NEWS & ANALYSIS FROM THE ANALYST’S COUCH Non-Hodgkin lymphoma therapy landscape Kritika Chaudhari, Salman Rizvi and Basharut A. Syed Quality Stock/Alamy Stock Photo Credit: Non- Hodgkin lymphoma (NHL) comprises and/or δ (PI3Kγ/δ) inhibitors, idelalisib response after two cycles of chemotherapy. a wide spectrum of lymphoid neoplasms (Zydelig; Gilead Sciences), copanlisib Although blinatumomab is associated that affect approximately 1.5 million people (Aliqopa; Bayer HealthCare Pharmaceuticals) with substantial neurological toxicity and worldwide. B cell lymphomas (BCLs) account and duvelisib (Copiktra; Verastem Oncology). a cumbersome administration schedule for the majority (>85%) of cases of NHL; The FDA has also granted approval to — continuous infusion via an ambulatory the others are derived from T cells or natural pembrolizumab (Keytruda; Merck & Co.), pump for 4 to 8 weeks — the drug shows killer cells. NHL is frequently categorized a PD1 inhibitor, for patients with R/R an overall response rate (ORR) of 69% and by prognosis into slow- progressing or primary mediastinal BCL. complete response (CR) in 37% of patients indolent NHL (iNHL), or fast-progressing Options for patients who have exhausted across all subtypes. or aggressive NHL (aNHL). Follicular prior lines of therapy include the CD19 Roche’s polatuzumab vedotin, an lymphoma (FL) and diffuse large BCL chimeric antigen receptor (CAR)-T cell anti- CD79B ADC, is being evaluated in (DLBCL) are the most common indolent therapies tisagenlecleucel (Kymriah; combination with chemotherapy plus and aggressive subtypes, respectively, and Novartis) and axicabtagene ciloleucel rituximab for the treatment of patients account for around one-fifth and one-third (Yescarta; Kite Pharma), which were with previously untreated DLBCL. of NHL cases each. approved in 2017. Treatment with these Although there was no difference in CAR- T cell therapies carries a risk of cytokine survival in the phase II data for patients Current treatments release syndrome and neurological toxicities. with FL, the results for those with DLBCL Clinical guidelines recommend the Moreover, the high costs — from US$373,000 were highly encouraging (PFS of 6.7 months use of anti-CD20 immunotherapy — to $475,000 — and logistical challenges versus 2 months, and a median overall mainly rituximab (Rituxan; Roche) or of delivering CAR-T treatments present a survival of 11.8 months versus 4.7 months for obinutuzumab (Gazyva; Roche, FL only) serious concern. polatuzumab vedotin plus bendamustine and — combined with chemotherapy agents rituximab (BR) compared with BR alone), such as bendamustine or the four-drug Emerging therapies auguring well for the ongoing phase III cyclophosphamide, doxorubicin, vincristine A number of promising NHL therapies POLARIX study, which has an expected and prednisone (CHOP) regimen as the are in development (TABLE 1). Amgen’s primary completion date of December first- line option. Response rates for most blinatumomab (Blincyto), a bispecific 2019. The efficacy and safety profile of subtypes of NHL are high (DLBCL 80%; FL T cell engager (BiTE) antibody construct polatuzumab vedotin is expected to be 90%) with a 3-year progression-free survival that binds to CD3 on T cells and CD19 similar to that of brentuximab vedotin and (PFS) of around 70%, but many patients on B cells and is approved for B cell acute has the potential to change the front-line relapse. Therapy for relapsed/refractory lymphoblastic leukemia, is in phase II/III standard of care for DLBCL. (R/R) NHL remains challenging and trials in patients with R/R aggressive B cell MOR208 (MorphoSys/Xencor), a CD19- tends to be customized and driven by NHL who do not have a complete metabolic targeting monoclonal antibody (mAb), physician and patient preferences, but typically involves anti- CD20 antibodies and chemotherapy. The immunomodulatory Table 1 | Selected products in late-stage development for NHL drug lenalidomide (Revlimid; Celgene) Drug Developer Mode of action Status in combination with rituximab is also available to patients who are not eligible Blinatumomab Amgen CD19 BiTE mAb Phase III for high- dose chemotherapy. For eligible Polatuzumab vedotin Roche CD79B ADC Phase III patients, high- dose chemotherapy supported MOR208 MorphoSys/Xencor CD19 mAb Phase II/III by autologous stem cell transplantation can Enzastaurin Denovo Pharma PKCβ/AKT inhibitor Phase III induce prolonged remission. Recent approvals for treating R/R NHL Duvelisib Verastem PI3Kγ/δ inhibitor Phase II subtypes include the CD30-targeting Umbralisib TG Therapeutics PI3Kδ inhibitor Phase II antibody–drug conjugate (ADC) Venetoclax AbbVie/Roche BCL2 inhibitor Phase II/III brentuximab vedotin (Adcetris; Seattle Nivolumab Bristol- Myers Squibb PD1 inhibitor Phase II/III Genetics), two Bruton's tyrosine kinase (BTK) inhibitors, ibrutinib (Imbruvica; Avelumab Merck KGaA/Pfizer PDL1 inhibitor Phase II Janssen Biotech/Pharmacyclics (AbbVie)) and JCAR017 Juno Therapeutics/Celgene CAR- T therapy Phase II acalabrutinib (Calquence; AstraZeneca), ADC, antibody–drug conjugate; BCL2, B cell lymphoma 2; BiTE, bispecific T cell engager ; CAR , chimeric and three phosphoinositide 3-kinase γ antigen receptor ; PKCβ, protein kinase C β; PI3K , phosphoinositide 3-kinase. NatURE REVIEWS | DRUG DISCOVERY VOLUME 18 | SEPTEMBER 2019 | 663 NEWS & ANALYSIS 2018 2023 T cell lymphoma. Although PI3K inhibitors have been associated with high levels of 0.1 0.6 1.6 toxicity, umbralisib, owing to its improved 0.4 0.2 safety profile, could challenge both idelalisib 0.4 and copanlisib as a later-line option for US$6.4 US$9.3 1.2 Anti-CD20 mAbs BCLs. However, for market penetration, billion billion Kinase inhibitors 4.7 a head- to-head comparison with rituximab, Chemotherapy agents 2.4 the current gold standard, will be required. 