In the Literature: January 2017

TON - January 2017, Vol 10, No 1 - In the Literature

In This Article

Gaps in Use of Tyrosine Kinase Inhibitors in Medicare Beneficiaries with Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs) have demonstrated effectiveness among patients diagnosed with chronic mye­loid leukemia (CML). However, orally administrated cancer medications, such as TKIs, can be costly, particularly for Medicare beneficiaries. Previous studies have shown that patients insured through Medicare Part D incur approximately $3000 in out-of-pocket costs for the first month of a TKI, potentially limiting their access to treatment. A recent study evaluated factors associated with TKI initiation among Medicare beneficiaries diagnosed with CML, and patient adherence to therapy (Winn AN, et al. J Clin Oncol. 2016 Oct 3. Epub ahead of print).

Using SEER-Medicare data, the researchers identified 393 patients aged ≥66 years diagnosed with CML between 2007 and 2011 who were continuously enrolled in Medicare Part D for 1 year before diagnosis. During that period, 3 FDA-approved first-line treatments were available for CML, including imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

The use of TKIs was far lower than expected in Medicare beneficiaries; 30% of newly diagnosed patients had not started TKI therapy within 6 months of diagnosis. Only 68.2% of patients initiated TKI treatment within 180 days after diagnosis. Low-income beneficiaries who received cost-sharing subsidies for prescription drugs started treatment sooner than those without cost-sharing subsidies. However, when restricting to patients who lived for 180 days or more after diagnosis, the effect of cost-sharing on TKI initiation was not statistically significant (adjusted risk ratio [RR], 1.08; 95% confidence interval [CI], 0.92-1.27). Other factors associated with earlier initiation of a TKI were a more recent diagnosis, and living in a big metropolitan area versus an urban area. Patients with more comorbidities and those older than age 80 years were associated with later initiation of TKIs.

Overall, 61% of patients were adherent to TKI therapy, defined as ≥80% of days covered during 6 months after TKI initiation. Patients aged >80 years were less adherent to treatment than patients aged <70 years, whereas a more recent year of diagnosis was associated with increased adherence (adjusted RR, 1.07; 95% CI, 1.01-1.13, per year).

“Our findings highlight important gaps in TKI use among Medicare beneficiaries with CML and suggest that high cost sharing may result in delays in initiation of these life-saving medications,” the researchers concluded.

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Mutations Responsible for Relapse Despite PD-1 Therapy Uncovered in Melanoma

Durable responses in patients with metastatic cancers have been achieved with a variety of immunotherapies, such as PD-1 inhibitors. However, recent studies show that 25% of patients with melanoma who had an objective response to PD-1 inhibitors still had disease progression. To pinpoint the triggers for this resistance, researchers evaluated the genomic evolution in patients who had received treatment with anti–PD-1 antibodies (Zaretsky JM, et al. N Engl J Med. 2016;375:819-829).

Of the 78 patients with metastatic melanoma who received pembrolizumab (Keytruda), 42 had objective responses, but 15 of them then had disease progression. Of these 15 patients, 4 met the selection criteria for analysis of the biopsy samples paired from baseline and relapsing lesions, which included pathologic analyses, DNA and RNA analyses, and attempting to establish cell lines to identify resistance mechanisms.

Using whole-exome sequencing, the researchers detected clonal selection and outgrowth of the acquired resistant tumors, and in 2 of the 4 patients they found resistance-associated loss of mutations in the genes encoding interferon (IFN)-receptor–associated Janus kinase (JAK)1 or JAK2, concurrent with deletion of wild-type allele. Specifically, the investigators identified a Q503* nonsense mutation in JAK1 in patient 1 and an F457 splice mutation in JAK2 in patient 2. To assess the functional consequences of the observed JAK2 mutations, the researchers compared the response of primary cell lines established at baseline and after relapse in patient 2; they found an absence of JAK2 protein expression after relapse, resulting in a lack of response to IFN-γ. Furthermore, the cell line failed to upregulate a wider panel of IFN-induced transcripts involved in the antigen presentation and T-cell chemotaxis.

Truncation in the antigen-presenting protein beta-2-microglobulin (B2M) gene was identified in a third patient, resulting in a loss of outer-membrane localization of major histocompatibility complex class I molecules. This finding is in line with the role of B2M in proper major histocompatibility complex class I folding and transport to the cell surface, and has been previously recognized as a mechanism of acquired resistance to immunotherapy.

“The nearly identical mechanism of acquisition, functional consequence, and evidence of clonal selection for JAK1 or JAK2 mutations in two independent cases with a similar clinical course of acquired resistance suggests that resistance to interferon gamma contributes to immune resistance and escape. This genetic alteration of immune resistance joins the previously described loss of B2M in decreasing immune-cell recognition of cancer cells, leading to acquired resistance to cancer immunotherapy,” the researchers concluded.

Additional cases will require close examination to assess the generalizability of the study results, they added.

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Ricolinostat Shows Promise in Patients with Relapsed or Refractory Multiple Myeloma

Histone deacetylase (HDAC) inhibitors are a new class of drugs investigated for multiple myeloma. Encouraging findings from preclinical trials that assessed the oral, first-in-class selective HDAC6 inhibitor ricolinostat with lenalidomide (Revlimid) led to a study that evaluated the safety and preliminary activity of ricolinostat in combination with lenalidomide and dexamethasone in a small cohort of patients with relapsed or refractory multiple myeloma (Yee AJ, et al. Lancet Oncol. 2016;17:1569-1578).

This multicenter, phase 1 trial enrolled 38 patients with relapsed and/or refractory multiple myeloma who had received ≥1 previous therapies. All patients had measurable disease, a Karnofsky performance score of ≥70, adequate bone marrow reserve and hepatic function, and a creatinine clearance of ≥50 mL/min. Patients were given escalating doses of ricolinostat (from 40 mg to 240 mg once daily and up to 160 mg twice daily) according to a standard 3 plus 3 design according to 3 different regimens on days 1 to 21, with a conventional 28-day schedule of lenalidomide and dexamethasone. The median follow-up was 5.9 months.

The primary end points were dose-limiting toxicities, maximum tolerated dose of ricolinostat plus lenalidomide and dexamethasone, and the dose and schedule of ricolinostat for future phase 2 clinical trials.

Two dose-limiting toxicities were observed in patients receiving ricolino­stat 160 mg twice daily; 1 grade 3 syn­cope, and 1 grade 3 myalgia adverse event in different cohorts. A maximum tolerated dose was not reached. The researchers chose ricolinostat 160 mg once daily on days 1 to 21 as the phase 2 dose. Ricolinostat was well-tolerated, and its adverse events were generally mild. The most common adverse events were fatigue, diarrhea, neutropenia, upper respiratory tract infection, anemia, and thrombocytopenia. Pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low tolerable level of class I HDAC inhibition. Coadministration of ricolinostat and lenalidomide did not have an effect on pharmacokinetics.

Preliminary efficacy data showed an overall response of 55% in the 38 patients, and a median PFS of 20.7 months, which was similar to findings from trials combining new agents with lenalidomide and dexamethasone.

The improved tolerability of rico­linostat suggests a potential benefit of selective inhibition of HDAC6 compared with pan-HDAC inhibition. “Although the results from this phase 1 study are preliminary, they are promising and require substantiation with larger studies than this one.

They set the stage for another agent, ACY-241, a selective HDAC6 inhibitor that is structurally similar to ricolinostat but administered as a tablet rather than an oral solution,” the investigators concluded.

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Last modified: February 2, 2017