Plan a Successful Lymphoma or CLL Product Launch

Oncology

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Several key abstracts were presented at #ASCO17 covering data in lymphoma and chronic lymphocytic leukemia (see bottom of this post for the abstract details):

Abstract 7500First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.
Abstract 7503A genetic risk-stratified, randomized phase 2 intergroup study of fludarabine/antibody combinations in symptomatic, untreated chronic lymphocytic leukemia (CLL): Results from Cancer and Leukemia Group B (CALGB) 10404 (Alliance).
Abstract 7506Radiotherapy to bulky disease PET-negative after immunochemotherapy in elderly DLBCL patients: Results of a planned interim analysis of the first 187 patients with bulky disease treated in the OPTIMAL>60 study of the DSHNHL.
Abstract 7508Autologous (auto) versus matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic (allo) hematopoietic cell transplantation (HCT) in follicular lymphoma (FL) patients (pts) with early chemoimmunotherapy failure (ECF): A Center for International Blood and Bone Marrow Transplant Research (CIBMTR) analysis.

Although there is still a high unmet medical need in this area, the marketplace will be filling up with new oncologic entities in the next several years either as novel entities or as indication extensions (i.e. blinatumomab, obinutuzumab, ixazomib, venetoclax, pembrolizumab, daratumumab, rituximab, carfilzomib, and venetoclax). This poses a strain on public and private payer budgets as many of these targeted biologics are more expensive than the typical standards of care and most are accompanied by a diagnostic.

As the treatment space becomes more crowded, there will be more emphasis placed on cancer care pathways and adherence to protocols and practice guidelines. Integrations into electronic medical record systems to review when and how certain medications are prescribed and for which patients will be closely monitored by administrators responsible for budgets.

As one navigates through the myriad of guidelines and protocols that are available nationally and internationally, it is dizzying trying to figure out which ones are actually preferentially used by clinicians in their day to day practice. In Europe, the National Institute for Health and Care Excellence (NICE) generates their own practice guidelines. The European Society for Medical Oncology (ESMO) has several hematological malignancy guidelines available in the lymphoma and CLL space:

In the US, most clinicians follow the guidance issued by the National Comprehensive Cancer Network (NCCN) and their treatment guidelines. To review these guidelines without having to log into the NCCN website, one can leverage the Medscape website.

In Canada, each of the provinces, have their own treatment protocols for lymphomas and CLL:

Manufacturers, either as experienced veterans in the Oncology space or as brand new entrants, all must carefully navigate local, regional, and national protocols and the preferences of their key prescribers to truly understand the influencing factors on treatment decisions. It is important to gain an understanding of how electronic medical records and mandated protocol adherence is managed at each clinic, agency, jurisdiction, health team or institution and what level of influence they ultimately have on when and how treatments are prescribed. Often times, there are usage limitations or stipulations put into place and managed through filters such as prior authorizations. In addition, understanding how multidisciplinary teams influence decisions and what other stakeholders have a seat at the table will help manufacturers gain traction with their cancer treatments. Finally, including patients in a brand’s marketing and medical strategy serves to not only gather real-world data but also to validate patient journeys and intervention junctions. Patients can help to clarify where competitive points of differentiation exist versus other competitor products and can also illuminate where adherence, treatment delivery, packaging, communication, and follow-up experience issues can be further mined by manufacturers.

