In the Literature – August 2016
In This Article
- Ixazomib Extends Progression-Free Survival in Multiple Myeloma
- Pembrolizumab Shows Potential Antitumor Activity in Advanced Gastric Cancer
- ASCO Endorses Canadian Clinical Practice Guideline on Active Surveillance for Localized Prostate Cancer
- Delayed Relapses After Anti–PD-1 Therapy Linked to Mutation in Patients with Melanoma
Ixazomib Extends Progression-Free Survival in Multiple Myeloma
The introduction of proteasome inhibitors and immunomodulatory drugs has improved outcomes of patients with multiple myeloma. Ixazomib is the first oral proteasome inhibitor approved by the FDA for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 previous therapy. The recently published TOURMALINE-MM1 trial evaluated the efficacy and safety of ixazomib in patients with relapsed, refractory, or relapsed and refractory multiple myeloma (Moreau P, et al. N Engl J Med. 2016;374:1621-1634).
The randomized, double-blind, placebo-controlled, phase 3 trial included 722 patients with multiple myeloma who had received 1 to 3 previous therapies. The patients were randomized to ixazomib 4 mg or to placebo, in 28-day cycles, on days 1, 8, and 15; in addition, all patients received lenalidomide 25 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8, 15, and 22.
The treatment continued until disease progression, treatment-related side effects, or intolerability occurred. The primary end point was progression-free survival (PFS).
The median PFS was significantly longer in the ixazomib group than in the placebo group (20.6 months vs 14.7 months, respectively). A PFS benefit was observed with the ixazomib regimen across prespecified subgroups, including patients with high-risk cytogenetic abnormalities (21.4 months).
The overall response rate was higher in the ixazomib group than in the placebo group (78.3% vs 71.5%, respectively), and the corresponding rates of complete response plus very good partial response were 48% and 39%.
The median time to response was 1.1 months in the patients receiving the ixazomib combination compared with 1.9 months in the placebo group. The median duration of response for the treatment groups was 20.5 months and 15 months, respectively. At a median follow-up of 23 months, the median overall survival had not been reached in either treatment arm.
In the ixazomib and the placebo groups, the rates of serious adverse events (47% vs 49%, respectively) and deaths (4% vs 6%, respectively) were similar; 74% and 69% of patients had grade ≥3 adverse events, respectively. Grades 3 and 4 thrombocytopenia were more frequent in the ixazomib group (12% and 7%, respectively) than in the placebo group (5% and 4%, respectively), as was the incidence of peripheral neuropathy (27% vs 22%, respectively).
This study demonstrates that triplet therapy with ixazomib is associated with significantly longer PFS, regardless of whether patients had standard-risk or high-risk chromosomal abnormalities; the additional toxic effects were limited.
Because of its efficacy and adverse-event profile, ixazomib provides a good treatment option for patients with multiple myeloma.
Pembrolizumab Shows Potential Antitumor Activity in Advanced Gastric Cancer
Data from several studies support the targeting of the programmed death ligand 1 (PD-L1) pathway in gastric cancer, the fifth most common cancer worldwide. Furthermore, the data indicate that PD-L1 expression has been detected in >40% of human gastric cancer samples. Because of the substantial unmet need and molecular rationale for targeting the PD-L1 pathway, the researchers sought to evaluate the safety and activity of the anti–PD-1 antibody pembrolizumab in patients with PD-L1–positive recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction in the KEYNOTE-012 trial (Muro K, et al. Lancet Oncol. 2016;17:717-726).
KEYNOTE-012 was a multicenter, open-label, phase 1b trial that assessed single-agent pembrolizumab in 39 patients in several cohorts of patients with various tumor types, including advanced gastric cancer, urothelial cancer, triple-negative breast cancer, or head and neck cancer.
Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks for 24 months or until disease progression or unacceptable toxicity. Response was assessed every 8 weeks in accordance with the Response Evaluation Criteria in Solid Tumors v1.1. Of the 39 patients evaluable for safety, 36 were evaluable for response on central assessment.
The median follow-up was 10.8 months. The primary end points were safety in patients who received at least 1 dose of pembrolizumab and who had a postbaseline scan or who discontinued therapy because of disease progression or a treatment-related adverse event before the first postbaseline scan.
Partial responses were observed in 8 (22%) patients. Overall, a decrease in target lesion size was observed in 17 (53%) of 32 patients. The median time to response was 8 weeks. At the last analysis, 4 of the 8 responders were alive without disease progression and with no additional cancer therapy.
No unexpected toxic effects were observed. A total of 6 grade 3 or 4 treatment-related adverse events were reported in 5 (13%) patients, consisting of grade 3 fatigue in 2 patients, grade 3 hypothyroidism in 1 patient, grade 3 peripheral sensory neuropathy in 1 patient, and grade 4 pneumonitis in 1 patient. There were no treatment-related deaths.
In this patient population with recurrent or metastatic PD-L1–positive gastric cancer, this study supports the importance of the PD-1 pathway. The data also demonstrate the safety and antitumor activity of pembrolizumab in patients with previously treated gastric cancer, warranting further study in phase 2 and 3 trials.
