September 2014, Vol 3, No 6

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What Makes a Treatment “Clinically Meaningful”?

Jennifer L Malin, MD, PhD


Two presentations at ASCO struck Jennifer Malin, MD, PhD, medical director of oncology at WellPoint, Inc, as good examples of value in cancer care, while many others did not make the value-based list. Malin described these studies at an ASCO Highlights of the Day session.

ASCO’s Proposed Criteria for Clinically Meaningful Outcomes

Malin’s perspective was based on criteria that ASCO recently proposed as a means of evaluating clinical trial results in terms of “clinically meaningful outcomes” (Ellis LM, et al. J Clin Oncol. 2014;32:1277-1280). Depending on the tumor and prior treatment, ASCO proposed that any new regimen for metastatic disease should convey improvement in median overall survival (OS) of 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,” she predicted.

Studies Showing Value

Among studies presented at ASCO that were clearly clinically meaningful were a study in a poor-prognosis subset of lymphoma and one in early-stage, HER2-positive breast cancer.

A phase 2 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, and prednisone; R2CHOP) appeared to reduce the negative prognostic significance of the non-germinal center B-cell (non-GCB) phenotype (a subset of DLBCL) (Abstract 8520). At 2 years, progression-free survival (PFS) for this subset was 60% and OS was 75% with the R2CHOP regimen, mirroring outcomes in the GCB patients.

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,” she commented.

The second study was a meta-analysis of 5 randomized adjuvant trastuzumab trials. The analysis focused on 4220 HER2-positive patients with mostly lymph node–positive tumors ?2 cm, a group for whom the benefit of trastuzumab has not clearly been established (Abstract 508).

Ciara O’Sullivan, MD, of the National Cancer Institute, reported that trastuzumab reduced recurrences and deaths by about 30% in all groups except for patients with 1 or no positive lymph nodes, whose mortality risk was reduced by just 2%.

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

Examples of Lack of Value

Malin then described several studies that illustrated a lack of clinically meaningful outcomes and therefore value.

One was a phase 1 study of escalating doses of cabozantinib plus abiraterone in castration-resistant prostate cancer in which a prostate-specific antigen decline of >75% was observed in 63% of men with the 20 mg dose and in 13% with the 40 mg dose (Abstract 5027). The investigators noted the combination’s tolerability and preliminary efficacy, which they claimed “support the investigation of this combination for further clinical development.”

According to Malin, however, the 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/docetaxel in the neoadjuvant breast cancer setting, finding a 20% relative increase in the rate of pathologic complete response (Abstract 507). 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 (Abstract 502). While the median PFS was approximately 18 months, deemed encouraging by the investigators, the estimated total drug and incremental drug costs – $325,530 and $170,000, respectively – gave Malin pause.

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

Can Data Like These Guide Conversations?

Oncologists could use data such as these to have more meaningful conversations with patients about treatment options, 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 J, et al (N Engl J Med. 2012;367:1616-1625) revealed that 25% of patients with advanced lung cancer and about 35% of patients with metastatic colorectal cancer believed it was “very likely” their treatments could 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 trade-offs in toxicity and cost, and be more likely not to want them,” she said.

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