The Lynx Group

In the Literature - May 2015

May 2015, Vol 6, No 4

In This Article

Patient-Reported Outcomes Needed in Clinical Trials of Cancer Therapies for Accurate Drug Safety Evaluations

Accurately reporting the occurrence and severity of drug-related adverse events in clinical trials is important for determining the drug’s true risk–benefit ratio. Currently, however, toxicity profiles are based on clinician assessment rather than on patient assessment, and the underreporting of toxicities by physicians could affect the drug’s absolute estimates of toxicity. A recent study evaluated the concordance between the patients’ and physicians’ reporting of toxicities during anticancer treatments and the potential underreporting of toxicities by physicians (Di Maio M, et al. J Clin Oncol. 2015;33:910-915).

The study used toxicity responses from 1090 patients with cancer who enrolled in 3 clinical trials—1 clinical trial for patients with breast cancer, ELDA (Elderly Breast Cancer—Docetaxel Adjuvant), and 2 clinical trials for patients with advanced non–small-cell lung cancer, GECO (Gemcitabine–Coxib) and TORCH (Tarceva or Chemotherapy).

The patients’ responses were collected at the end of each treatment cycle using the European Organisation for Research and Treatment of Cancer quality-of-life questionnaires. The physicians’ responses were collected using case report forms; any toxicity grade of >0 was considered “toxicity reported by the physician.” Overall, 6 drug-related adverse events were evaluated, including nausea, vomiting, hair loss, anorexia, constipation, and diarrhea.

The results revealed that for all 6 toxicities, the Cohen’s ? ranged between 0.15 and 0.45, indicating poor-to-moderate agreement between physician and patient reporting of adverse events. In addition, the percentages of toxicities reported by the patients were always higher than the percentages that were reported by the physicians.

For example, anorexia was reported in 62.3% of patients, 60.0% reported nausea, 26.0% of patients reported vomiting, 51.0% reported constipation, 50.8% reported hair loss, and 35.7% reported diarrhea.

Conversely, 18.5% of physicians reported anorexia in their patients, nausea in 44.8%, vomiting in 23.5%, constipation in 18.6%, hair loss in 19.1%, and diarrhea in 22.8%. Furthermore, any physician report of grade 0 was considered underreporting and included 74.4% for anorexia, 40.7% for nausea, 47.3% for vomiting, 69.3% for constipation, 50.8% for diarrhea, and 65.2% for hair loss.

The researchers attributed physician underreporting to several factors, including less attention paid to adverse events that do not require treatment modifications, judgment of adverse events as not related to treatment, and not reporting adverse events that are expected with the given treatment.

According to the investigators, the results from this study underline the importance of patient-reported toxicity information in clinical trials of cancer medications, especially because of the high risk for physician underreporting of treatment-related adverse events. Integrating patient-reported outcomes into drug safety evaluation can ensure that patients’ preferences are at the forefront of anticancer treatment decision-making.

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Ibrutinib Highly Active in Patients with Waldenström’s Macroglobulinemia

In a recently reported phase 2 study of 63 patients with Waldenström’s macroglobulinemia and/or MYD88 and CXCR4 mutations who had received at least 1 previous treatment, ibrutinib (Imbruvica) was highly active, safe, and associated with durable responses (Treon SP, et al. N Engl J Med. 2015;372:1430-1440).

This study led to the expedited FDA approval of ibrutinib on January 29, 2015, for the treatment of patients with Waldenström’s macroglobulinemia; ibrutinib is the first FDA-approved therapy for this indication.

Waldenström’s macroglobulinemia is a B-cell lymphoma associated with a buildup of clonal lymphoplasmacytic cells and monoclonal immunoglobulin (Ig) M secretion. In this study, the investigators assessed the effect of MYD88 and CXCR4 mutations on outcomes in 63 previously treated patients with Waldenström’s macroglobulinemia who received a daily dose of ibrutinib. The study’s primary objective was the overall response rate (?25% reduction in IgM levels), partial response rate (?50% reduction), very good partial response rate (?90% reduction), complete response rate (100%), and major response rate (complete response or major response). The secondary objectives included progression-free survival and drug safety.

The study results indicated that MYD88L265P was present in 56 patients and CXCR4WHIM was present in 21 patients; all patients with wild-type MYD88 had wild-type CXCR4 (CXCR4WT). After receiving ibrutinib, the median serum IgM levels decreased from 3520 mg/dL to 880 mg/dL, and the median hemoglobin levels increased from 10.5 g/dL to 13.8 g/dL. Furthermore, bone marrow involvement decreased from 60% to 25%. The overall and major response rates were 90.5% and 73%, respectively; a very good partial response was reported in 10 patients, a partial response in 36 patients, and a minor response in 11 patients. The overall and major response rates were highest in patients with the MYD88L265PCXCR4WT genotype, followed by the MYD88L265P CXCR4WHIM and MYD88WT­CXCR4WT genotypes. The median times to at least minor and partial responses were 4 weeks and 8 weeks, respectively, and the me­dian duration of treatment was 19.1 months. The estimated 2-year progression-free survival rate was 69.1%, and the overall survival rate was 95.2%.

