W hite P ape r|Recognizing Value inOncology InnovationThomas F. Goss, PharmD, Emilie H. Picard, MS, and Andrew Tarab, MHABoston Healthcare Associates, Inc., Boston, MA, and Washington, DCJ U N E 2 012INTRODUCTIONIn recent years, the United States has witnessedsignificant progress in the fight against cancer. In 2011,the American Cancer Society (ACS), using data fromthe Centers for Disease Control and Prevention (CDC),the National Cancer Institute (NCI), and the NorthAmerican Association of Central Cancer Registries(NAACCR), reported a decline in the death rate and anincrease in the survival rate of all cancers combined inboth men and women. In this report, the authors state,“The improvement in survival reflects a combinationof earlier diagnosis and improved treatments.”1Improved cancer therapies are a significant factorcontributing to advances in cancer care, with researchestimating that new medicines have accounted for50-60 percent of the increase in cancer survival ratessince 1975.2 Cancer death rates began to fall for thefirst time in the 1990’s and are continuing to decline.According to the NCI’s Surveillance, Epidemiologyand End Results (SEER) database, since its peak in1991, the cancer death rate has fallen by 20 percent.3Contrary to popular belief, this progress is not typicallydriven by dramatic, individual developments in cancertherapeutics, but more commonly is the result ofrecognizing incremental advances through clinicalresearch over time.Additionally, initial approval is often centered on asingle and specific disease indication due to regulatoryrequirements and practicalities of clinical trial design.In some cases, where current treatment options maybe lacking or ineffective, and patients are in needof new treatment options, the FDA may deem itappropriate to approve new cancer treatments basedon compelling surrogate endpoints, such as tumorshrinkage or molecular markers. Following such anapproval, companies are required to conduct furtherstudies to validate the surrogate endpoints with longterm clinical outcomes data.While the intrinsic “value” (or clinical properties) ofa therapy does not change, our understanding of thebenefits and risks of the therapy evolves over timethrough the continual testing and validation that iscommon in oncology. Therefore, FDA approval oftenmarks the “starting point” for a number of additionalstudies of the therapy, followed by the developmentof a larger body of evidence to help us understand thefull value of the treatment and, more importantly, tohelp clinicians understand how best to use availabletherapies when treating their patients.This white paper demonstrates why the full clinicalvalue of a cancer therapy is often much greater thanrecognized at the time of initial FDA approval. Whilesome medicines prove to be less valuable thanexpected, the process of early research, initial FDAmarket approval, and ongoing post-market researchmean this is the exception rather than the rule. First,we will discuss the clinical research paradigm andits impact on the data available at the time of initialapproval. We will then identify the pathways by whichadditional clinical value is often recognized, including:At the same time considerable progress is being seen,biopharmaceutical companies engaged in oncologyresearch and development are facing increasingpressure to demonstrate the value of new cancermedicines, some of which report seemingly modestsurvival benefits (in terms of weeks or months) at thetime of initial Food and Drug Administration (FDA)approval. However, these seemingly modest benefitsoften demonstrate significant clinical advantages forpatients as further research is conducted and, thus,it is important to note that the true clinical value of atherapy often cannot be fully captured in the clinicaltrial data submitted for initial FDA approval.• Use in the initial FDA-approved indication• Use earlier in treatment line and earlier disease stage• Use in different disease indications†• Use in combination with other agents• Use in combination with specific biomarkersThe development process for all therapies is rigorous,but, in order to comply with standards of medicalethics, oncology research is initially focused on sickerpatients who have often tried and failed other availabletreatment options. This limits the level of benefitthat is likely to be observed in pre-approval testing.These pathways may provide a framework for abetter understanding of the true clinical value ofa therapy over time. Each of these pathways fordemonstrating product benefit is qualitativelyillustrated in Figures 1-4 using several real-worldexamples and will be discussed in this paper.†2 This may include both new indications approved by the FDA and off-label uses supported by research and deemed clinically appropriateby physicians. The evidence in this paper focuses on new FDA-approved indications.|Recognizing Value in Oncology InnovationImatinib (Gleevec ®)In 2001, the FDA approved imatinib for the treatment of advanced stages of chronic myeloid leukemia (CML) and second-linetreatment for the earlier, chronic phase of the disease. Approval was based on surrogate endpoints showing that patientsresponded to the treatment at the cellular level, but long-term survival data were not yet available.The clinical benefit was confirmed in 2007 with survival data, which showed 88 percent survival for patients after six years oftreatment compared with an average of 48 percent survival for patients after five years which was shown in earlier studies. Theuses of imatinib have expanded since initial approval; most recently, in 2012, it was approved for 36-month adjuvant treatmentof patients who had complete resection of gastrointestinal stromal tumors.FIGURE 1. Imatinib (Gleevec®): Clinical Value Over TimeUse in different diseaseindicationsUse earlier in treatment lineand/or disease stageUse in initial FDAapproved indicationClinical ValueImatinibUse in combination with otheragents and/or biomarkersLaunch:200120032005200720092011Indications:4• Initial Indication - May 2001: Patients with Ph+ chronic myeloid leukemia (CML) in blast crisis, accelerated phase, orchronic phase after failure of interferon-alpha therapy (IFN)• Feb 2002: Patients with Kit (CD117) positive inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST)• Dec 