Improvement In Overall Response Rate Research Articles

The emerging role of melflufen and peptide-conjugates in multiple myeloma.

The past two decades have witnessed an impressive expansion in the treatment landscape of multiple myeloma, leading to significant improvements in progression-free; as well as overall survival. However, almost all patients still experience multiple relapses during their disease course, with biological and cytogenetic heterogeneity affecting response to subsequent treatments. The purpose of this review is to provide a historical background regarding the role of alkylating agents and an updated data regarding the use of peptide-drug conjugates such as melflufen for patients with multiple myeloma. The combination of daratumumab-melflufen-dexamethasone evaluated in the LIGHTHOUSE study showed a statistically significant improvement in progression-free survival compared to single-agent daratumumab (not reached vs. 4.9 months respectively; P = 0.0032), with improvement in overall response rate to 59% vs. 30% respectively; P = 0.03. There have been an interest in developing and utilizing peptide-drug conjugates such as melflufen for treatment of patients with multiple myeloma, especially in the relapsed setting given historical results with alkylating agents, the use of which has been limited by dose-related toxicities in a disease that remains largely incurable. Single agent melflufen initially showed promising results especially in specific subgroups of heavily pretreated patients before the decision to suspend all clinical trials evaluating this agent after results from the OCEAN phase 3 trial. Subsequent reported analyses especially for melflufen-based combinations appear promising and suggest a potential use of peptide-drug conjugates provided optimal patient selection, as well as identification of the best companion agent.

Efficacy of disitamab vedotin (RC48) plus tislelizumab and S-1 as first-line therapy for HER2-overexpressing advanced stomach or gastroesophageal junction adenocarcinoma: A multicenter, single-arm, phase II trial (RCTS).

4009 Background: Integrating immunotherapy with trastuzumab and chemotherapy has shown a significant improvement in overall response rate (ORR) and progression-free survival (PFS) in HER2-overexpression gastric or gastroesophageal junction cancer (GC/GEJC). However, the overall survival (OS) did not achievestatistical significance, and there was no benefit in patients with a PD-L1 combined positive score (CPS) <1. RC48, an antibody-drug conjugate drug, has proven its effect in advanced HER2-positive (HER2 3+ or 2+ by IHC, regardless of FISH positivity) GC/GEJC in later-line treatment setting. This trial was to assess the efficacy and safety of combining RC48, immunotherapy (Tislelizumab), and S-1 as a first-line treatment for HER2-overexpressing GC/GEJC. Methods: This was a single-arm, multi-center, phase II trial conducted in patients with HER2-overexpressing metastatic or unresectable GC/GEJC for first-line treatments. Participants received RC48 (2.5 mg/kg), Tislelizumab (200 mg), and S-1 (40-60 mg BID for 14 days) every 3 weeks until disease progression or intolerable toxicities. The primary endpoint was ORR, while the secondary endpoints included disease control rate (DCR), PFS, OS, and safety. Results: A total of 47 patients were enrolled from 8 centers, median 65 (39 ~ 81) years old, 37 male, 37 GC and 8 GEJC, and all adenocarcinoma. Of them, 30 (63.8%) were HER2 IHC 3+, 11 (23.4%) HER2 IHC 2+/FISH+, and 6 (12.8%) IHC 2+/FISH-. Patients with PD-L1 CPS≥5, ≥1 accounted for 14.9%, 36.2% respectively. With a median follow-up duration of 116.5 days, patients received a median of 5.0 treatment cycles. As of January 20, 2024, 40 patients were included for efficacy analysis, and 44 patients for safety. The ORR reached 95.0% (38/40, 95% CI: 83.1-99.4%), clinical Complete Response rate was 20.0% (5/40, 95% CI: 4.2-26.8%), and the DCR was 100.0% (95% CI: 91.2-100.0%). The median PFS and OS were not reached, while the 6-month and 9-month PFS rates were 100.0% and 80.8%, the 6-month and 9-month OS rates were 100.0% and 83.8%. ORR among the HER2 IHC 3+, IHC 2+/FISH+, and IHC 2+/FISH- groups showed no significant difference (93.3%, 100.0%, 100.0%). ORR for patients with CPS≥1 or < 1 were 100.0%, 92.9%, respectively. One stage IVA GC patient (cT4bN3M0, HER2 3+, CPS 0) and another stage IVB GEJC one (cT3N2M1, HER2 2+/FISH+, CPS≥5) received radical surgery and both achieved pathological complete response. Grade 3/4 treatment-related adverse events occurred in 40.9% of patients, notably neutropenia, fatigue, and diarrhea. Conclusions: The combination of RC48, Tislelizumab, and S-1 showed notable efficacy with manageable safety in the first-line treatment of advanced HER2-overexpressing GC/GEJC patients. These findings support further exploration in this context. Clinical trial information: NCT05586061 .

