Thomas F. Goss Pharm.D. Senior Vice President Boston Healthcare Associates

Our Understanding of the Benefits and Risks of Therapies Evolves over Time as Evidence Accumulates

In recent years, the United States has witnessed significant progress in the fight against cancer, with a 5-year survival rates increasing from 49% in the mid-1970s to 68% today. Improved therapies have contributed significantly to these advances in cancer care, with one study reporting that new medicines have accounted for 50–60% of the increase in cancer survival rates since 1975. The progress driving these advances is commonly the result of an accumulation of knowledge over time, as a greater understanding of the science underlying the more than 200 diseases we collectively call cancer grows.

Although initial approval by the FDA is a significant milestone based on demonstration of a treatment’s safety and efficacy through carefully designed and controlled clinical trials, the research does not stop at FDA approval. Additional knowledge is gained through ongoing post-approval research and the accumulation of data from the real-world use of these medicines in patients. While the intrinsic “value” (or clinical properties) of a therapy does not change, our understanding of the benefits and risks of the therapy evolves over time as evidence accumulates.

We have examined this issue and identified a number of pathways that many cancer therapies have in common for providing additional value following an initial FDA approval.  We summarize these pathways and several examples to illustrate the benefits.

Use within a Single FDA-Approved Indication

In some cases, when patients are in need of new treatment options, the FDA may approve cancer treatments based on demonstration of compelling surrogate endpoints (e.g., tumor shrinkage) before the completion of definitive long-term studies can prove a survival benefit. As clinical investigation of safety and efficacy continues, the impact on overall survival and tumor progression can be fully realized using the long-term clinical outcomes data, as demonstrated by the example of crizotinib.

Crizotinib (Xalkori®). Crizotinib was granted accelerated approval by the FDA in 2011 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that tests positive for the protein anaplastic lymphoma kinase (ALK). Approval was based on two studies that demonstrated that 50% and 61% of patients, respectively, experienced tumor shrinkage, indicating that the medicine was reasonably likely to predict a defined clinical benefit in these patients. In 2013, the FDA updated labeling to reflect the clinical benefit of crizotinib that had been confirmed through ongoing studies. Patients receiving crizotinib experienced an average increase in progression-free survival of 7.7 months, which was more than double the three months of the chemotherapy arm of the trial.

Use Earlier in Treatment Line and Earlier Disease Stage

Because cancer is frequently progressive and life-threatening, investigational therapies are necessarily tested first in patients with advanced stages of cancer, who have exhausted existing standard treatment options. This creates a theoretical “ceiling” on the amount of clinical benefit that can be expected during initial clinical research. As additional testing is conducted following FDA approval, a therapy may demonstrate efficacy earlier in treatment line (when used prior to other available therapies) and/or disease stage (when used earlier in disease progression) as illustrated by the case of bortezomib.

Bortezomib (Velcade®). Bortezomib was initially approved in 2003 to treat multiple myeloma patients who had received two prior therapies and were not responding (third-line therapy). In 2005 the label was expanded to include use earlier in the treatment regimen as a second-line therapy.  Study data revealed that the time for the disease to progress was significantly longer in patients receiving bortezomib (6.2 months) compared to those receiving standard treatment (2.5 months). In 2008 the FDA granted approval for the use of bortezomib as a first-line multiple myeloma treatment after study results demonstrated that patients treated with bortezomib experienced significantly longer time to progression (20.7 months) compared to standard treatment (15 months). Ongoing research revealed the value of bortezomib as a first-line treatment, earlier in the progression of the disease, than initial results suggested.

Use in Additional Disease Indications

Oncology therapies often have clinical value in types of cancers distinct from the original indication(s) for which they are approved. Studies conducted and reported after the initial approval commonly explore additional indications and, in many instances, a therapy demonstrates significant clinical benefit in a different disease as demonstrated by the case of lenalidomide below.

Lenalidomide (Revlimid®). Lenalidomide was originally approved in 2005 to treat patients with myelodysplastic syndrome (MDS) who had a specific genetic mutation. MDS is a collection of disorders where the bone marrow fails to produce enough healthy blood cells. In clinical studies, patients treated with lenalidomide no longer needed blood transfusions. In 2006, lenalidomide received approval for use in combination with dexamethasone to treat patients with multiple myeloma who had failed other treatments (and in 2015 lenalidomide was approved as a first-line treatment). In 2013, lenalidomide was approved for use against mantle cell lymphoma, as the first oral therapy available for patients with this rare blood cancer.

Use in Combination with other Agents

Cancer research frequently involves investigating different combinations of new and existing therapies to improve outcomes. The use of therapies in combination has often produced superior outcomes by enhancing antitumor activity by both allowing patients to receive a full-dose of drugs while managing adverse effects, and by attacking the tumor through multiple mechanisms of action to enhance response, as illustrated by the case of everolimus below.

Everolimus (Afinitor®). Everolimus, a rapamycin (mTOR) inhibitor, was approved by the FDA in 2009 for the treatment of advanced renal cell carcinoma (RCC).  In July 2012 everolimus was approved for use in combination with exemestane to treat post-menopausal women with advanced hormone-receptor positive, HER2-negative breast cancer. In this form of cancer, a class of medicines called aromatase inhibitors had proven effective at controlling tumors by depriving them of the estrogen hormone, which stimulates their growth. However, over time, many tumors developed resistance to these treatments. Everolimus helped prolong the effectiveness of these treatments by combating that resistance.

Use in Combination with Specific Biomarkers

Growing understanding of cancer at the molecular level has translated to new diagnostic tools that allow physicians to identify patients as candidates for a therapy based on the presence or absence of a particular gene or mutation (biomarker). Biomarkers are used to predict therapeutic response and/or sensitivity to adverse events, allowing clinicians to better select the patients who are most likely to benefit from particular targeted therapies. Ibrutinib illustrates this pathway below.

Ibrutinib (Imbruvica®). In February 2014, ibrutinib received approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have tried at least one prior therapy. In July of that year, FDA expanded the use of ibrutinib to treat patients with CLL who carry a deletion in chromosome 17 (17p deletion), regardless of whether or not they have received prior therapy. The clinical study resulting in this expanded indication demonstrated that patients with the 17p deletion who were treated with ibrutinib experienced a 75% reduction in the risk of disease progression and death.


Dramatic advances in overall cancer survival have been realized in recent years. Because innovative cancer therapies play a significant role in these advances, it is vital that the ongoing and incremental nature of oncology research be recognized by researchers, clinicians, patients, payers, and policymakers alike. Assessments of clinical value must reflect ongoing accumulation of evidence over time in order to reflect the value that individual therapies can bring to treating patients, often across several different cancers.

Thomas F. Goss, Pharm.D. ([email protected]), is senior vice president, Boston Healthcare Associates.

Previous articleCareer Development Woes
Next articleThe Uproar over Fetal Tissue Donations