2002: Newly diagnosed adult patients with Ph+ CML-chronic phase (CP)• May 2003: Pediatric patients with Ph+ CML-CP recurrence after stem cell transplant or IFN resistance• Sep 2006: Newly diagnosed pediatric patients with Ph+ CML-CP• Oct 2006:• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL)• Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements• Adult aggressive systemic mastocytosis (ASM) patients without D816V c-Kit mutation or those with unknown c-Kit mutational status• Adult hypereosinophilic syndrome and/or chronic eosinophilic leukemia patients with FIP1L1- PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and HES and/or CEL patients who are FIP1L1-PDGFRα fusion kinase negative or unknown• Adult patients with inoperable, recurrent, and/or metastatic dermatofibrosarcoma protuberans• Dec 2008: Adjuvant treatment of adult patients following resected Kit (CD117) positive GIST• Feb 2012: 36 months’ treatment post-surgery in patients with resected Kit (CD117) positive GISTThe above is a graphical representation of the change in demonstrated clinical value over time as additional data and evidence becameavailable for the drug. Thus, increased clinical value is supported by the demonstration of an increase in clinical benefit, such as survival orother benefits, and/or by the demonstration of an increase in the range of possible uses, such as use in additional disease indications or usein combination with other agents.Recognizing Value in Oncology Innovation|3Docetaxel (Taxotere ®)Docetaxel was initially approved in 1996 as a treatment for locally advanced or metastatic breast cancer. In 1999, it receivedapproval as a second-line metastatic treatment for non-small cell lung cancer (NSCLC). Within three years, the FDA grantedapproval to move it to first-line treatment of NSCLC.It was then approved for inoperable, locally-advanced squamous cell carcinoma of the head and neck (SCCHN) in 2006. In 2007,docetaxel was approved for use as adjuvant therapy in operable, locally advanced SCCHN after a trial established mediansurvival of 70.6 months for patients on docetaxel compared to 30.1 months for the control group. Evaluation of docetaxelbased on early trial results would have substantially underestimated its impact on survival by more than 4.5 years.FIGURE 2. Docetaxel (Taxotere®): Clinical Value Over TimeUse in different diseaseindicationsUse earlier in treatment lineand/or disease stageUse in initial FDAapproved indicationClinical ValueDocetaxelUse in combination with otheragents and/or biomarkersLaunch:199619982000200220042006200820102012Indications:4• Initial Indication - May 1996: Treatment of patients with locally advanced or metastatic breast cancer who haveprogressed during anthracycline-based therapy or have relapsed during anthracycline-based adjuvant therapy• Dec 1999: Treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failureof prior platinum-based chemotherapy• Nov 2002: In combination with cisplatin for first-line treatment of patients with unresectable, locally advanced ormetastatic NSCLC• May 2004: In combination with prednisone as a treatment for patients with androgen independent (hormonerefractory) metastatic prostate cancer• Aug 2004: In combination with doxorubicin and cyclophosphamide for the adjuvant treatment of patients withoperable node positive breast cancer• Mar 2006: In combination with cisplatin and fluorouracil for the treatment of patients with advanced gastricadenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received priorchemotherapy for advanced disease• Oct 2006: In combination with cisplatin and fluorouracil for the induction treatment of patients with inoperablelocally advanced squamous cell carcinoma of the head and neck (SCCHN)• Sep 2007: In combination with cisplatin and fluorouracil for the induction treatment of patients with locallyadvanced SCCHNThe above is a graphical representation of the change in demonstrated clinical value over time as additional data and evidence becameavailable for the drug. Thus, increased clinical value is supported by the demonstration of an increase in clinical benefit, such as survival orother benefits, and/or by the demonstration of an increase in the range of possible uses, such as use in additional disease indications or usein combination with other agents.4|Recognizing Value in Oncology InnovationTrastuzumab (Herceptin ®)In 1998, the FDA approved trastuzumab for limited use in metastatic breast cancer patients whose tumors expressedthe protein HER2. At the time of approval, there were no data on overall survival, but the treatment in combination withchemotherapy slowed disease progression. In December 2001, clinical trial data showed that median overall survival increased25 percent with the addition of trastuzumab.Early in 2008, trastuzumab was approved for use in an earlier disease stage for women with HER2-positive disease, and hasbecome a potentially curative first-line adjuvant therapy for patients with HER2+ tumors. In 2010, it received an additionalindication for metastatic gastric or gastroesophageal junction adenocarcinomas overexpressing HER2.FIGURE 3. Trastuzumab (Herceptin®): Clinical Value Over TimeUse in different diseaseindicationsUse earlier in treatment lineand/or disease stageUse in initial FDAapproved indicationClinical ValueTrastuzumabUse in combination with otheragents and/or biomarkersLaunch:19982000200220042006200820102012Indications:4• Initial Indication - Sep 1998: Second-line treatment of patients with HER2+ metastatic breast cancer • Trastuzumab + paclitaxel for first-line treatment of patients with HER2+ metastatic breast cancer• Nov 2006: Trastuzumab + doxorubicin, cyclophosphamide, and paclitaxel, for the adjuvant treatment of patients withHER2-overexpressing, node-positive breast cancer• Jan 2008: Use as a single agent for the second-line treatment of adjuvant treatment of HER2+ node-negativeestrogen receptor/progesterone receptor (ER/PR) negative or with one high-risk feature, or node-positive breastcancer following multi-modality anthracycline based therapy• May 2008: For adjuvant treatment of HER2+ node positive or node negative (ER/PR negative or with one highrisk feature) breast cancer as (1) part of a treatment regimen consisting of