Efficacy of platinum chemotherapy agents in adenosquamous carcinoma of the pancreas.

e16317 Background: Adenosquamous carcinoma of the pancreas (ASCP) is an aggressive, infrequent subtype of pancreatic cancer that combines a glandular and squamous component and is associated with poor survival. Data regarding adjuvant therapy remain controversial. Methods: Patients with advanced PASC from 2005 to 2021 were consecutively included in this retrospective study. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Results: Eighteen PASC patients treated surgically were included (median age, 69.3 years; males, 58.2%). All patients received adjuvant chemotherapy. Ten patients (55%) received newer platinum based regimen combination (FOLFIRINOX) and eight patients (45%) received gemcitabine-based regimens. Platinum based regimen as compared to gemcitabine regimen showed an improvement of overall response rate (42.5% and 12.3 %, p=0.001), PFS (median,10.4 versus 3.1 months, p=0.03) and OS (median, 15.8 vs 6.9 months, p=0.21).Multivariate analysis revealed that, among all patients (n=18), the following factors were independently predictive of poor survival: margin-positive resection (HR =3,15; 95% CI, 1.5-5.9; P<0.001), lymph node involvement (HR =2.9; 95% CI, 1.7 -7.5; P=0.003), and lack of inclusion of a platinum agent in the adjuvant regimen (HR =2.6; 95% CI, 1.5 -4.9; P=0.035). Conclusions: Given the rarity of ASC, optimal management remains poorly defined, particularly in the postoperative period. Therapies based on platinum chemotherapeutics may be preferable to all other chemotherapy regimens.

TP53-mutated acute myeloid leukemia and myelodysplastic syndrome: biology, treatment challenges, and upcoming approaches.

Improved understanding of TP53 biology and the clinicopathological features of TP53-mutated myeloid neoplasms has led to the recognition of TP53-mutated acute myeloid leukemia/myelodysplastic syndrome (TP53m AML/MDS) as a unique entity, characterized by dismal outcomes following conventional therapies. Several clinical trials have investigated combinations of emerging therapies for these patients with the poorest molecular prognosis among myeloid neoplasms. Although some emerging therapies have shown improvement in overall response rates, this has not translated into better overall survival, hence the notion that p53 remains an elusive target. New therapeutic strategies, including novel targeted therapies, immune checkpoint inhibitors, and monoclonal antibodies, represent a shift away from cytotoxic and hypomethylating-based therapies, towards approaches combining non-immune and novel immune therapeutic strategies. The triple combination of azacitidine and venetoclax with either magrolimab or eprenetapopt have demonstrated safety in early trials, with phase III trials currently underway, and promising interim clinical results. This review compiles background on TP53 biology, available and emerging therapies along with their mechanisms of action for the TP53m disease entity, current treatment challenges, and recently published data and status of ongoing clinical trials for TP53m AML/MDS.

