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    Checkpoint inhibitors flourish

    New understandings portend practice changes

    Dr. TsaoKey publications from the past year have enhanced our understanding of immunomodulatory drugs for advanced and metastatic skin cancers. Others could portend significant practice changes in areas such as sentinel lymph node (SLN) biopsy, says Hensin Tsao, M.D., Ph.D.

    Investigating ipilimumab

    Well-balanced in terms of patient numbers and disease substages, the pivotal trial of ipilimumab (Yervoy, Bristol-Myers Squibb) as adjuvant treatment for stage 3 melanoma showed a 24% reduction in recurrence risk at seven years,1 says Dr.  Tsao, who reviewed data during the recent MauiDerm 2017 meeting. He is professor of dermatology at Harvard Medical School and director of the Melanoma and Pigmented Lesion Center/Department of Dermatology at Massachusetts General Hospital.

    “Similarly, there’s a 28% reduction in risk of death at five years.” Regardless of treatment, he adds, “Overall survival at five years, even in some stage 3 melanoma settings, can be 50% to 70%.”

    Like interferon, Dr. Tsao says, ipilimumab can sometimes be extremely difficult to take due to side effects.

    “The most important thing oncologists worry about is colitis,” which impacted 15.5% of study patients versus 1.5% for placebo in the trial. Colitis moreover caused five deaths in ipilimumab-treated patients. “That is significant  —  if one had stage 4 melanoma, and there was some risk of death from the drug, but then the natural outcome is bleak, one might take the risk and work through the side effects.”

    But because ipilimumab treatment alone carries a risk of death, he says, a patient with stage 3 melanoma and no evidence of metastases anywhere else might think twice about using it.

    Acquired resistance to immune checkpoint inhibitors including ipilimumab and other drugs that target programmed death 1 (PD1) and the ligand PD-L1 has been associated with JAK mutations.2

    “Usually we think about acquired resistance with molecular therapies,” Dr. Tsao says. In histology from a patient whose tumor recurred around 300 days after treatment, “Most of the immune markers were still there. But for some reason — perhaps immunoreactivity or a mutation — recurrence occurred.”

    In two of four patients who relapsed, deep sequencing uncovered JAK1 mutations.

    “JAK mediates signaling from all the interferons. JAK1 mediates all interferons, while JAK2 specifically mediates interferon γ,” Dr. Tsao explains

    The investigators from UCLA also showed that the patient-derived cells with the JAK mutations were no longer responsive to the suppressive effects of interferon, he says.

    Overall, “We’re beginning to get a sense for what’s going on with the checkpoint inhibitors. This is critical because the ideal patient, dosing schedule and combination of checkpoint/molecular therapies are still not clarified.”

    U.S. Food and Drug Administration approval for checkpoint inhibition has moved beyond stage 4 melanoma to approval for stage 3, Dr. Tsao says.

    “It’s also moving beyond melanoma — many cancers now are eligible for checkpoint inhibition. The long-term cure rate for ipilimumab is now 22%.

    We don’t know for the anti-PD1 drugs yet. And the reasons why some tumors are innately insensitive to anti-PD1/PD-L1 treatments are also not known,” he says.

    The most common cutaneous side effect of anti-PD1 treatment is pruritus, he says. In a pooled analysis of 576 patients treated with nivolumab (Opdivo, Bristol-Myers Squibb), 17.2% experienced pruritus.3 As for timing, “The skin complications come up very quickly, some time between five to 10 weeks (median). Gastrointestinal symptoms start appearing a little before 10 weeks also, but the incidence is lower overall.” Generally, he adds, the percentages of patients afflicted with these side effects persisted in the study up to 40 weeks.

    However, he says, adverse reactions could be a favorable sign.

    “It appears that patients with any adverse reaction have a higher objective response rate (ORR), because these reactions are autoimmune, suggesting; therefore, that the patient can mount an effective immune response.”

    Nivolumab-treated patients with no reactions had an ORR of 17.8%, versus 48.6% for patients who experienced any adverse reaction. And the more adverse reactions a patient had, the higher the response rate (although grade 3 or 4 reactions did not confer higher response rates).

    Dr. Tsao adds, “The response rates do not appear to worsen with systemic immune modulating agents like steroids. That’s one of the greatest challenges when giving some kind of steroid to these patients. Whether it’s for pruritus or rash, you must work with the oncologist to see if he or she is comfortable with the use of any steroids,” because any anti-inflammatory treatment is theoretically immunosuppressive.

    Next: Evidence in MCC

    John Jesitus
    John Jesitus is a medical writer based in Westminster, CO.


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