doxorubicin, cyclophosphamide, andeither paclitaxel or docetaxel, (2) with docetaxel and carboplatin, or (3) as a single agent following multi-modalityanthracycline based therapy• In combination with paclitaxel for first-line treatment of HER2+ metastatic breast cancer• Single agent for treatment of HER2+ breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease• Oct 2010: Treatment of patients with metastatic gastric or gastroesophageal junction adenocarcinomaoverexpressing, HER2 and who have not received prior treatment for metastatic diseaseThe above is a graphical representation of the change in demonstrated clinical value over time as additional data and evidence becameavailable for the drug. Thus, increased clinical value is supported by the demonstration of an increase in clinical benefit, such as survival orother benefits, and/or by the demonstration of an increase in the range of possible uses, such as use in additional disease indications or usein combination with other agents.Recognizing Value in Oncology Innovation|5Cetuximab (Erbitux ®)Cetuximab was first approved in 2004 for use in combination with irinotecan as a treatment for a type of metastaticcolorectal cancer.Subsequent studies revealed that the presence or absence of mutations in the KRAS gene could predict response to thetreatment, allowing clinicians to confidently target treatment to a subgroup of patients likely to benefit. Analysis of pooled datareported an average overall survival of 5.6 months in patients with the KRAS mutation, compared to 15.6 months in patientswith no mutation. The label was revised by the FDA to reflect this new clinical information in 2009.Other post-approval studies expanded the use of cetuximab. In 2006, treatment approval was granted for the treatment ofsquamous cell carcinoma of the head and neck (SCCHN), and in 2011, it was approved as first-line treatment in combinationwith platinum-based chemotherapy with fluorouracil. Cetuximab can also be used in combination with an existing treatmentregimen (FOLFIRI), reducing the risk of colon cancer growth or spread by 15 percent.FIGURE 4. Cetuximab (Erbitux®): Clinical Value Over TimeUse in different diseaseindicationsUse earlier in treatment lineand/or disease stageUse in initial FDAapproved indicationClinical ValueCetuximabUse in combination with otheragents and/or biomarkersLaunch:200420052006200720082009201020112012Indications:4• Initial Indication - Feb 2004: Use in combination with irinotecan, cetuximab is indicated for the treatment ofepidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer in patients who are refractoryto irinotecan-based chemotherapy; as a single agent, indicated for the treatment of EGFR-expressing, metastaticcolorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy• Mar 2006: In combination with radiation therapy, for the treatment of locally or regionally advanced squamous cellcarcinoma of the head and neck (SCCHN), and for use as a single agent for the treatment of patients with recurrentor metastatic SCCHN for whom prior platinum-based therapy has failed• Oct 2007: Single-agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma after failure of bothirinotecan- and oxaliplatin-based regimens• July 2009: Patient population was refined to target those with wild type (i.e., the most typically observed variantof the gene) kirsten ras oncogene homolog (KRAS), and not recommended for those whose tumors had KRASmutations in codon 12 or 13• Nov 2011: First-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinomaof head and neck in combination with platinum-based chemotherapy with fluorouracilThe above is a graphical representation of the change in demonstrated clinical value over time as additional data and evidence becameavailable for the drug. Thus, increased clinical value is supported by the demonstration of an increase in clinical benefit, such as survival orother benefits, and/or by the demonstration of an increase in the range of possible uses, such as use in additional disease indications or usein combination with other agents.6|Recognizing Value in Oncology InnovationIMPACT OF THE CLINICALRESEARCH PARADIGMCancer is a complex, life-threatening cluster ofdiseases and the clinical development process foroncology therapeutics is equally and understandablycomplex. When any new drug or biologic reaches FDAreview, it has already undergone years of researchin the lab, in animal models, and in patients. Due tothe complicated nature of cancer, clinical research forthese medicines takes an average of 1.5 years longerthan treatments for other disease areas.5Even with this extensive testing, the clinical benefitdemonstrated by the data at the time of initial FDAapproval is often constrained because of the nature ofoncology clinical research. Because of ethical concernsand regulatory requirements, pre-approval research isgenerally focused on proving safety and efficacy for theproposed indication(s), rather than on demonstratingthe full intrinsic therapeutic value of the treatment.Due to the life-threatening nature of cancer, ethicalstandards are at the forefront of caring for patients andplay a significant role in shaping cancer research andtreatment. An oncologist must rely on proven therapieswith known risks and benefits when treating newlydiagnosed cancer patients. Therefore, investigationaltherapies are necessarily tested first in patientswith advanced-stage cancer who have exhaustedexisting standard treatment options. These late-stagepatients typically have been heavily pre-treated andhave already failed most available treatments. Whilethis does not impact the actual intrinsic propertiesof a therapy, it creates a theoretical “ceiling” on theamount of clinical benefit that can be observed duringthe initial phases of research. As a result, therapies thatmay significantly improve survival and/or convey otherbenefits in early-stage disease often fail to differentiatethemselves in this late-stage, difficult-to-treat patientpopulation. Only after the therapy has demonstratedefficacy in patients with late-stage disease or diseasethat is resistant to standard therapy can it be testedin earlier-stage cancers or as a first-line therapy. It istypically at these earlier stages that a new treatmentis more likely to significantly improve