Efficacy and Safety Profile of Lenalidomide vs Lenalidomide + R-CHOP in patients with Diffuse Large B Cell Lymphoma: A Systematic Review

The most frequent cause of non-Hodgkin lymphoma, which accounts for around one-third of cases, is diffuse large B cell lymphoma (DLBCL). Immune chemotherapy combined with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard therapy for DLBCL. Objective: To analysing the utilization of Lenalidomide versus Lenalidomide R-CHOP regimen in treatment of DLBCL in terms of treatment efficacy and safety. Methods: PRISMA guidelines were followed for conducting this study. A thorough literature search was done from November 15 to November 25, 2022. A variety of databases, including PubMed, Google Scholar, and other, were used to conduct the literature search. Finally, for this systematic review, 10 studies were chosen. Results: In our study the monotherapy with Lenalidomide was found less significant in terms of improvement in Overall response rate, complete response among patients with DLBCL. However; Lenalidomide + R-CHOP was more effective in improving overall response rate (ORR) with ORR of 92.89% vs 30.58% and complete response rate (CRR) of 80.20% vs 12.53%. The partial response rate (PR) was comparable between two therapies. similarly, the Progression free survival was also better in combination therapy. Haematological and Non-Hematological adverse effects of grade >3 were found higher among patients with combination therapy and Neutropenia was commonly observed adverse effect. Conclusions: Combination therapy was associated with significant improvement in disease outcome, however; the adverse effects were reported high in combination therapy vs monotherapy.

Metastatic renal cell cancer and first-line combinations: for which patients? (focus on tolerance and health-related quality of life)

Until recently, the first-line treatments used in metastatic renal cell carcinoma were based on first-generation anti-VEGFR (vascular endothelial growth factor receptor) tyrosine kinase inhibitors (TKIs) as monotherapy. Trials combining immunotherapy (IO) (anti-CTLA4 + anti-PD-1) or immunotherapy with TKIs showed striking results in the first-line setting with improvement in overall response rates, progression-free survival and overall survival versus sunitinib. This allowed the combinations to gain registration in the US and Europe in the first-line advanced or metastatic clear-cell renal cell carcinoma setting. However, this improved activity comes at the cost of increased toxicity. Immunotherapy-related toxicities usually occur earlier within the first six months. With immunotherapy came a new range of toxicities making it more necessary to work with networks of specialists to better address autoimmune toxicity in particular. The safety profile is also impacted by the type of TKI used. In most cases, health-related quality of life (HRQoL) favours combinations over the comparator sunitinib. This article aims to review and assess the safety and HRQoL data on these new combinations.

Mebendazole; from an anti-parasitic drug to a promising candidate for drug repurposing in colorectal cancer

AimsMetastatic colorectal cancer (mCRC) predominantly contributes to cancer-related mortalities secondary to distant metastasis. This study aimed at investigating anti-tumor activity and safety of mebendazole in patients with mCRC. Materials and methodsThis prospective, randomized double blind placebo-controlled study enrolled 40 mCRC patients who were randomized into two groups; the control group (n = 20) which received 6 cycles of bevacizumab with FOLFOX4 plus placebo tablets BID and mebendazole group (n = 20) which received 6 cycles of bevacizumab with FOLFOX4 plus mebendazole 500 mg orally BID for 12 weeks. Computed tomography scanning and serum levels of carcinoembryonic antigen (CEA), vascular endothelial growth factor (VEGF), liver and renal parameters were assessed at baseline and after 12 weeks. One-year overall survival and progression free survival (PFS) were also determined. Data were analyzed using paired, independent sample-t-tests, Mann-Whitney U, Chi-Square and Kaplan-Meier tests and p < 0.05 was considered statistically significant. Key findingsMebendazole was well tolerated and its addition to bevacizumab and FOLFOX4 enhanced tumor response to treatment which was translated by significant improvement of overall response rate 12 weeks after intervention [10 % (2) versus 65% (13) for control and mebendazole groups, respectively; p = 0.000] and significant elevation of PFS (median: 3 and 9.25 months for control and mebendazole groups, respectively; p = 0.000). Furthermore, mebendazole produced significant decline in VEGF level (p = 0.006) with non-significant variation in CEA level (p = 0.063). SignificanceMebendazole may represent an attractive candidate for drug repositioning against mCRC secondary to its safety and efficacy in enhancing tumor response to chemotherapy. Clinicaltrials.gov IDNCT03925662, retrospectively.