ASCO Endorses Canadian Clinical Practice Guideline on Active Surveillance for Localized Prostate Cancer
The prevalence of prostate cancer and its high mortality rate continue to garner great interest in defining the optimum treatment strategies for detection, treatment, and follow-up. Cancer Care Ontario (CCO) published its Active Surveillance for the Management of Localized Prostate Cancer guideline in 2015. Recently, a panel of experts from the American Society of Clinical Oncology (ASCO) reviewed and endorsed CCO’s guideline (Chen RC, et al. J Clin Oncol. 2016;34:2182-2190).
The recommendations “are clear, thorough, and based on the most relevant scientific evidence in this content area and present options that will be acceptable for many patients,” noted the ASCO panel, which endorsed all the recommendations with qualifications, except the role of daily 5-alpha-reductase inhibitors. ASCO’s key recommendations include:
- For most patients with low-risk (Gleason score ≥6) localized prostate cancer, active surveillance is recommended. ASCO added that factors including age, prostate cancer volume, patient preference, and/or African-American ethnicity should be taken into account when making management decisions
- Active treatment (ie, radical prostatectomy or radiotherapy) is recommended for most patients with intermediate-risk (Gleason score 7) localized prostate cancer. For select patients with low-volume, intermediate-risk (Gleason 3 + 4 = 7) localized prostate cancer, active surveillance may be offered. ASCO advised that patients with a Gleason score of 7 (3 + 4) who are being considered for active surveillance should only include men with low-volume Gleason pattern 4 pathology and/or who are aged >75 years
- Active surveillance protocols should include prostate-specific antigen testing every 3 to 6 months, digital rectal examinations at least annually, and at least a 12-core confirmatory transrectal ultrasound guided biopsy within 6 to 12 months, and then serial biopsy every 2 to 5 years thereafter or more frequently if clinically warranted. ASCO noted that ancillary radiographic and genomic tests are investigational, but that they may play a role in patients with discordant clinical and/or pathologic findings
- Patients under active surveillance who are reclassified to a high-risk category (Gleason score ≥7) and/or have significant increases in tumor volume in subsequent biopsies should be offered active therapy.
The CCO guideline recommendation of daily 5-alpha-reductase inhibitors stated that these agents may have a role in men undergoing active surveillance for prostate cancer.
However, the FDA has issued a warning about a possible low, but increased, risk for high-grade prostate cancer with these inhibitors. The CCO expert panel stated that the benefits of 5-alpha-reductase inhibitors outweigh the risks, but the ASCO panel did not endorse this recommendation because there is no evidence to support their use in this setting.
The CCO guideline acknowledged that there is currently not enough evidence to make recommendations on which clinicians should be responsible for the management of active surveillance protocols. The ASCO panel agreed, adding that “a multidisciplinary approach should be taken when a change to active treatment is considered.”
Delayed Relapses After Anti–PD-1 Therapy Linked to Mutation in Patients with Melanoma
Although durable responses have been achieved with various immunotherapies for melanoma, including anti–PD-1 drugs, some patients have delayed relapses occurring months to years after the initial response to anti–PD-1 therapy. The exact mechanism leading to the acquired resistance associated with immunotherapies in melanoma has not been identified, but results of a new study suggest that such delayed acquired resistance to anti–PD-1 therapy, seen a long time after an initial response to immunotherapy, may be attributed to mutations in pathways involved in antigen presentation and in interferon-receptor signaling (Zaretsky JM, et al. N Engl J Med. 2016 Jul 13. Epub ahead of print).
Using biopsy samples from 4 patients with metastatic melanoma that progressed after responding to the PD-1 inhibitor pembrolizumab, the researchers analyzed the patients’ DNA and RNA and established cell lines to assess CD8 T-cell activity and to detect genetic mutations in the paired baseline and relapsing lesions.
CD8 T-cells, which infiltrate during an active response and destroy cancer cells, were surprisingly still present and plentiful during relapse, suggesting that these T-cells could no longer wield their cytotoxic activity on the cancer cells, because of a lack of reduced immune-cell recognition and activation, or because of the cancer cells’ loss of sensitivity to their effector molecules.
Whole-exome sequencing further revealed that the resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated JAK1 or JAK2 were found in 2 of the 4 patients. The investigators noted that the inactivation of these genes is especially beneficial to cancer cells during treatment with PD-1 inhibitors compared with other immunotherapies, because the loss of interferon-induced adaptive expression of PD-L1 allows cancer cells to continue the inactivation of CD8 T-cells, as well as to avoid increases in antigen presentation and antiproliferative effects.
In addition to interferon insensitivity via mutations in JAK1 or JAK2, the researchers identified another potential mechanism of delayed resistance to PD-1 blockade: 1 patient with melanoma had a mutation in the gene that encodes the beta-2-microglobulin protein (ie, B2M), which is a component of the major histocompatibility complex (MHC) class I molecules. The inactivation of B2M promotes resistance to immunotherapies via a loss of MHC class I expression, which is essential for CD8 T-cell recognition of cancer cells.
“Understanding the molecular mechanisms of acquired resistance by focused comparison of biopsy samples from paired baseline and relapsing lesions may open options for the rational design of salvage combination therapies or preventive interventions and may guide mechanistic biomarker studies for the selection of patients, before the initiation of treatment, who are unlikely to have a response,” the investigators noted.
“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.
They added that the potential mechanisms of resistance to PD-1 inhibitors were identified in 3 of the patients, but “additional cases will need to be closely examined to assess the generalizability of these findings.”