patient survivalby modifying the course of the disease by slowing orhalting its progression.In addition to the ethical obligations associated withcancer research, regulatory requirements also influenceclinical research in oncology. The FDA must considerboth the amount of information it requires and theneed to get promising treatments to seriously ill cancerpatients quickly. The agency appropriately requiresclear demonstration of the safety and efficacy of a newtreatment, and therefore pre-approval research activitiesare focused on these essential regulatory endpoints.Long-term outcomes data can take many years todevelop, and studies evaluating survival and otherlong-term endpoints are often still ongoing whena therapy is first approved based on surrogateendpoints. Surrogate endpoints are markers such astumor shrinkage, cellular response, or measurementsof certain biomarkers that are often – but not always –predictive of clinical benefits, such as overall survivalor time to disease progression.Medicines reviewed under the standard FDA pathmay be approved based on clinical benefits orestablished surrogate markers. The acceleratedapproval path for medicines that fill unmet medicalneeds for patients with serious diseases allows forapproval based on less established markers thatare “reasonably likely” to predict clinical benefit;however, the FDA requires further study andconfirmation of clinical benefit after approval.6,7 Asresearchers continue to develop their knowledge ofthe molecular basis of cancer, surrogate markers havebecome a critical tool for more accurately evaluatingmedicines in a shorter period of time.In addition to FDA-required post-approval studies,the innovator company may also initiate continuedresearch to expand understanding of the full clinicalvalue of the treatment. Post-marketing researchmay evaluate the therapy’s efficacy in less-advanceddisease, in combination with other therapies, inpatient subpopulations, and in different cancer typesaltogether. This research usually leads to a broaderunderstanding of the product’s full clinical valueand may prove a greater benefit to patients thandemonstrated at the time of initial approval. It mayalso indicate patient subpopulations or treatmentcombinations in which the therapy is either more orless beneficial than a proven alternative, leading tomore targeted and effective prescribing by clinicians.This accumulation of data and further recognitionof benefit can also result in additional or expandedFDA-approved indications for an already-approvedRecognizing Value in Oncology Innovation|7therapy. A recent study by Boston ConsultingGroup examined the post-marketing developmentof approved biological drugs. The study reportedthat in 2004, 47 percent of the Biologics LicensingApplications (BLAs) for recombinant DNA productsand monoclonal antibodies regulated by the FDACenter for Drug Evaluation and Research (CDER)received at least one additional FDA-approvedindication after initial approval.8 At least one-third ofthese agents are approved to treat oncology patientsand, from 2005 to 2007, 25 oncology therapeuticsreceived FDA approval for at least one expanded oradditional indication.9USE IN THE INITIALFDA-APPROVED INDICATIONAs discussed above, the FDA at times approvestherapies based on promising molecular or cellularresponse and other surrogate endpoints beforethe completion of long-term outcome studies. Inthese cases, the impact on overall survival or tumorprogression may not be certain until those longterm studies are completed – often years after theinitial approval. The FDA carefully balances theneed to get new medicines to patients with fewtreatment options with the need for conclusivescientific evidence supporting surrogate markers.Biopharmaceuticals approved under thesecircumstances are granted approval contingentupon continued research and clinical investigationof safety and efficacy.The case of imatinib (Gleevec®) offers an exampleof the time lag between initial approval (based onsurrogate endpoints) and demonstration of clinicalbenefit (based on conventional survival endpoints)(see Figure 5). In 2001, under the acceleratedapproval provisions of 21 CFR 314 Subpart H,the FDA approved imatinib for the treatment ofadvanced stages of chronic myeloid leukemia(CML) and second-line treatment for the earlier,chronic phase of the disease.10 In announcing theapproval, the FDA noted that there was no evidenceof clinical benefit, defined as a reduction in diseaserelated symptoms or mortality.11 The drug wasapproved because initial trial data demonstrated8|Recognizing Value in Oncology Innovationthat patients were responding to the drug treatmenton a molecular level, and the FDA noted that thebenefit of an immediate approval for a treatment ina disease area with few effective treatment optionsoutweighed the remaining uncertainty of the drug’soverall clinical benefit.It would take another six years for the clinicalbenefit of imatinib to be confirmed by survivaldata. In 2007, continued follow-up data from theInternational Randomized IFN vs. ST1571 (IRIS) studydemonstrated that disease progression fell to zeropercent in 553 CML patients treated with imatinib.Three hundred sixty-four of these patients werestill taking the drug by the study’s sixth year, with areported overall survival of 88 percent.12 This resultstands in stark contrast to the average five-yearsurvival rate of 48 percent for CML patients from1990 to 2000, prior to the approval of imatinib.13FIGURE 5.Value Recognition: Use in InitialFDA-Approved IndicationImatinib (Gleevec®)In 2001, imatinib was approved for second-linetreatment in chronic myeloid leukemia (CML).Approval was based on hematologic and cytogenicresponse rates in trial participants; there wereno studies demonstrating clinical benefits suchas improvement in disease-related symptoms orincreased survival. In 2007, six years after initialapproval of imatinib for use in CML, the IRIS studysix-year results reported that CML patients treatedwith imatinib had disease progression rates of zeropercent, with an estimated overall survival rate of88 percent.12Similarly, while initial approval for use ingastrointestinal stromal tumors (GIST) patientswas granted in 2002, clinical data demonstratingover four years of overall survival and 1.5-2 