A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).

TPS4597 Background: Non-clear cell renal cell carcinomas (nccRCC) account for approximately 25% of RCC patients (pts.). Data on treatment strategies for this heterogenous group of RCC are still limited, since most clinical trials focus on clear-cell RCC (ccRCC) histology. Recently combination therapies with immune checkpoint inhibitors (IO, avelumab or pembrolizumab) and tyrosinekinaseinhibitors (TKI) (axitinib) have been approved for treatment in RCC in all International Metastatic RCC Database Consortium (IMDC) risk groups. Additionally nivolumab and ipilimumab (IO/IO) has been approved for treatment in intermediate and high risk pts. showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) compared to sunitinib. Moreover retrospective analysis in nccRCC pts. have shown promising results for IO-based therapies as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky &gt;70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ̃306 pts. stratified for papillary or non-papillary non-clear cell histology and by the IMDC risk score. Pts. will be randomized 1:1 to either i) nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by nivolumab fixed dose 240mg IV every 2 weeks or fixed dose 480mg IV every 4 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 214 patients (132 pts with papillary, 76 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423.

Paediatric severe aplastic anaemia treatment: where to start?

Paediatric severe aplastic anaemia treatment: where to start?

Pomalidomide, bortezomib, and dexamethasone for multiple myeloma previously treated with lenalidomide (OPTIMISMM): outcomes by prior treatment at first relapse

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.

A meta-analysis of the therapeutic effect of gefitinib combined with chemotherapy and chemotherapy alone in treating non-small cell lung cancer.

Whether the combination of gefitinib and chemotherapy is beneficial for advanced non-small cell lung cancer (NSCLC) remains controversial. This study aimed to summarize the currently available evidence and compare the efficacy and safety of gefitinib combined with chemotherapy versus chemotherapy alone for treating advanced NSCLC. Literature on comparing the effects of gefitinib combined with chemotherapy and chemotherapy alone in treating NSCLC was retrieved from the PubMed, EMBASE and Cochrane Database. The primary outcome measures included progression-free survival (PFS) and overall survival (OS). Revman 5.3 was used for data processing. Seven randomized controlled trials were included, involving a total of 1418 patients. There appeared a significant improvement in PFS (hazard ratio (HR) = 0.60 [95% CI 0.43, 0.82], P = .001) after treatment with gefitinib combined with chemotherapy when compared with chemotherapy alone. The subgroup analysis showed a significant advantage of sequential administration (HR = 0.67 [95% CI 0.57, 0.79], P < .00001). There was no significant improvement in OS (HR = 0.92 [95% CI 0.71, 1.20], P = .54), and no significant improvement in overall response rate (ORR) (HR = 0.98 [95% CI 0.67, 1.44], P = .93). The risks of rash and diarrhea (odds ratios) were higher in gefitinib combined with chemotherapy group when compared with chemotherapy alone, and there were significant differences on grade 3/4 rash and thrombocytopenia between 2 groups. Gefitinib combined with chemotherapy is superior to chemotherapy alone in PFS, sequential administration prolongs the patients' PFS, however, a survival advantage is not shown in OS or ORR. Gefitinib combined with chemotherapy aggravates rash, diarrhea and thrombocytopenia.

Pexidartinib (TURALIO™): The First FDA-Indicated Systemic Treatment for Tenosynovial Giant Cell Tumor.