Fortunately, Impetus Digital can assist manufacturers with establishing an advisory board platform, leveraging the expertise of select stakeholders to give timely and expert advice on how best to navigate, launch, or increase brand awareness in the lymphoma and CLL space. Stakeholders can include oncologists, GPOs, nurses, other allied healthcare providers, payers, and patients. Enrolled advisors can be engaged through a series of online touchpoints either in the form of web meetings or online asynchronous assignments delivered as survey questions via InSite Surveyor™, discussion questions via InSite Exchange™, or annotation exercises. Through these series of advisor online touchpoints, manufacturers can solicit feedback on their regulatory, market access, medical, or marketing strategies, as well as gain insights on how to navigate around generics and biosimilars entering the market. They can also learn how to differentiate their product from other medications and how to position their product in treatment protocols. In addition, advisors can consist of geneticists and, through the use of small online working committees, can assist in the creation of diagnostic testing protocols or the development of biomarker service or channel strategies. Oncology advisors can also provide valuable feedback on launch planning, regulatory and reimbursement dossiers, patient assistance programs, private infusion clinic best practices, and loss of exclusivity strategies. Also, manufacturers can leverage virtual working groups to help develop clinical papers leveraging real-world data, medical education materials, press releases, and patient advocacy programs.

The virtual nature of the boards and working groups can help to increase the engagement rates of advisors who are often extremely busy and being utilized by multiple manufacturers for similar purposes. Also, the assignments, which are compelling, relevant, and timely, can give the advisors or steering committee members time to pause, reflect, process, and review their colleague’s comments on their own time, allowing for more thoughtful and granular insights shared through the online forums. All of the assignments are created, programmed, project managed, and reported out by Impetus and their technical team (medical subject matter experts); hence, the manufacturer’s workload is minimal and so are the costs when compared to more traditional in-person consultancy meetings.

Abstract 7500: BRIGHT Study: (iNHL and MCL)

J Clin Oncol 35, 2017 (suppl; abstr 7500)

Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP (Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported.

Abstract 7503:

Background: Prior to use of novel targeted agents for CLL, debate existed regarding the best chemoimmunotherapy regimen to build upon in patients (pts) with non-del(11q) disease. The role of lenalidomide (L) was also not defined. CALGB 10404 was a randomized phase 2 study addressing these questions. Methods: Pts with untreated CLL requiring therapy were randomized to treatment with fludarabine + rituximab (FR), FR + 6 monthly consolidative treatments of L (5 mg days 1-21/28 x 1 then 10 mg days 1-21/28 x 5) (FR+L), or FR + cyclophosphamide (FCR). Based on pretreatment central interphase cytogenetic screening, pts with del(11q22.3) in at least 20% of cells were excluded from the primary analysis, testing whether 2-year progression-free survival (PFS) rate was improved in non-del(11q) pts within each arm. A target accrual of 103 non-del(11q) pts per arm provided at least 84% power to detect an increase in 2-year PFS rate from 60% to 73%; the critical value was 69% using a single stage design and type I error rate of 4%. Results: A total of 342 non-del(11q) CLL pts were randomized to treatment with FR (n = 123), FR+L (n = 109), or FCR (n = 110). Baseline characteristics were similar across arms. Two-year PFS rates with exact 90% CIs were 64% (57-71%) (FR), 71% (63-78%) (FR+L), and 74% (66-80%) (FCR). Median PFS was significantly shorter with FR compared to FR+L (p = 0.03) and FCR (p < 0.01): 43 (95% CI: 33-50), 66 (95% CI: 45-not reached), and 78 (95% CI: 58-not reached) months respectively. Median overall survival (OS) has not been reached for any arm. OS at 1, 2, and 3 years was similar across arms, although there was a plateau in OS with no events beyond 41 months in the FR+L arm, different from FR/FCR where events continued to occur. The most common adverse events were cytopenias and infections. Conclusions: FR+L and FCR met the protocol defined primary endpoint. FR+L extended PFS relative to FR and a plateau in survival differentiated this arm from the FR/FCR arms. Future studies comparing FR+L to FCR or incorporating L into other novel treatment regimens are justified.