yearsof progression-free survival in GIST patients werenot available until 2008.14EARLIER USE IN TREATMENT LINEAND DISEASE STAGEFDA-approved indications for oncology therapiesare generally limited to a specific line of therapy anddisease stage. Advancement in treatment line refersto the movement of an agent to be used as an earliertherapeutic option within a particular disease stage.Advancement in disease stage denotes the movementof an agent for use in an earlier stage of diseaseprogression (e.g., movement from end-stage therapy inadvanced or metastatic cancer‡ to adjuvant therapy§ inearly-stage, operable disease). These shifts may signal achange in therapeutic intent from palliative to potentiallycurative use. Generally, oncology drugs advance first intreatment line, then advance in disease stage.Docetaxel (Taxotere®) illustrates the progression of adrug’s clinical use both earlier in treatment line andin disease stage (see Figure 6). Docetaxel receivedapproval for use as a second-line metastatic treatmentfor non-small cell lung cancer (NSCLC) in 1999. And in2002, the FDA granted approval for the use of docetaxelas a first-line treatment in metastatic disease in NSCLC,demonstrating movement earlier in the treatment line.4In another disease area, docetaxel was approved forinoperable, locally advanced squamous cell carcinomaof the head and neck (SCCHN) in 2006. In this advanceddisease stage, patients treated with docetaxel had anoverall survival of 1.5 years – four months longer thanthe control group.4 A year later, the FDA approveddocetaxel as adjuvant treatment for patients withoperable, locally advanced SCCHN, where the therapyis associated with nearly six years of median overallsurvival, an improvement of more than three yearsover the control group.4 Evaluation of docetaxel basedsolely on its clinical data in the treatment of inoperable,locally advanced SCCHN would have substantiallyunderestimated the treatment’s impact on overallsurvival in the disease by more than 4.5 years.Earlier in docetaxel’s history, a similar pattern was observedfor breast cancer. The agent was initially approved formetastatic treatment, but its use was eventually moved toearlier disease stages for use in the adjuvant setting.As demonstrated in Figure 4, Erbitux has followeda similar path. It was approved in 2012 for first-linetreatment of patients with recurrent or metastaticcancer of the head and neck; however its originalindication was metastatic colorectal cancer.FIGURE 6.Value Recognition: Use Earlier in Treatment LineDocetaxel (Taxotere®)In 1999, docetaxel was approved in combinationwith cisplatin for the treatment of patients withmetastatic non-small cell lung cancer (NSCLC)after failure of prior platinum-based chemotherapy,meaning second-line treatment or beyond. Mediansurvival was 7.5 months compared to 4.6 months forthe control group. In 2002, docetaxel was approvedfor first-line treatment of metastatic non-small celllung cancer patients. When used as first-line therapyin combination with cisplatin, median survival was10.9 months.15Value Recognition: Use Earlier in Disease StageDocetaxel (Taxotere®)Docetaxel was initially approved for breast cancerin 1996. In 2006, it was approved for inoperableadvanced or metastatic squamous cell carcinomaof the head and neck (SCCHN) after a clinical trialdemonstrated median overall survival of 18.6months for patients on docetaxel compared to 14.2months for the control group. In 2007, docetaxelwas approved for use as adjuvant therapy inoperable, locally advanced SCCHN after a clinicaltrial established median survival of 70.6 months forpatients on docetaxel compared to 30.1 months forthe control group. Docetaxel’s survival benefit relativeto the control group was approximately 10 timeslarger when used as adjuvant therapy in operablecancer than as treatment in later-stage inoperablecancer, its original indication in the disease.4Imatinib (Gleevec®)In 2006, imatinib moved earlier in the chronic myeloidleukemia (CML) treatment line when it was approvedfor first-line therapy in Ph+ CML-chronic phasepatients. A similar pattern was seen in GIST, whereapproval for use in the adjuvant setting was grantedin 2008 following termination of the pivotal trial afterinterim analysis demonstrated significant benefitswith imatinib and in 2012, when it was approvedfor 36-month adjuvant treatment of patients whohad complete resection of gastrointestinal stromaltumors. Randomized trials to examine the efficacy ofimatinib in neoadjuvant settings for treatment of GISTare still underway however, only preliminary findingshave been released.16,17 Metastatic cancer occurs when cancer cells travel from the primary tumor site to other parts of the body and continue to grow in the newlocation(s); it is indicative of more advanced, or progressing, disease.§ Adjuvant therapy is administered postoperatively, where there is no visible cancer but there is still risk of cancer cells in the body.‡Recognizing Value in Oncology Innovation|9FIGURE 6. ContinuedValue Recognition: Use Earlier in Disease StageTrastuzumab (Herceptin®)In 2006, trastuzumab moved from treatment ofmetastatic breast cancer into adjuvant treatmentfor operable breast cancer, with a hazard ratio of0.48 for disease-free survival events in patientstreated with trastuzumab + paclitaxel versuspaclitaxel alone after anthracycline. In otherwords, the rate of relapse or recurrence in patientstreated with combinations including trastuzumabis approximately half of that in patients treatedwith paclitaxel alone. Trastuzumab use was alsoassociated with a 33-percent reduction in risk ofdeath.18 In 2008, a clinical trial found that whenused as a single agent following chemotherapy,trastuzumab had a hazard ratio 0.54 for diseasefree survival events compared to observation,indicating that approximately twice as manypatients on paclitaxel alone were relapsingas compared with those patients receivingtrastuzumab in combination therapy. When usedboth as a single agent and in combination, the rateof relapse or recurrence in patients on trastuzumabbased therapy was approximately half that whencompared with observation of those on alternativetherapeutic regimens.19with imatinib experienced, on average, more thanfour years of overall survival, and between 1.5-2 