Tenosynovial giant cell tumor is a rare proliferative tumor that arises from the synovium, bursae, or tendon sheaths due to an overproduction of colony-stimulating factor 1. Historically, treatment options for patients with local or diffuse tenosynovial giant cell tumor have been limited to surgical interventions. However, for some patients, surgical resection could worsen functional limitations and/or morbidity. In August 2019, the FDA approved pexidartinib (TURALIO™, Daiichi Sankyo), the first systemic treatment option for adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations that were not amenable to improvement with surgery. Pexidartinib is an oral tyrosine kinase inhibitor with selective inhibition of colony-stimulating factor 1 receptor and is the first systemic therapy to show significant improvement in overall response rates when compared with placebo. Clinicians using pexidartinib should monitor for liver-related adverse events, which may require treatment interruption, dose reduction, or treatment discontinuation. Pexidartinib provides a novel non-surgical treatment option for patients with tenosynovial giant cell tumor that may significantly improve patients’ overall response, range of motion, physical function, tumor volume, and stiffness.

A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).

TPS5103 Background: Non-clear cell renal cell carcinomas (nccRCC) are a heterogeneous group of tumors accounting for approximately 25% of RCC patients (pts.). Since most clinical trials focus on clear-cell RCC (ccRCC) only, data on treatment strategies for nccRCC are limited. The combination of Nivolumab and Ipilimumab (IO/IO) has recently been approved for treatment in RCC showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) in intermediate and high-risk pts. compared to sunitinib in a phase-III trial. Furthermore retrospective analysis in nccRCC patients have shown promising results for IO/IO as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky &gt; 70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non-papillary non-clear cell histology and by the International Metastatic RCC Database Consortium (IMDC) risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 122 patients (78 pts with papillary, 37 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423 .

Randomized phase II trial of CBDCA+nab-PTX vs CDDP+GEM in patients with chemo-naïve squamous cell lung cancer: NJLCG1302

Abstract Background The subset analysis of CA031 trial showed a significant improvement of overall response rate (ORR) for carboplatin (CBDCA) plus weekly nab-paclitaxel (CnP) versus CBDCA plus paclitaxel in patients (pts) with squamous cell histology (41% vs 24%). We conducted a phase II study comparing CnP to cisplatin plus gemcitabine (CG), one of the standard regimens in pts with squamous cell lung cancer (SCC). Methods Chemo-naive stage IIIB/IV or postoperative recurrent SCC pts were randomly assigned to receive either cisplatin (80 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1, 8 every 3 weeks or CBDCA (AUC 6 mg/ml/min) on day 1 plus nab-PTX (75 mg/m2) on days 1, 8, 15 every 3 weeks. The primary endpoint was ORR. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicity. Assuming that an ORR of 40% in eligible pts indicates potential usefulness and ORR of 20% is the lower limit of interest, the estimated accrual was 32 pts in each arm. Allowing for dropouts, the accrual goal was determined to be 35 pts in each arm (alpha, 0.05; beta, 0.20). Results Between June 2013 and October 2018, 71 pts were enrolled and assigned to CG arm (n = 35) and CnP arm (n = 36). The median follow-up time was 10.2 months. At data cutoff, ORR was 40% (95% confidence interval [CI]: 24.5-55.5) in CG arm and 47% (95%CI: 31.7-62.7) in CnP arm. DCR was 74% in CG arm and 80% in CnP arm. Median PFS was 4.6 months in CG arm and 4.3 months in CnP arm. Median OS was 10.9 months in CG arm and 10.0 months in CnP arm. Of the grade 3 or higher adverse events, anemia was more common in CnP arm (CG, 17% and CnP, 53%). There was one treatment-related death in CG arm and no treatment-related death in CnP arm. Conclusions In this study, both CnP and CG arms met the primary endpoint. Carboplatin-based CnP regimen was likely to be equivalent to CG for SCC.

The efficacy and safety of immune checkpoint inhibitor combination therapy in lung cancer: a systematic review and meta-analysis.