4.1 IMiDs/PIs Others Market indicators The worldwide NHL market generated Fig. 1 | Non- Hodgkin lymphoma worldwide drug sales ($US billions, 2018 and 2023). revenues of $6.4 billion in 2018, a substantial IMiDs, immunomodulatory drugs; mAbs, monoclonal antibodies; PIs, protease inhibitors. increase from the 2013 value of $4.5 billion (2013–2018 compound annual growth rate (CAGR) of 7.3%) (FIG. 1). In 2018, anti-CD20 is being evaluated in a phase II/III study could find a role in NHL if used in the right mAbs, namely rituximab and obinutuzumab, (B- MIND) in combination with combination. dominated the NHL market, accounting bendamustine versus BR in R/R DLBCL. Juno Therapeutics/Celgene’s lead for 65% of the sales, followed by targeted In the phase II L-MIND study, MOR208 anti- CD19 CAR- T candidate, lisocabtagene small- molecule BTK or PI3Kγ/δ inhibitors was well tolerated and had an ORR of 49% maraleucel (JCAR017), is in a phase II (ibrutinib and idelalisib) with collective sales with 29 of 33 responses ongoing and a CR (PLATFORM) exploratory study in of $1.2 billion (19% of sales). Lenalidomide in 31% of patients with R/R DLBCL when R/R B cell malignancies. Published data and bortezomib (Velcade; Takeda/Johnson used in combination with lenalidomide. suggest that JCAR017 has potentially lower & Johnson) contributed ~2% of total NHL However, mAbs targeting CD40, CD22 or toxicity than existing CAR- T therapies sales in 2018. human leukocyte antigen-DR in lymphomas and might be delivered in an outpatient The NHL market is projected to reach failed to outperform rituximab and setting. Such deployment will both improve $9.3 billion by 2023 (CAGR of 7.7% in whether a CD19-targeted mAb does so in a patient satisfaction and drastically reduce 2018–2023), driven largely by premium- pivotal phase III study remains to be seen; treatment costs. priced biologic and targeted therapies. if successful, MOR208 in combination with Several small molecules that target Polatuzumab vedotin, MOR208 and chemotherapy could provide an alternative survival pathways are also in late-stage venetoclax are expected to reach the market front- line option for DLBCL. Moreover, development. Of note, venetoclax during the forecast period. In addition, anti- CD19 antibody- based therapies could (Venclexta/Venclyxto; AbbVie/Roche), CAR- T therapies are emerging as arguably potentially be a cheaper alternative to a BCL2 inhibitor, is currently in a the most promising treatment option for anti- CD19 CAR- T therapies. phase II/III (SYMPATICO) trial with most NHL subtypes. Their safety, logistics Novartis’s ofatumumab (Arzerra), ibrutinib for mantle cell lymphoma. and cost effectiveness in the long run will a CD20-targeted mAb already approved Venetoclax is approved for second-line determine uptake. in R/R chronic lymphocytic leukaemia CLL; surprisingly, it failed to show efficacy Importantly, with the loss of exclusivity (CLL), was evaluated in a phase III in patients with FL. The combination of for rituximab, the growth of the anti-CD20 (COMPLEMENT A+B) study in venetoclax and ibrutinib with an anti-CD20 mAb class is likely to be hampered by the combination with bendamustine in B cell mAb could further enhance the efficacy entry of biosimilars, including Truxima iNHL that is unresponsive to rituximab. of the treatment regimen. (Celltrion) and Rixathon/Riximyo (Sandoz), Top- line results failed to show any significant Of the three oral kinase inhibitors in both of which have been approved. improvement in PFS. Previously, in the development, Denovo Pharma’s enzastaurin A subcutaneous version of rituximab (Hycela) ORCHARD study, in the R/R DLBCL is the most advanced, as it is in a phase III and obinutuzumab, a second- generation setting, ofatumumab was not associated with (ENGINE) study in combination with anti- CD20 product, may slow the expected improved outcomes relative to rituximab rituximab plus CHOP as a first-line erosion during the forecast period. Despite treatment. Ofatumumab and rituximab treatment for patients with de novo genomic the progress, significant unmet needs target different epitopes on CD20. marker 1 (DGM1)-positive high-risk remain in NHL treatment; in addition Two checkpoint inhibitors are also DLBCL. Enzastaurin is thought to target to effective and curative modalities, progressing through the NHL pipeline. protein kinase C β (PKCβ) and/or AKT.