yearsof progression- free survival.20This represents a significant improvement in overallsurvival, as a study published in 2000 indicatesoverall survival for GIST patients prior to imatinibapproval was approximately 14 months.21 In addition,imatinib is now approved for an array of additionalindications, ranging from second-line treatment forpediatric CML patients to adults with aggressivesystemic mastocytosis (ASM) (see Figure 7). Researchon imatinib continues today in other cancers, suchas squamous cell carcinoma of the head and neck(SCCHN), mesothelioma, and glioblastoma.22Many other drugs have proven to be beneficial inmultiple cancers with similar underlying geneticmutations. For example, in 2010, twelve years afterinitial approval for patients with HER2+ breastcancer, trastuzumab became available to patientswith HER2 overexpressing metastatic gastric orgastroesophageal junction adenocarcinoma whohave not received prior treatment for metastaticdisease. This first indication for another type ofcancer was based on trials that showed an increasein overall survival from 11 months to 13.5 months –a 22 percent increase.23FIGURE 7.USE IN ADDITIONAL DISEASEINDICATIONSOncology therapies often have clinical value in typesof cancers distinct from the original indication(s) forwhich they are approved. Studies conducted andreported after the initial approval commonly exploreadditional indications and, in many instances, atherapy demonstrates significant clinical benefit in adifferent disease. The clinical development of imatinib,for example, did not end with the original CMLindication. Imatinib’s approved indications expandedto the treatment of unresectable** and/or metastaticgastrointestinal stromal cancer (GIST) in February 2002based on surrogate endpoints, less than a year afterinitial approval for the CML indication.In 2008, the earlier FDA decision was corroborated byclinical data demonstrating that GIST patients treated**Value Recognition: Use in AdditionalDisease IndicationsImatinib (Gleevec®)Less than a year after initial approval, imatinib wasapproved for use in gastrointestinal stromal tumors(GIST) patients with Kit-positive tumors. Similar toits initial approval, the expanded GIST indicationwas based on a surrogate endpoint: objectiveresponse rate (percentage of cases in which tumorshrinkage occurred). A significant improvementin overall survival from approximately 14 monthsprior to imatinib use to over four years withimatinib was eventually realized and clinicallyvalidated. Ongoing trials are also investigating theuse of imatinib in several additional disease areas,including squamous cell head and neck cancer,thyroid cancer, breast cancer, mesothelioma, andnon-Hodgkin lymphoma.22 An unresectable tumor is one that cannot be removed through surgery.10|Recognizing Value in Oncology InnovationUse in Combination withOther AgentsCancer’s complexity requires continual research inorder to learn how to utilize new therapies mosteffectively. Through experience and rigorous clinicaltesting, physicians develop an understanding ofhow best to use a therapy in combination withother chemotherapeutic agents and treatmentmodalities (e.g., surgical resection, radiation,and supportive care). As the available arsenal ofoncologic agents continues to grow, effective useof these drugs in combination becomes paramount.However, the therapeutic value of a possibletreatment combination is difficult to demonstratethrough clinical testing, due to the great numberof potential therapeutic combinations available,each potentially only applicable to smallpopulation subsets with specific characteristics.While combination therapies frequently resultin improved clinical outcomes, they also candemonstrate instances where the hypothesizedbenefit of a specific combination is not supportedby the empirical data. The development anddissemination of objective clinical data is acornerstone of oncology research and serves tofurther the clinician’s understanding of how to useavailable treatment options.for metastatic colorectal cancer than FOLFIRI alone(see Figure 8). One study found that the additionof cetuximab to FOLFIRI reduced the risk of cancergrowth or spread by 15 percent. 25Several other studies explored the clinical benefitof adding cetuximab to a regimen of capecitabine,oxaliplatin, and bevacizumab in the treatmentof advanced metastatic colorectal cancer. Thestudies indicate that the addition of cetuximabto regimens containing the targeted therapybevacizumab actually reduces median progressionfree survival compared to the standard regimenwithout cetuximab. 26 These studies do notnegate the benefits associated with cetuximab incombination with other cytotoxic chemotherapyregimens; however, they provide new insights intohow cetuximab should and should not be used,ultimately maximizing the benefit it provides tocancer patients.Despite the difficulty of demonstrating theeffectiveness of drug pairs, combination therapyhas become well-established in oncology forseveral reasons, and a considerable amount ofcancer research involves different combinationsof new and existing therapies. Because manycancer therapies cause severe side effects, often apatient cannot tolerate a full dose of a highly toxicdrug or biologic. Additionally, different therapiesact through different mechanisms in the body tocombat tumor growth. The combination approachhas been demonstrated to enhance anti-tumoractivity by allowing both the administration of fulldoses of agents while managing the dose-limitingadverse effects and utilizing multiple mechanismsof action to reduce tumor growth, often producingsuperior outcomes.24 For example, the addition ofcetuximab (Erbitux®) to FOLFIRI (folinic acid [alsoknown as leucovorin], fluoruracil, and irinotecan),demonstrates greater efficacy as first-line therapyRecognizing Value in Oncology Innovation|11FIGURE 8.Value Recognition: Use in Combination withOther AgentsCetuximab (Erbitux®)An analysis of first-line cetuximab alone or incombination with FOLFIRI (folinic acid, fluoracil,and irinotecan) in metastatic colorectal cancerfound that at the end of the monotherapy phase,response rate was 27.6 percent. During thecombination phase, however, this response rateincreased to 55.2 percent.Progression-free survival for cetuximab + FOLFIRIwas