The value of immune checkpoint inhibitor (ICI) combination therapy for patients with lung cancer remains unclear. We conducted a meta-analysis using PubMed, Embase, and ClinicalTrials.gov databases to identify eligible randomized controlled trials (RCTs) that might provide a reference for clinical practice. The selection criteria were defined according to the population, intervention, comparison, outcome and study design (PICOS) framework. In all, 12 RCTs with 5,989 patients were included in this meta-analysis. Our results showed that ICI combination therapy was significantly associated with the improvement of overall response rate (ORR) (RR =1.44 [95% CI 1.19, 1.74], P=0.0002), progression-free survival (PFS) (HR =0.67 [95% CI 0.59, 0.77], P<0.00001), and OS (HR =0.81 [95% CI 0.70, 0.95], P=0.008) in lung cancer. In subgroup analyses, combination ICI therapy significantly prolonged OS in non-small-cell lung cancer (NSCLC) patients (HR =0.80 [95% CI 0.73, 0.88], P<0.00001) but not in SCLC (HR =0.94 [95% CI 0.82, 1.08], P=0.40) patients. Data suggested that PD-1 inhibitors had higher efficacy and safety profiles than PD-L1 and CTLA-4 inhibitors in combination ICI therapy for lung cancer patients. Furthermore, tolerability analysis revealed higher incidences of grade ≥3 AEs, fatigue, and increased transaminases from combination ICI therapy. In conclusion, our meta-analysis indicated that combination ICI therapy should be considered in clinical practice and future study designs for NSCLC patients. However, the current data do not support the large-scale clinical application of combination ICI therapy in SCLC patients.

Response rates to single-agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non-small cell lung cancer

IntroductionExploratory analysis of clinical trials in various tumor types have demonstrated potential improvements in overall response rate (ORR) to chemotherapy after exposure to vaccine-based immunotherapy. The objective of this retrospective study was to determine if single-agent chemotherapy (3rd-line or beyond) would yield improved ORR when given after exposure to programmed death-(ligand)1 inhibitors (anti-PD1) in metastatic non-small cell lung cancer (NSCLC). Materials and methodsWe queried the Thoracic GEMINI database of MD Anderson Cancer Center for patients treated between 06/12 and 11/16 who received at least one single-agent chemotherapy as 3rd-line or beyond, following progression after platinum-based chemotherapy and anti-PD1. We evaluated efficacy outcomes to each therapy, including ORR by RECIST version 1.1, progression-free survival (PFS), and overall survival (OS). ResultsOut of 306 anti-PD1-treated patients registered in the database, 28 met eligibility criteria − 54% were male, median age was 66 years, 82% had adenocarcinoma, and 71% were former/current smokers. The anti-PD1 and single-agent chemotherapy most commonly used were nivolumab (86%) and docetaxel (50%), respectively. ORR to single-agent chemotherapy after exposure to anti-PD1 was 39% (11/28 patients, 8 confirmed). In contrast, ORR to first-line chemotherapy in this cohort was 37%. Liver metastasis was the only factor associated with response to single-agent chemotherapy on univariate analysis (p<0.05). ConclusionIn NSCLC patients, the confirmed ORR to single-agent chemotherapy after immunotherapy exposure was higher as compared to historical data from the pre-anti-PD1 era, and approached ORR to first-line platinum-based chemotherapy. Further investigation of a possible immunotherapy-induced chemosensitization effect is warranted.

Bevacizumab as first-line treatment in HER2-negative advanced breast cancer: pros and cons.

