) that has activity against MM with additive effects when combined with Dex. At the interim analysis of MM-009/010, Len/Dex achieved a significant benefit over Dex, providing a longer median TTP, higher response rates, and higher CR rates. Aim: This prospective subgroup analysis was performed to determine the potential benefit of starting Len/Dex at first relapse by analyzing outcomes versus Dex among patients (pts) who had received only 1 versus >1 prior line of therapy. Methods: Pts who had received 1–3 prior treatments and were not refractory to Dex were randomized to either oral lenalidomide (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on Days 1–4, 9–12, 17–20 every 4 weeks for 4 months, then 40 mg on Days 1–4 every cycle thereafter) or placebo plus Dex. The EBMT criteria were used for response. Randomization was stratified at entry by number of prior therapies (1 versus > 1). Results: Of 692 randomized pts, 241 pts (34%) received only 1 prior therapy. Those receiving 2nd-line Len/Dex had a significantly longer median TTP (66 vs. 20 wks) and a higher RR (CR + PR); (63% vs. 26%) versus those receiving 2nd-line Dex. After a median follow-up of 12.1 mos for all pts, 2nd-line Len/Dex provided significantly improved overall survival (OS) (hazard ratio 1.85, P = 0.03) versus 2nd-line Dex. Among the 451 pts who had received > 1 prior line of therapy, the median TTP (44 vs. 20 wks), RR (57% vs. 20%), and OS (hazard ratio 1.50, P = 0.03) were higher with Len/Dex vs. Dex. Response to Len/Dex was superior to that of Dex regardless of the type of prior therapy. Comparing pts who received Len/Dex as 2nd-line versus later salvage therapy, the median TTP was longer and response rates higher in pts treated in second-line. Conclusions: Len/Dex provided higher response rates and improved TTP compared with Dex at first relapse and beyond. TTP and response rates were superior when Len/Dex was administered earlier at first relapse compared with its use as later salvage therapy. These data support the use of Len/Dex for pts as 2nd-line therapy for relapsed MM. [Table: see text]

Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C trial

In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)-based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa-2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All patients had failed prior treatment with IFN or peginterferon +/- RBV and had Ishak fibrosis scores > or = 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/mm3 (n = 559); (B) bridging fibrosis with platelet counts < or =125,000/mm3 (n = 96); (C) cirrhosis (Ishak 5 and 6) with platelet counts >125,000/mm3 (n = 198); and (D) cirrhosis with platelet counts < or =125,000/mm3 (n = 193). SVR rates were 23%, 17%, 10%, and 9% in groups A, B, C, and D, respectively (P < .0001 for trend). Reduction in SVR as a function of increasingly severe disease was independent of age, percent African American, HCV genotype, HCV level, and type of prior therapy. Dose reduction lowered SVR frequencies, but to a lesser extent than disease severity. By logistic regression, cirrhosis (P < .0001) was the major determinant that impaired virologic response, independent of dose reduction or platelet count. In conclusion, disease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C. New strategies are needed to optimize antiviral therapy in these "difficult-to-cure" patients.

Patient selection for salvage cryotherapy for locally recurrent prostate cancer after radiation therapy.

Our objective was to identify clinical pretreatment factors associated with early treatment failure after salvage cryotherapy. Between 1992 and 1995, 145 patients underwent salvage cryotherapy for locally recurrent adenocarcinoma of the prostate. Treatment failure was defined as an increasing postcryotherapy serial prostate-specific antigen (PSA) level of more than or equal to 2 ng/mL above the postcryotherapy nadir or as a positive posttreatment biopsy. We evaluated the following factors as predictors of treatment failure: tumor stage and grade at initial diagnosis, type of prior therapy, stage and grade of locally recurrent tumor, number of positive biopsy cores at recurrence, and precryotherapy PSA level. Among patients with a prior history of radiation therapy only, the 2-year actuarial disease-free survival (DFS) rates were 74% for patients with a precryotherapy PSA less than 10 ng/mL and 28% for patients with a precryotherapy PSA more than 10 ng/mL, P <.00001. The DFS rates were 58% for patients with a Gleason score of less than or equal to 8 recurrence and 29% for patients with a Gleason score greater than or equal to 9 recurrence, P <.004. Among patients with a precryotherapy PSA less than 10 ng/mL, DFS rates were 74% for patients with a prior history of radiation therapy only and 19% for patients with a history of prior hormonal therapy plus radiation therapy, P <.002. Patients failing initial radiation therapy with a PSA more than 10 ng/mL and Gleason score of the recurrent cancer more than or equal to 9 are unlikely to be successfully salvaged. Patients failing initial hormonal therapy and radiation therapy are less likely to be successfully salvaged than patients failing radiation therapy only.

Gestational trophoblastic disease metastatic to the central nervous system.

To evaluate characteristics of patients with central nervous system (CNS) lesions of gestational trophoblastic disease (GTD) and determine prognostic and therapeutic implications applicable to management. We retrospectively reviewed the records of 454 patients treated at the Southeastern Regional Trophoblastic Disease Center between 1966 and 1992 with at least 2 years of follow-up, and identified 42 (9.3%) with CNS metastases. Sixteen patients presented for primary therapy and 27 patients had received significant therapy prior to presentation. Three heavily treated moribund patients died before their first cycle of chemotherapy and were excluded from analysis. Brain metastases were documented by physical exam and radionuclide imaging (before 1976), computed tomography scan (after 1976), or magnetic resonance imaging (after 1986). Patients received multiagent chemotherapy with methotrexate, actinomycin D, and chlorambucil (MAC)- or etoposide-based regimens. All patients received radiation therapy. No intrathecal chemotherapy was given. Craniotomy was employed in seven cases. Remission was defined as three weekly hCG levels below assay sensitivity (< 5 mIU/ml). Overall survival was 44%. Twelve of 16 patients (75%) who presented with CNS metastases with no prior therapy (Group A), 5 of 13 (38%) patients who had prior treatment (Group B), and none of 10 patients who developed CNS metastases during therapy (Group C) survived (P < 0.05). Two of four patients who failed in the CNS after treatment for CNS lesions were salvaged. Demographic characteristics of Groups A and B were similar. No significant differences with respect to WHO score, interval from pregnancy to onset of disease, or age among these groups were found. Group B patients had a four-fold higher incidence of liver metastases. Survival of Group A patients was not related to conventional clinical prognostic factors. Inverse (nonsignificant) correlations were found for Group B patients between survival and WHO score, hCG level, size and number of metastatic lesions, but not type of prior therapy. Survival was higher in those with prior molar pregnancies (56%) as contrasted with aborted (50%) or term (27%) gestations. Selective use of craniotomy helped alleviate intracranial pressure and resect refractory foci. Chemotherapy combined with radiation therapy in GTD patients with CNS metastases yields survival rates comparable to those reported for intrathecal methotrexate regimens. Tumor burden as indicated by hCG level and size/number of metastases in previously treated patients may correlate with survival. Patients who develop CNS metastases during active therapy have a very poor outcome.