Sequencing Of Novel Agents Research Articles

Stratification for RRMM and Risk-Adapted Therapy: Sequencing of Therapies in RRMM.

Simple SummaryIn recent years, many new therapeutic options for newly diagnosed, as well as relapsed and refractory multiple myeloma (MM) have been approved. They have dramatically improved progression-free and overall survival. Despite these advances, MM still remains incurable and eventually all cases will become refractory to standard treatments. Many new substances and drug classes have become available, which has greatly increased treatment options. However, the right sequencing of novel treatments has become the main challenge in MM therapy. Guidelines can provide helpful recommendations, but diversifying treatment patterns make a one-fits-all approach impossible. This review aims to summarize existing evidence regarding the sequencing of novel agents and will also focus on groups of special interest such as elderly and frail patients.The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation.

Sequencing of novel agents in relapsed/refractory B-cell acute lymphoblastic leukemia: Blinatumomab and inotuzumab ozogamicin may have comparable efficacy as first or second novel agent therapy in relapsed/refractory acute lymphoblastic leukemia.

The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity. In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared. Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety-two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09). Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL.

Utilizing Real-World Evidence (RWE) to Improve Care in Chronic Lymphocytic Leukemia: Challenges and Opportunities.

This review discusses important findings from real-world evidence (RWE) studies impacting the field of chronic lymphocytic leukemia (CLL), from prognostication to long-term management and sequencing of novel agents. RWE data, which represents a heterogeneous cohort of patients treated at non-academic centers and off-clinical trial, demonstrate several key differences between findings in randomized controlled trials (RCT) of novel agents in CLL. While toxicity and discontinuation rates are higher, survival outcomes are encouraging in clinical practice, with often equivalent outcomes from reduced-dose or time-limited therapy of drug. Though sequencing of novel agents lacks robust RCT data, RWE data provide important guidance for selection and sequencing of novel agents. RWE has critically informed our practice by providing diverse patient data and real-time analysis for important clinical questions outpacing the rapidly growing field of CLL.

Improved Outcomes for Relapsed/Refractory Classic Hodgkin Lymphoma Following Autologous Stem Cell Transplantation in the Era of Novel Agents

Improved Outcomes for Relapsed/Refractory Classic Hodgkin Lymphoma Following Autologous Stem Cell Transplantation in the Era of Novel Agents

Real-World Evidence for Chronic Lymphocytic Leukemia in the Era of Targeted Therapies.

The landscape of chronic lymphocytic leukemia has transformed in the era of small molecule inhibitor targeted therapies. While randomized controlled trials remain the criterion standard in evaluating new therapies, they are often unable to keep pace with the clinical questions that arise during the use of novel agents. Real-world evidence is generated through analysis of data such as electronic medical records, payer claims, and patient registry databases and can provide invaluable information to supplement randomized controlled trials, such as outcomes in patient populations excluded from clinical trials, rates of discontinuation or dose reductions in clinical practice, survival outcomes, and optimal sequencing of novel agents. This review aims to discuss major findings from recent, relevant, real-world evidence publications that have greatly informed our understanding of chronic lymphocytic leukemia as it is treated in clinical practice.

Relapsed CLL: sequencing, combinations, and novel agents.

Although the therapy of chronic lymphocytic leukemia (CLL) has changed rapidly over the last 5 years, the key considerations in selecting a therapy for a previously treated patient with CLL continue to include the nature of the prior therapy and the duration of prior remission to that therapy, the prognostic features of the disease, and the health and comorbidities of the patient in question. For patients treated initially with chemoimmunotherapy, randomized trials have demonstrated the benefit of targeted therapy. Retrospective data suggest that ibrutinib is preferred as a first kinase inhibitor, whereas recent data with venetoclax and rituximab may challenge the choice of ibrutinib as a first novel agent in the relapsed setting. Data on sequencing of novel agents remain quite sparse, consisting of 1 prospective trial that demonstrated the efficacy of venetoclax in patients who have experienced progression with a kinase inhibitor, as well as a retrospective real-world analysis supporting this observation. Novel agents in advanced clinical development include primarily next-generation Bruton's tyrosine kinase and phosphatidylinositol 3-kinase δ inhibitors, with other classes still in phase 1 trials. Clinical trials of combination time-limited therapies with the goal of deep remission and discontinuation are also in progress.

How should we sequence and combine novel therapies in CLL?