Bevacizumab, a humanized, anti-vascular endothelial growth factor-A monoclonal antibody, has shown efficacy in a number of cancers. However, its use in metastatic breast cancer (MBC) remains controversial. A literature review using the PubMed database was performed to update the currently available clinical trials evidence on bevacizumab in the first-line treatment of breast cancer. In addition, the proceedings of selected oncology annual meetings were searched for relevant presentations. This article reviews the available evidence for bevacizumab as first-line therapy for MBC and discusses its current and future applicability in the management of MBC. Three phase III trials (ECOG-2100, AVADO, RIBBON-1) demonstrated that the addition of bevacizumab to chemotherapy is well-tolerated and improves progression-free survival and objective response rates in the first-line setting. These findings were supported by a large clinical practice-based study (ATHENA) and a recent clinical trial in which bevacizumab added to paclitaxel showed notable activity in triple-negative MBC. However, bevacizumab has thus far not demonstrated a significant benefit in overall survival. The addition of bevacizumab to chemotherapy is well-tolerated and produces substantial improvements in overall response rate and progression-free survival, compared with chemotherapy alone, in advanced HER2-negative breast cancer. Nevertheless, it has thus far not demonstrated a significant benefit in overall survival. Whether prolongation of progression-free survival is enough to consider bevacizumab efficacious is unclear. Based on the available clinical trials results, bevacizumab is a part of the complex therapeutic strategy of advanced HER2-negative breast cancer.

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma

Carfilzomib (Kyprolis®) is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome (the proteolytic core particle within the 26S proteasome), inducing growth arrest and apoptosis. This intravenous drug is approved in the EU and the USA as combination therapy with oral lenalidomide and intravenous or oral dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. In the multinational, phase III ASPIRE study in this patient population, carfilzomib triple combination therapy significantly prolonged progression-free survival (PFS), reflecting a clinically relevant gain in PFS of 8.7months, compared with lenalidomide plus dexamethasone. Improvements in overall response rate and patients' global health status were also observed with carfilzomib triple combination therapy. A significant improvement in overall survival (OS) is yet to be demonstrated, with the prespecified stopping boundary not crossed at the time of the prespecified interim analysis, although OS data were not mature by the cut-off date. Carfilzomib triple combination therapy had a manageable tolerability profile. The incidences of the most frequently reported grade 3 or higher adverse events of special interest (with the exception of neutropenia, anaemia and thrombocytopenia) were low in both the carfilzomib triple combination therapy and lenalidomide plus dexamethasone groups. Although final OS data are awaited, current evidence suggests carfilzomib in combination with lenalidomide and dexamethasone is a welcome addition to the treatment options currently available for patients with relapsed multiple myeloma.

Safety Profile of Oral Ixazomib: Experience from 761 Patients (Pts) Across 14 Phase 1 or Phase 1/2 Clinical Studies