The data revealed that grade ?2 adverse events included neutropenia (22%), thrombocytopenia (14%), postprocedural bleeding (3%), epistaxis (3%), and atrial fibrillation (5%). Neutropenia and thrombocytopenia were especially common in heavily pretreated patients, and fish oil supplement contributed to grade 2 epistaxis. In addition, all atrial fibrillation events occurred in patients with a history of ­arrhythmia.

The researchers concluded that ibrutinib is safe and effective in patients with Waldenström’s macroglobulinemia, and that MYD88 and CXCR4 mutation status affects responses to ibrutinib.

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PIK3CA Mutations Associated with Poor Response to HER2-Targeted Breast Cancer Therapies

There is limited information about the effects of phosphatidylinositol 3-kinase (PI3K) on the biology of breast cancer and its role in determining response to breast cancer therapy. In a recent study, the investigators assessed whether mutations in the PI3K catalytic subunit (PIK3CA) correlated with response to neoadjuvant HER2-targeted therapies in patients with breast cancer (Majewski IJ, et al. J Clin Oncol. 2015;33:1334-1339).

The researchers used HER2-positive breast tissue biopsies from 355 patients who had been recruited to the Neo­ALTTO clinical trial, where the patients received neoadjuvant lapatinib and/or trastuzumab (Herceptin). The therapy response was measured by pathologic complete response, as defined by no invasive cancer in the breast and no pathologic involvement in the axillary nodes; event-free survival; and overall survival.

The study results showed that PIK3CA­mutations were found in 23% of HER2-positive breast tumors. For each treatment arm, the pathologic complete response rate was lower in patients with PIK3CA mutations compared with patients without PIK3CA mutations.

The difference was especially evident in patients who received the combination of trastuzumab and lapatinib; in this treatment arm, patients with PIK3CA mutations had a pathologic complete response rate of 28.6% compared with 53.1% in patients without these mutations. PIK3CA mutations did not affect event-free survival or overall survival in patients who received trastuzumab and/or lapatinib.

The researchers concluded that in HER2-positive tumors, PIK3CA mutations confer a lower clinical benefit from trastuzumab, lapatinib, and the combination of trastuzumab plus lapatinib than tumors without a PIK3CA mutation. According to the investigators, these findings support further research of HER2 therapies and PIK3CA mutations in the clinic.

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Better Outcomes with Nivolumab plus Ipilimumab than with Ipilimumab Monotherapy for Untreated Melanoma

In a recent double-blind, randomized, phase 2 study of patients with untreated metastatic melanoma, the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) resulted in a significantly greater objective response rate (ORR) and progression-free survival compared with ipilimumab monotherapy (Postow MA, et al. N Engl J Med. 2015 Apr 20. Epub ahead of print).

A total of 142 patients with untreated metastatic melanoma were randomly assigned in a 2:1 ratio to receive ipilimumab and nivolumab or ipilimumab alone. The study’s primary end point was the rate of investigator-assessed objective response in patients with BRAF V600 wild-type tumors; the secondary end points included investigator-assessed progression-free survival in patients with BRAF wild-type tumors, the ORR and progression-free survival among patients with BRAF V600 mutation–positive tumors, and safety.

The study results demonstrated that among the 72 patients with BRAF wild-type tumors who received niv­olumab plus ipilimumab, the objective response was 61% (95% confidence interval [CI], 49-72) compared with 11% (95% CI, 3-25) in the 37 patients who received ipilimumab monotherapy; a complete response was reported in 22% of patients who re­ceived the combination therapy versus in none of the patients who received ipilimumab monotherapy. Furthermore, the median change in the tumor volume was a 68.1% decrease in patients who received the combination therapy compared with a 5.5% increase in patients who received ipilim­umab monotherapy.

Overall, the median duration of response was not reached in either group, and the ongoing response was 82% in the combination group versus 75% in the ipilimumab monotherapy group. In addition, the median progression-free survival was 4.4 months in the combination group, but was not reached in patients who received the combination therapy.

Among patients with BRAF-mutated tumors, the ORR was 52% (95% CI, 31-73) in the combination group versus 10% in the ipilimumab monotherapy group (95% CI, 0-45). Furthermore, the progression-free survival was 8.5 months in the combination group versus 2.7 months in the ipilimumab monotherapy group.

The study’s safety analysis showed that the rate of treatment-related adverse events was 91% in the combination group compared with 93% in the ipilimumab monotherapy group. Grade 3 or 4 drug-related adverse events, such as colitis, diarrhea, and elevated alanine aminotransferase levels, were reported more frequently with combination therapy than with ipilimumab monotherapy (54% vs 24%, respectively); however, the majority of these events were manageable.

According to the investigators, the combination of nivolumab plus ipilimumab was superior to ipilimumab monotherapy in terms of ORR, progression-free survival, and complete response in patients with BRAF wild-type advanced melanoma and in patients with BRAF-mutated advanced melanoma.

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