With the recent approval of several effective and well-tolerated novel agents (NAs), including ibrutinib, idelalisib, venetoclax, and obinutuzumab, patients with chronic lymphocytic leukemia (CLL) have more therapeutic options than ever before. The availability of these agents is both an important advance for patients but also a challenge for practicing hematologist/oncologists to learn how best to sequence NAs, both with respect to chemoimmunotherapy (CIT) and to other NAs. The sequencing of NAs in clinical practice should be guided both by an individual patient's prognostic markers, such as FISH and immunoglobulin heavy chain variable region (IGHV)-mutation status, as well as the patient's medical comorbidities and goals of care. For older, frailer patients with lower-risk CLL prognostic markers, NA monotherapy may remain a mainstay of CLL treatment for years to come. For younger, fitter patients and those with higher-risk CLL, such as del(17p) or unmutated IGHV, combination approaches may prove to be more valuable than NA monotherapy. Trials are currently evaluating the efficacy of several such combination approaches, including NA plus anti-CD20 monoclonal antibody, NA plus NA (with or without anti-CD20 monoclonal antibody), and NA plus CIT. Given the tremendous efficacy of the already approved NAs, as well as the promising data for next generation NAs, the development of well-tolerated, highly effective combination strategies with curative potential for patients with CLL has become a realistic goal.

Current Treatment of Chronic Lymphocytic Leukemia.

A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions. Ibrutinib was proven as a primary choice for patients with the TP53 gene deletion/mutation, who otherwise have no active treatment available. Idelalisib with rituximab is also an active therapy, but due to increased risk of serious infections, its use in first-line treatment is limited to patients for whom ibrutinib is not an option. A new indication for ibrutinib was recently approved for older patients with comorbidities, as an alternative to the already existing indication for chlorambucil with obinutuzumab. The use of kinase inhibitors is already well established in recurrent/refractory disease. Immunochemotherapy with fludarabine, cyclophosphamide, rituximab (FCR) remains a major first-line option for many CLL patients without the TP53 gene deletion/mutation, and who have no significant comorbidities or history of infections, and is particularly effective in patients with favorable features including mutated IGHV status. There are a number of issues regarding novel therapies for CLL that need further investigation such as optimum duration of treatment with kinase inhibitors, appropriate sequencing of novel agents, mechanisms of resistance to inhibitors and response to class switching after treatment failure, along with the potential role of combinations of targeted agents.

Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in CLL: Results from a Large Multi-Center Study of 683 US-Patients

Introduction: Ibrutinib (Ibr), idelalisib (Ide), andvenetoclax (Ven), are all now approved for treating CLL patients in the US. However, in the absence of head-to-head comparator trials, there is limited guidance as to the optimal sequence of these therapies and to the best choice upon failure of first selected agent. To address these gaps in current literature, 9 large US cancer centers and the Connect CLL Registry collaborated to capture the experience of 683 CLLpts treated with kinase inhibitors (KIs) - focusing on optimal sequencing and patterns of failure.Patients and Methods: We conducted a multicenter, retrospective analysis of CLLpts treated withIbr-, Ide- orVen-based therapy. We examined demographics, discontinuation rates, reasons for discontinuation, overall response rates (ORR), survival, and post kinase inhibitor (KI) salvage strategies. Primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death, or last follow-up) as determined by the Kaplan Meier (KM) method. Comparisons were made using the log rank (LR) test and COX regression analyses.Results: A total of 683 pts treated with KI therapy (Ibr=621/Ide=62) were identified (Table 1). Baseline characteristics were similar in theIbr and Ide-based groups. ORR toIbr as first KI was 69% [complete response (CR) 11%, partial response (PR) 45%, and PR-L 13%] and Ide was 81% (CR 5%, PR 71%,PR-L 5%). With a median follow-up from start of first KI of 17 months (range 1-60), median PFS and OS for the entire cohort from first KI was 35 months (216 events) and not reached respectively (107 events). Interestingly,pts treated withIbr (vs. Ide) as first KI had a significantly better PFS in all settings; front-line (figure a, HR 2.8, CI 1.3-6.3 p=.01), relapsed-refractory (figure b, HR 2.8, CI 1.9-4.1 p<.001), clinical trials (HR 3.3, CI 1.8-5.9 p<.001), commercial use (HR 2.5, CI 1.5-4.0 p<.001), del17p (HR 2.0, CI 1.2-3.4 p=.008), or complex karyotype (HR 2.5, CI 1.2-5.2 p=.02). Moreover, at the time of initial KI failure, the use of either an alternate KI orVen was associated with superior PFS as compared tochemoimmunotherapy (CIT) combinations (figure c). When treated with an alternate KI (Ibr followed by Ide or Ide followed byIbr),pts intolerant of a KI therapy due to toxicity had a superior PFS compared with those taken off a KI therapy due to CLL progression (p=0.03, LR test). Furthermore,Ibr-failurepts had a marginally better PFS if treated withVen (ORR 79%) vs. Ide (ORR 46%) (figure d, HR .6, CI.3-1.0 p=.06).Conclusions: In the largest experience of novel agents published to date in CLL,Ibr appears superior to Ide in all settings as first choice KI. Further, in the setting of KI failure, an alternate KI orVen therapy appear superior to CIT combinations. Alternate KI appear particularly effective in the setting of intolerance to a prior KI. The use ofVen uponIbr failure might be superior to the use of Ide. These data provide guidance for sequencing of novel agents and support the need for trials directly comparing novel agents and sequencing strategies in CLL. [Display omitted] [Display omitted] DisclosuresMato:Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Lamanna:Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Ujjani:Genentech: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy. Brander:Gilead: Honoraria; TG Therapeutics: Research Funding. Cheson:Acerta: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Svoboda:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Schuster:Genentech: Consultancy, Honoraria; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Hoffman-LaRoche: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen Research & Development: Research Funding. Nabhan:Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy; Infinity: Consultancy; Cardinal Health: Consultancy; Seattle Genetics: Research Funding; Astellas: Research Funding.