e78 BP-055 Subgroup Analysis by Prior Treatment of the Efficacy and Safety of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Relapsed or Relapsed and Refractory Multiple Myeloma in the PANORAMA 1 Study P.G. Richardson, V.T.M. Hungria, S.-S. Yoon, M. Beksac, M.A. Dimopoulos, A. Elghandour, W.W. Jedrzejczak, A. Guenther, T.N. Nakorn, N. Siritanaratkul, R.L. Schlossman, J. Hou, P. Moreau, S. Lonial, J.H. Lee, H. Einsele, M. Sopala, B.R. Bengoudifa, C. Corrado, J.F. San-Miguel Dana-Farber Cancer Institute, Boston, MA, USA; Irmandade da Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Ankara University School of Medicine, Ankara, Turkey; Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; Alexandria University, Alexandria, Egypt; Medical University of Warsaw, Warsaw, Poland; Division of Stem Cell Transplantation and Immunotherapy, 2 Department of Medicine, University Hospital SchleswigHolstein and University of Kiel, Kiel, Germany; King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand; Siriraj Hospital, Bangkok, Thailand; Chang Zheng Hospital, Shanghai, China; University Hospital of Nantes, Nantes, France; Winship Cancer Institute, Atlanta, GA, USA; Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea; Medizinische Klinik und Poliklinik II, University of Wurzburg, Wurzburg, Germany; Novartis Pharma AG, Basel, Switzerland; Clinica Universidad de Navarra, Pamplona, Spain Introduction: Panobinostat (PAN), a potent pan-deacetylase inhibitor, affects processes integral to growth and survival of multiple myeloma (MM) cells through alteration of protein metabolism and epigenetic mechanisms. In the PANORAMA 1 phase 3 trial, combination of PAN with bortezomib (BTZ) and dexamethasone (Dex; PAN-BTZ-Dex) led to a clinically significant increase in progression-free survival (PFS) of z4 mo vs placebo plus BTZ and Dex (Pbo-BTZ-Dex). This analysis examined efficacy and safety of PAN-BTZ-Dex based on prior treatment. Therapeutic options for patients (pts) who have received immunomodulatory agents (IMIDs) and protease inhibitors are limited, and with each relapse these options become progressively restricted by drug resistance or intolerance. Methods: The study design was described previously (San-Miguel JF, Lancet Oncol. 2014). A subanalysis assessed efficacy and safety of PAN-BTZ-Dex in pts based on prior treatment characteristics, including receipt of prior IMiDs, BTZ + IMiDs, and BTZ + IMiDs and 2 prior lines of therapy. Here, we focus on efficacy and safety of PAN-BTZ-Dex in pts with relapsed or relapsed and refractory MM who received 2 prior regimens, including BTZ and an IMiD (n1⁄4147). Results: Pts in the PAN-BTZ-Dex arm (n1⁄473) had improved efficacy compared with those receiving Pbo-BTZ-Dex (n1⁄474). Of note, in the studied subgroup, pts in the PAN arm had Clinical Lymphoma, Myeloma & Leukemia September 2015 a longer median PFS (12.5 mo) than those in the Pbo arm (4.7 mo, HR: 0.47 [95% CI, 0.31-0.72]; Figure). Pts in the PAN arm vs Pbo arm also showed improvements in overall response rate (ORR; 58.9% [95% CI, 46.8%-70.3%] vs 39.2% [28.0%-51.2%]) and complete response/near-complete response (CR/nCR) rate (21.9% [95% CI, 13.1%-33.1%] vs 8.1% [3.0%-16.8%]). Common grade 3/4 adverse events and laboratory abnormalities in the PAN arm vs Pbo arm included thrombocytopenia (68.1% vs 44.4%), neutropenia (40.3% vs 16.4%), diarrhea (33.3% vs 15.1%), and asthenia/fatigue (26.4% vs 13.7%). Importantly, incidence of ontreatment deaths was nearly identical in both arms (n1⁄45 [6.9%] vs n1⁄45 [6.8%]). Conclusion: This analysis identified a subpopulation of pts in whom PAN-BTZ-Dex more than doubled the PFS vs PboBTZ-Dex, with marked improvements in CR/nCR rate and ORR. The safety profile was similar to the overall population. Together, these findings support the approval of PAN-BTZ-Dex by the US FDA in pts with relapsed or relapsed and refractory MM with 2 prior regimens, including BTZ and an IMiD. BP-056 Safety Profile of Oral Ixazomib: Experience from 761 Patients (Pts) Across 14 Phase 1 or Phase 1/2 Clinical Studies S. Lonial, K. Colson, R.D. Harvey, S. Kumar, A.-M. Hui, G. Liu, D. Berg, P. Richardson Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Division of Hematology, Mayo Clinic, Rochester, MN, USA; Millennium Pharmaceuticals, Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company

Internal medical management of extranodal nasal type NK/T cell lymphoma

Extranodal nasal type NK/T cell lymphoma (ENKTL) is a highly aggressive non-Hodgkin lymphoma. Due to its low occurrence even in prevalent areas, there has been no large sample randomized controlled clinical trials. Therefore, no standard therapeutic strategy is currently identified in this disease. Tumor cells are insensitive to conventional anthracyclines-containing chemotherapy because of high expression of multi-drug resistant gene 1. Regimens that incorporate the use of L-asparaginase or gemcitabine result in substantial improvements in overall response rate and are promising treatment for ENKTL. Targeted therapy, immunomodulatory therapy and hematopoietic stem cell transplantation are still under research. Key words: Lymphoma, extranodal NK-T-cell; Drug therapy; Hematopoietic stem cell transplantation