Determining When a Treatment Is Clinically Meaningful

Dana Butler

September 2014, Vol 5, No 7 - Value in Oncology

Society of Clinical Oncology (ASCO) meeting, Jennifer Malin, MD, PhD, Medical Director of Oncology at WellPoint, Inc, discussed what makes certain treatments clinically meaningful and others less so. She discussed studies presented at the meeting that are good examples of value in cancer care and studies that show no value.

Dr Malin based her discussion on the criteria that ASCO recently proposed for evaluating clinical trial results with or without “clinically meaningful outcomes” (Ellis LM, et al. J Clin Oncol. 2014;32:1277-1280). These criteria consider the tumor type and the initial treatments used to evaluate whether a new regimen for metastatic cancer demonstrates improvement in median overall survival (OS) from 2.5 months to ?6 months.

“Powering studies to achieve these end points would be worth consideration. It would ensure that we make advances that provide clinically meaningful outcomes to patients, and it would also lead to smaller trial designs and would speed up innovation,” Dr Malin noted. She discussed 2 studies presented at the meeting that showed clear value, unlike many others that did not.

Examples of Value
One of the 2 studies showing clinically meaningful outcomes was a phase 2 study of a subset of patients with lymphoma and poor prognosis and 1 study that included patients with early-stage, HER2-positive breast cancer.

The study of 64 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) showed that the addition of lenalidomide to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone; R2CHOP) appeared to reduce the negative prognostic significance of the nongerminal center B-cell (GCB) phenotype (a subset of DLBCL). At 2 years, progression-free survival (PFS) for this subset was 50%, and OS was 75% with the “R2CHOP” regimen, mirroring outcomes in the patients with GCB.

This represented a 2-year relative increase in OS of 30%, at an estimated total drug cost of $73,682, and an incremental drug cost (for adding lenalidomide to R-CHOP) of $26,540.

“This regimen improves OS in patients previously known to have a poor prognosis. This is definitely a clinically meaningful improvement in outcome and provides great value, certainly in comparison to many other studies presented at ASCO,” Dr Malin commented.

A second study was a meta-analysis of 5 randomized trials of adjuvant trastuzumab. The analysis focused on 4220 HER2-positive patients with tumors ?2 cm (mostly lymph node–positive), a group for whom the benefit of trastuzumab has not clearly been established.

Commenting on this study, Ciara C. O’Sullivan, MD, of the National Cancer Institute, Bethesda, MD, said that trastuzumab reduced disease recurrence and mortality by approximately 30% in all groups, except in patients with 1 or no positive lymph nodes: their mortality risk was reduced by only 2%.

“Trastuzumab clearly provides tremendous value for these patients, at a total drug cost of $81,336 and incremental cost of $76,601,” Dr Malin said. “It may have limited value, however, in the group with 0 to 1 positive nodes.”

Studies Showing No Value
Among the studies that showed no clinically meaningful outcomes, and therefore no value, was a phase 1 study of escalating doses of cabozantinib plus abiraterone in patients with castration-resistant prostate cancer. In this study, a prostate-specific antigen decline of >75% was observed in 63% of the men who received the 20-mg dose and in 13% of the men receiving the 40-mg dose. The investigators noted the combination’s tolerability and preliminary efficacy, which they claimed “support the investigation of this combination for further clinical development.”

However, according to Dr Malin, these findings indicated “limited to no improvement in outcomes,” and carried a total drug cost of $92,410, and an incremental drug cost of $32,521.

Another study evaluated the benefit of adding bevacizumab to trastuzu­mab plus docetaxel in the neoadjuvant breast cancer setting, finding a 20% relative increase in the rate of pathologic complete response. For this, the total drug cost was $103,976, and the incremental cost was $77,267. The novel agent trebananib was evaluated in combination with paclitaxel and trastuzumab in patients with HER2-positive advanced breast cancer in a phase 1b study. Although the median PFS was approximately 18 months, which was deemed encouraging by the investigators, the estimated total drug and incremental drug costs—$325,530 and $170,000, respectively—gave Dr Malin pause.

“When our new drugs cost $170,000, we need to look for significant improvements in outcomes,” she commented.

Value Discussions with Patients
Oncologists could use such data to have more meaningful conversations with patients about treatment options, Dr Malin suggested.

“There are often discussions with patients about what are meaningful outcomes, and these ‘value’ discussions often end up in debates as to whether a week, a month, a year is meaningful,” she said.

A pivotal study by Weeks and colleagues published in the New England Journal of Medicine in 2012 showed that approximately 25% of patients with advanced lung cancer and approximately 35% of patients with advanced colorectal cancer believed it was “very likely” that their cancer therapies could actually cure them.

“I posit that patients are looking for cures. If they understood the more marginal benefits that our treatments bring, they may be more likely to understand the tradeoffs in toxicity and cost, and be more likely not to want them,” she said.