Sequencing Novel Agents in Relapsed/Refractory Multiple Myeloma: Use of Bortezomib-Based Therapy After Lenalidomide + Dexamethasone.

Abstract 1853Poster Board I-879The optimal sequencing of novel agents in multiple myeloma (MM) is not certain. In Ontario, we had a unique opportunity to assess the efficacy of bortezomib (btz) in patients (pts) with MM who progressed after preferential treatment with lenalidomide + dexamethasone (len+dex) given via access programs/clinical trials for relapsed/refractory (rel/ref) disease. These pts all received len+dex, followed by btz-based regimens for their next relapse without any interim therapy. Between 12/2005 and 5/2009, 49 MM pts received len+dex for recurrent MM (23 in first, 20 in second, 5 in third, and 1 in fourth relapse after primary therapy). Thirty-nine pts (80%) had previously undergone autologous stem cell transplantation as part of initial therapy. Median age was 56 (range 31-77) yrs; 27 (55%) were male. The immunoglobulin subtype included IgG (21), IgA (15), IgM (1), light chain only (11) and non-secretory MM (1). ISS myeloma stage at referral consisted of stage 1 in 25 (50%), stage 2 in 18 (37%), stage 3 in 8 (16%), and not evaluable in 2 (4%) . Median β2-microglobulin level was 257 nmol/L, creatinine 77 umol/L and albumin 39 g/L. FISH cytogenetics, available in 19 pts, showed 13q del in 7, t(4;14) in 3 and p53 del in 3 pts. The median treatment duration of len+dex was 5.3 (0.5-47.5) mos; best clinical response included nCR in 3 (6%), VGPR in 3 (6%), PR in 25 (51%), MR in 6 (12%), SD in 6 (12%) and progressive disease (PD) in 6 (12%). Subsequent btz-based therapy included btz alone in 20 (41%), btz + corticosteroids (CS) in 23 (47%), btz + CS + p.o. cyclophosphamide in 4 (8%), and btz + other drug(s) in 2 (4%) of the pts. The median duration of btz-based therapy was 3.0 (0.5-17.2) mos. The best clinical response to btz-based therapy was nCR in 1 (2%), VGPR in 8 (16%), PR in 12 (25%), MR in 7 (14%), SD in 9 (18%) and PD in 12 (25%). The median follow-up from the start of btz-based therapy was 6.5 (1-29.5) mos. The median PFS and OS were 5.6 (95% CI 3.7-8.6) mos and 10.8 (95% CI 5.3-11.8) mos, while the 1-yr progression-free survival (PFS) was 20% (95% CI 9-35%) and overall survival (OS) 33% (95% CI 17-49%) mos, respectively, from the start of btz. Assessment of prognostic factors such as age at diagnosis, gender, myeloma subtype, duration from initial therapy to first relapse, previous response to len+dex, and type of btz-based therapy did not reveal a correlation with PFS or OS. However, achievement of ≥ PR with btz correlated with PFS (p=0.05) and OS (p=0.004). We conclude that treatment of sequential MM relapses with btz-based therapy after progression on len+dex: 1) produces ≥ PR in 43%; 2) results in a median PFS similar to the 6.22 mos seen with btz in less heavily pretreated pts in the APEX trial (Richardson P, et al. New Engl J Med 2005; 352:24); 3) demonstrates the effectiveness of btz even after exposure to the potent len+dex combination; 4) provides baseline information for evaluating the relative efficacy of the sequential versus combination use of novel agents in rel/ref MM. Disclosures:Reece:Ortho Biotech: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Chen:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria. Anglin:Celgene: Honoraria. Trudel:Ortho Biotech: Honoraria, Research Funding; Celgene: Honoraria.