also significantly improved.25 Additionally,initial results from the CRYSTAL trial have reportedthat the addition of cetuximab to FOLFIRI infirst-line therapy reduces the risk for metastaticcolorectal cancer growth or spread by 15 percentcompared with FOLFIRI alone. Overall responserate to FOLFIRI + cetuximab was 46.9 percentcompared with 38.7 percent with FOLFIRI alone,and median progression-free survival was 8.9months and eight months, respectively.27 Furtherfollow-up results from the CRYSTAL trial noted thatin patients with tumors without KRAS mutations,adding cetuximab to FOLFIRI statisticallysignificantly increased the chance of a complete orpartial tumor response (p=0.0025), reduced the riskof progression (p=0.0167), and increased medianoverall survival by 3.9 months (p=0.22).28Trastuzumab (Herceptin®)Following its 2006 approval for use in adjuvantbreast cancer treatment, the FDA expandedtrastuzumab’s indications within adjuvanttreatment, after a clinical study showed thattrastuzumab + docetaxel and carboplatin, andtrastuzumab + docetaxel following doxorubicinand cyclophosphamide had hazard ratios fordisease-free survival events of 0.67 and 0.60,respectively.29 In other words, the rate of relapse orrecurrence in patients treated with combinationsincluding trastuzumab is approximately twothirds of that in patients treated with combinationtherapy without trastuzumab.12|Recognizing Value in Oncology InnovationUSE IN COMBINATION WITHSPECIFIC BIOMARKERSIn certain patient subsets, specific genetic profilesare associated with improved activation and/ormetabolism of a drug or improved activity, therebydemonstrating the potential for marked increases inclinical benefit in targeted populations.Biomarkers are molecules or genetic markers that can beused to predict therapeutic response and/or sensitivity toadverse events, allowing clinicians to better select patientswho are most likely to benefit from targeted therapies.Although much work needs to be done in this area,oncology researchers and those in other therapeutic areasare embracing the development of diagnostics that allowphysicians to stratify patients and determine which subsetsof patients may be most likely to benefit from therapy.The approval of cetuximab in patients with metastaticcolorectal cancer was based on clinical results that didnot account for the impact of observable mutations inthe KRAS gene, which have since been demonstrated topredict treatment response. The label was changed whenstudies showed that those with wild type KRAS (the typicalform of the gene) lived nearly three times as long on thedrug as and those whose tumors had KRAS mutationsin codon 12 or 13. This narrowing of the populationmost likely to benefit was based on retrospectivesubset analyses. Thus, the use of cetuximab now can beconfidently targeted to a subgroup of patients with thegreatest likelihood of response, while alternative regimenscan be selected for the patient subgroup in which the KRASbiomarker suggests that cetuximab would not be effective.Trastuzumab (Herceptin®) is another targeted therapy thathas demonstrated additional clinical value in combinationwith a specific biomarker (see Figure 9). Initial investigationof trastuzumab in metastatic breast cancer established antitumor activity, but tumor response occurred only in patientswith positive expression of human epidermal growthfactor receptor-2 (HER2). Approval was then granted onlyfor this specific subset of breast cancer patients, as theyrepresent the subpopulation with the highest probability ofreceiving treatment benefit. Without knowledge of the HER2biomarker’s role in trastuzumab response, the efficacyof the drug may not have been realized and this mayhave stunted further recognition of its benefit. Early in 2008,trastuzumab was approved for use in an earlier diseasestage for adjuvant therapy of women with HER2-positivedisease and has become a potentially curative first-lineadjuvant therapy for patients with HER2-positive tumors.FIGURE 9.Value Recognition: Use in Combination withSpecific BiomarkersCetuximab (Erbitux®)In 2008, a clinical study found KRAS mutationspresent in 27 percent of 89 patients. The mutation wasassociated with resistance to cetuximab in all 24 of thepatients whose tumor expressed the KRAS mutation.Among the 65 patients whose tumor did not expressthe KRAS mutation, a 40 percent response rate wasobserved. Overall survival was 10.1 months in patientsexpressing the mutation compared to 14.3 monthsin patients without the mutation. Further analysis ofpooled data suggests average overall survival of 5.6months in patients with the KRAS mutation, comparedto 15.6 months in patients with no mutation.30In another study, also published in 2008, 113 patientswith irinotecan-refractory metastatic colorectal cancerwere treated with cetuximab. In patients without theKRAS mutation, median overall survival was 10.8months compared to 6.8 months in patients expressingthe KRAS mutation.31 In a subset of these patients inwhom an initial response was observed (decrease oftumor by >9.66 percent at week six assessment), themedian OS was 18.7 months compared to 7.7 months.These studies indicate that KRAS status is predictive ofresponse to epidermal growth factor receptor (EGFR)inhibitor therapy, allowing the use of better targetedtherapy and resulting in improved survival.Trastuzumab (Herceptin®)In 1998, the FDA approved trastuzumab for limiteduse in HER2+ metastatic breast cancer based ontime to progression of 7.2 months for patients ontrastuzumab + chemotherapy, compared to 4.5 monthswith chemotherapy alone. There was no overallsurvival data at the time, but there was evidence thattrastuzumab elicited an objective response in HER2+breast cancer. In December 2001, new data indicatedmedian overall survival of 25.1 months for trastuzumab+ chemotherapy as compared to 20.3 months forchemotherapy alone in patients with HER2+ metastaticbreast cancer. The trial also demonstrated that patientswith the greatest HER2 expression had median overallsurvival of 24.8 months on trastuzumab + paclitaxelcompared to 17.9 months on paclitaxel alone, and 30.8months overall survival on trastuzumab + anthracyclinecompared to 20.9 months on anthracycline alone.4Looking ahead: Emergingtrends shaping valuein oncologySeveral