Abstract 7506:

Background: RT to bulky sites improves outcome of elderly DLBCL patients [Lancet Oncol 2008; 9: 105-116; J Clin Oncol 2014; 32:112-1118]. Whether RT can be spared in PET-negative pts. after R-CHOP was prospectively addressed in OPTIMAL >60. Methods: 61 to 80 y-old pts. were randomized in a 2×2 factorial design to 6xCHOP-14 or 6xCHLIP-14 (liposomal instead of conventional vincristine) plus 8 x rituximab 375 mg/m2(R) q 2 wks. or 12xR (days -4,-1,1,4,14,28,42,56,91,126,175, 238). Pts. with bulk (>=7.5 cm) PET-positive after 6 cycles chemotherapy were assigned to RT (39.6 Gy), while PET-negative bulks were observed. Results: 187/505 (37%) had bulky disease and were compared to 117/306 (38%) RICOVER-60 pts. (38%) who had received 6xCHOP-14+8R. OPTIMAL>60 pts. were older (70 vs. 68 years) and had more IPI=3 (33% vs. 29%) and IPI=4,5 (34% vs. 23%) compared to RICOVER-60. PET was performed in 166/187 OPTIMAL>60 bulk pts. (reasons for no PET: early death: 5; excessive toxicity: 3; protocol violation: 1, non-compliance: 4, change of diagnosis: 6, others: 2). 80/166 (48%) bulks remained PET-positive after 6 cycles of chemotherapy and 62/80 (78%) were irradiated (reasons for no RT: progression: 8; medical reasons: 9; negative biopsy: 1), reducing RT from 67/117 (57%) in RICOVER-60 by 42% to 62/187 (33%) in OPTIMAL>60. Despite the unfavorable demographics, outcome of the 187 bulk pts. in OPTIMAL>60 was non-inferior to RICOVER-60, not even in the least intensive of the 4 OPTIMAL>60 treatment arms consisting of 47 pts. who received 6xCHOP-14+8R as in RICOVER-60. 2-year PFS and OS in OPTIMAL>60 was 79% and 88%, respectively, compared to 75% and 78% of the 117 RICOVER-60 pts. In a multivariable analysis adjusting for the IPI risk factors, the hazard ratio of the OPTIMAL>60 compared to the RICOVER-60 bulk pts. was 0.7 (95% CI: 03.; 1.5; p=0.345) for PFS and 0.5 (95% CI: 02.; 1.3; p=0.154) for OS. Conclusions: RT can be spared in bulky disease PET-negative after chemotherapy. This strategy results in a 42% reduction of RT without compromising the outcome of these patients.

Abstract 7508:

Background: Contrary to most FL, high-risk FL pts with ECF (i.e. relapse within 2 yrs of frontline chemoimmunotherapy) have a 5 yr OS of only 50%. (Casulo, JCO 2015). We used the CIBMTR database to compare autoHCT versus either MSD or MUD alloHCT as the first transplant approach in FL pts with ECF. Methods: Adult FL pts (age ≥18) undergoing autoHCT or alloHCT between 2002-2014 and receiving first line rituximab-based chemoimmunotherapies with evidence of ECF (defined as disease relapse or progression within 2 yrs of treatment initiation) were included. The primary endpoint was OS; secondary endpoints were progression-free survival (PFS), relapse and non-relapse mortality (NRM). Results: 440 pts had ECF (auto = 240, MSD = 105, MUD = 95) (Table 1). The 5 yr adjusted probabilities (AjP) of NRM were significantly lower with autoHCT (5%), versus MSD (17%) or MUD (33%) HCT (p<0.0001). 5 yr AjP of relapse were significantly lower with MSD (31%) or MUD HCT (23%), versus autoHCT (58%; p<0.0001). AjP of 5 yr PFS following auto, MSD and MUD HCT were 38%, 52% and 43% (p=.006) respectively. The AjP of 5 yr OS was significantly higher following autoHCT (70%) or MSD HCT (73%) versus MUD HCT (49%; p=0.004). Conclusions: AutoHCT for FL pts with ECF has low NRM and 5 yr OS rates (70%) that are provocatively higher than historical data (~50%). MSD HCT had the lowest relapse rate with similar survival. A prospective trial confirming the role of HCT in ECF FL is warranted.

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