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Targeted Therapies Highlighted at This Year’s ASH Annual Meeting


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In a webcast press briefing prior to the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition, journalists got a peek at some of the most anticipated abstracts. ASH President Kenneth C. Anderson, MD, Director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston, shared the program committee’s picks for top news in the area of targeted therapies. 

Mogamulizumab in Cutaneous T-Cell Lymphoma

The anti-CCR4 monoclonal antibody mogamulizumab (investigational in the United States) significantly improved progression-free survival, compared to vorinostat (Zolinza), in patients with previously treated cutaneous T-cell lymphoma, investigators of the phase III MAVORIC study reported.1

[The MAVORIC trial] is extending a targeted therapy, a monoclonal antibody, to lymphomas in the T-cell area and is very promising.
— Kenneth C. Anderson, MD

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In a previous phase I/II study from the Mayo Clinic, 37% of patients responded to mogamulizumab, setting the stage for the phase III trial reported at the ASH meeting that compared mogamulizumab to standard treatment with vorinostat, a histone deacetylase inhibitor, Dr. Anderson noted. “We are highlighting this study because of the large number of patients who had at least three prior therapies, in whom a novel therapy doubled the progression-free survival and improved response rates and quality of life,” he said. 

MAVORIC is the largest randomized trial and the first pivotal trial to use progression-free survival as a primary endpoint. It randomized 372 patients to mogamulizumab at 1.0 mg/kg every 2 weeks or vorinostat at 400 mg/d. Treatment with mogamulizumab resulted in a median progression-free survival of 7.7 months, vs 3.1 months with vorinostat, translating into a 47% reduction in risk (P < .0001). 

“This is extending a targeted therapy, a monoclonal antibody, to lymphomas in the T-cell area and is very promising,” Dr. Anderson commented.

Brentuximab Vedotin Plus AVD as Front-Line Therapy

In the phase III ECHELON-1 study of 1,334 patients with advanced Hodgkin lymphoma, brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, dacarbazine (A+AVD), compared to standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), significantly improved the primary endpoint of modified progression-free survival (time to progression, death, or evidence of incomplete response followed by subsequent anticancer therapy).2 Risk was reduced by 23% with A+AVD (P = .035), and the 2-year modified event-free survival was 82.1% with A+AVD vs 74.4% with ABVD. 

“The idea is that by incorporating brentuximab vedotin into the experimental arm, we can avoid the pulmonary toxicity associated with bleomycin,” Dr. Anderson said. “The incorporation of the novel agent into a multidrug combination resulted in a 23% reduced risk of progression or death. The regimen was shown to have efficacy and tolerability.” 

Blu-285 KIT Inhibitor in Systemic Mastocytosis

A phase I first-in-man trial evaluated Blu-285, a potent, highly selective inhibitor of KIT D816V in patients with advanced systemic mastocytosis.3 The KIT D816V mutation is a key oncogenic driver that is found in about 90% of patients with this malignancy. The only currently approved agent to treat advanced systemic mastocytosis is the multikinase inhibitor midostaurin (Rydapt). 

“We think this abstract is very exciting because it is reminiscent of the [imatinib] story in CML [chronic myelogenous leukemia] 20 years ago,” Dr. Anderson commented. “[Imatinib] targets the particular BCR-ABL leukemia that causes CML, and due to this selective tyrosine kinase inhibitor, we have long-term survivors. In this new study, Blu-285 targets the mutation that causes the proliferation of malignant mast cells. Excitingly, in this dose-escalation trial, the vast majority of patients responded and are still on treatment.” 


[C]ombinations of targeted therapies predicated on preclinical rationale, with different mechanisms of action, and showing synergy in preclinical studies, can be very active clinically.
— Kenneth C. Anderson, MD

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In the ongoing phase I study, 20 patients had been treated in 7 dose cohorts as of the July 2017 cutoff. Most had received prior antineoplastic therapy. Blu-285 demonstrated significant clinical activity across all dose levels. In 28 of 30 patients, reductions in mast cell burden and D816V-mutant allele fraction relative to baseline were durable and occurred regardless of disease subtype, prior therapy, concomitant mutations, and performance status. 

“This targets the cause of this rare disease, and it is very promising,” Dr. Anderson commented. “Not only did patients feel better, but clinical signs such as peripheral edema were decreased.”

Ibrutinib Plus Venetoclax in Relapsed CLL

In the CLARITY trial of 50 patients with relapsed, refractory chronic lymphocytic leukemia (CLL), the novel agent venetoclax (Venclexta), which targets BCL2, was given along with ibrutinib (Imbruvica), which targets the Bruton’s tyrosine kinase protein.4 Both agents have been used effectively as monotherapy in CLL, but in combination they appear to be synergistic.

The eradication of minimal residual disease (MRD) is associated with improved outcomes, regardless of treatment. In CLARITY, eradication of MRD at 12 months was the primary endpoint, which was achieved by the combination of ibrutinib plus venetoclax. 

TARGETED THERAPY TRIALS AT ASH

  • The anti-CCR4 monoclonal antibody mogamulizumab doubled the median progression-free survival time vs vorinostat in patients with previously treated cutaneous T-cell lymphoma in the phase III MAVORIC study.
  • Brentuximab vedotin added to doxorubicin, vinblastine, dacarbazine (A+AVD), compared to standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), significantly improved modified progression-free survival in the phase III Echelon-1 study in advanced Hodgkin lymphoma.
  • In patients with systemic mastocytosis, the highly selective KIT D816V inhibitor Blu-285 led to durable reductions in mast cell burden and KIT D816V-mutant allele fraction relative to baseline in 28
    of 30 patients. 
  • In patients with relapsed chronic lymphocytic leukemia, a combined regimen of ibrutinib and venetoclax led to morphologic clearing of disease in the bone marrow of 84% of patients and to minimal residual disease negativity in 28%.

After 6 months of combination therapy, 84% of 25 evaluable patients had no morphologic evidence of CLL in the marrow biopsy, 76% had fewer than 1% CLL cells in the marrow, and 28% achieved MRD negativity. “This means fewer than 1 malignant cell in 10,000 normal bone marrow cells,” Dr. Anderson noted. “This is in patients with CLL that is refractory, to therapy and had 17p deletion, which indicates high-risk disease. All 25 patients responded, and 15 achieved a complete response.”

“The results show that combinations of targeted therapies with different mechanisms of action that show synergy in preclinical studies can also be very active clinically,” he commented. ■

DISCLOSURE: Dr. Anderson reported no conflicts of interest.

REFERENCES

1. Kim YH, Bagot M, Pinter-Brown L, et al: Anti-CCR4 monoclonal antibody, mogamulizumab, demonstrates significant improvement in progression-free survival compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma: Results from the phase III MAVORIC study. 2017 ASH Annual Meeting. Abstract 817. To be presented December 11, 2017.

2. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma: The phase 3 Echelon-1 study. 2017 ASH Annual Meeting. Abstract 6. Presented December 10, 2017.

3. DeAngelo DJ, Quiery AT, Radia D, et al: Clinical activity in a phase I study of Blu-285, a potent, highly selective inhibitor of KIT D816V in advanced systemic mastocytosis. 2017 ASH Annual Meeting. Abstract 2. Presented December 10, 2017.

4. Hillmen P, Munir T, Rawstron A, et al: Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY study): High rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. 2017 ASH Annual Meeting. Abstract 428. Presented December 10, 2017.


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