key scientific and research trends areemerging that likely will have a significant impact onthe pathways identified in this paper. These trends canbe expected to increase the pace and complexity ofthe process through which understanding of clinicalvalue evolves over time, including:1.Basic scientific advances are changing ourunderstanding of cancer. We now understand thatcancer is actually more than 200 separate diseases,often defined by molecular/genetic variations ratherthan histology or anatomical location. We know thatthe level of gene expression and mutations mayvary even among cells within the same tumor.2.Targeted therapy is increasingly central to cancercare. Use of drugs and diagnostics in combinationhelps increase efficacy and reduce toxicityby targeting specific tumor pathways. Futurediscovery, development, and approval of targetedtherapy requires ongoing research to betterunderstand the types of cancer that can benefitfrom this approach.3.Combination treatments are growing inimportance. Attacking highly adaptive tumor cellsrequires a multi-pronged approach which, in turn,requires extensive refinement and evaluation overtime. The continued treatment with combinationtherapies is expected to lead to additionalimprovements over time.4.New tools for rapid learning are emerging. Cancerresearch is on the leading edge of efforts to createrapid learning systems that allow researchers andclinicians to collect and analyze large amounts dataas a treatment is used in patients. These systemscould allow continued assessments of actual drugbenefits versus risks as information on real-worldpatient experience becomes available for analysisand interpretation.In 2002, the label would again be expanded toinclude the use of a fluorescence in situ hybridization(FISH) diagnostic test to quantify the HER2 statusof patients, allowing the clinician to make a moreinformed treatment decisions.4Recognizing Value in Oncology Innovation|13CONCLUSIONSAs this paper shows, the full clinical benefit ofoncology medicines often is not entirely known at thetime of initial FDA approval. Oncology researcherscontinue to conduct additional research before andafter initial approval, and oncologists in the clinicexplore the best ways to use a new medicine whenit becomes available. It is through this accumulationof data that a therapy’s clinical value can be morefully evaluated and understood over time. Becauseof the nature of the research process, initial trial dataalone cannot reflect the clinical value of a therapyearlier in treatment or disease stage, across differentdiseases, in combination with the complete array ofother therapies, or within target populations identifiedthrough specific biomarkers. In some cases, it maynot even reflect the therapy’s clinical value within theinitial FDA indication if the medicine is approved basedon surrogate markers rather than long-term outcomes.Demonstrating the clinical benefit of a treatment is anongoing process in which researchers and cliniciansevaluate all aspects of how the drug or biologic isused and how it affects patients (see Figures 1-4).Therefore, the full impact of cancer therapy is oftenrecognized only after years of additional postapproval research. The potential for greater benefitstill exists as long as the therapy is rigorously testedin innovative new ways.As a result of many interrelated factors, dramaticadvances in overall cancer survival have beenrealized by the cancer community in recent years.Because innovative cancer therapies play a significantrole in these advances, it is vitally important that theongoing and incremental nature of oncology researchbe recognized by researchers, clinicians, patients, andpolicymakers alike. Only by examining the entire setof evidence – sometimes accumulated over a periodof time – are we able to judge the clinical value thatindividual therapies can bring to treating patients,often across several different cancers. Thus, theclinical benefit we observe at the time that a new anticancer therapy receives FDA approval is generallyonly a partial reflection of the ultimate benefit thatwill be understood for that therapy, as a direct resultof the mechanisms outlined in this paper. Continuedresearch investment into how biopharmaceuticals canbe used to improve patient outcomes after approvalremains a key priority and opportunity to achievecritical advances in oncology.14|Recognizing Value in Oncology InnovationREFERENCES1Siegel R et al. Cancer Statistics, 2011: The Impact ofEliminating Socioeconomic and Racial Disparities onPremature Cancer Deaths. CA: A Cancer Journal forClinicians. 2011: 61(4): 212-36.2Lichtenberg FR. The Expanding Pharmaceutical Arsenalin the War on Cancer. National Bureau of EconomicResearch Working Paper No. 10328. February 2004.3National Cancer Institute, Surveillance Epidemiology andEnd Results, http://seer.cancer.gov/faststats/index.php(accessed 16 December 2011).4“FDA Product Label(s).” FDA.gov http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm5DiMasi JA and Grabowaki HG. Economics of NewOncology Drug Development. 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New England Journal Medicine. 1973;288:998-1006.Recognizing Value in Oncology Innovation|15Boston Healthcare AssociatesBoston Healthcare helps biopharmaceutical, medical device, and diagnostics companies unlock the value ofinnovation in the global healthcare marketplace. Clients rely on Boston Healthcare to create opportunities,navigate complexity, grow their businesses, and achieve their objectives through reimbursement and marketaccess strategy, health economics and outcomes analysis, market and pricing strategies, and businessdevelopment support—all delivered to help clients capture value.Boston Healthcare’s unique approach, combining strategic consulting with a deep understanding of theevidence-driven value environment, gives clients a real-world edge in assessing, creating, and capturing growthopportunities. For more information, visit www.bostonhealthcare.com.We would like to thank Stephen Chan, Katherine Slawsky, Christopher Prottas, and John Feldmann for theirprevious contribution to this paper.Funded by a grant from the Pharmaceutical Research and Manufacturers of America.Recognizing Value inOncology InnovationW hite P ape r|J U N E 2 012