Bevacizumab Beyond Progression: Does ThisMake Sense?Lee M. Ellis, The University of Texas M. D. Anderson Cancer Center, Houston, TXDaniel G. Haller, University of Pennsylvania, Philadelphia, PA

For almost five decades after fluorouracil was patented, littlechanged in the management of patients with colorectal cancer (CRC).Without competition, it was the one-eyed man in a land of the blind.Perseverance and optimism led to the finding nearly two decades agothat a cytotoxic with modest effects in advanced disease had significantefficacy in adjuvant therapy. Over the last 10 years, we have witnesseda radical change in the use of systemic therapy for metastatic CRC,with the introduction of three cytotoxics and three monoclonal anti-bodies (MoABs). New treatment paradigms have evolved that includethe use of multiple chemotherapeutic agents in several lines of therapy,the ability to convert unresectable patients with liver metastases toresectable status, and the incorporation of MoABs targeting vascularendothelial growth factor (VEGF) and the epidermal growth factorreceptor (EGFR) into everyday practice. With this relative abundanceof treatment options, it comes as no great surprise that both clinicalresearchers and clinicians have experienced increased difficulty defin-ing a standard of care for patients with metastatic CRC, if indeed asingle standard is either expected or desired. Traditional lines of ther-apy have become blurred—particularly with the use of biologics—andthe availability of sequential therapy has created new challenges indetermining an actual overall survival benefit for any new agents orregimens. The relative wealth and availability of drugs, the complexi-ties of combination therapy, and the use of breaks in therapy havecalled into question the likelihood that any new intervention will allowfor firm, data-driven recommendations supporting the use any par-ticular regimen as the gold standard of success leading to improve-ment in overall survival. Exciting new data showing that KRASmutational status predicts for resistance to anti-EGFR MoAB therapyare likely to further modify treatment algorithms and to challengeconventional methods of assessing optimal use of anticancer agents.1-3

Although we all recognize that there is an art in caring for our patients,the regulatory and reimbursement agencies may not allow the use ofartistic license. Thus, we must provide both clinical and biologic argu-ments for the use of particular agents or regimens in the care ofour patients.

In this issue of Journal of Clinical Oncology, Grothey et al4 reportresults from a large observational study (Bevacizumab Regimens In-vestigation of Treatment Effects and Safety [BRiTE]) suggesting thatthe continuation of bevacizumab, despite changing the chemothera-peutic regimen after progression on a bevacizumab/chemotherapyregimen (bevacizumab beyond progression), led to an overall survivalof approximately 32 months. This contrasted with patients who re-

ceived further therapy but without bevacizumab, in whom overallsurvival was approximately 20 months. The latter survival duration isconsistent with findings in recent first-line phase III trials with chem-otherapy and bevacizumab.5 There was a third group of patients witha poorer performance status who did not receive therapy beyond firstprogression, and they will not be discussed further in this editorial. Wenow must evaluate these data to determine the impact of these find-ings on day-to-day practice and to hypothesize why continuation ofbevacizumab as a component of multidrug regimens may improveoverall survival.

The study by Grothey et al4 provides a glimpse into the everydaypractice of oncology in the United States. Surprisingly, perhaps, onlyapproximately 60% of patients received all three active chemothera-peutic agents during their course of treatment. In a prior publication,Grothey et al6 showed that patients who received all three activechemotherapeutic drugs (fluorouracil, oxaliplatin, and irinotecan)had a better overall survival than patients who did not. Thus, it isunclear why less than two thirds of patients in this observational studyreceived all three active drugs during the prolonged course of therapy.Furthermore, only 51% of patients who did not receive bevacizumabbeyond progression were treated with EGFR inhibitors. On the basisof National Comprehensive Cancer Network guidelines, patients whoexperience progression on first-line bevacizumab-containing regi-mens should receive an anti-EGFR antibody in subsequent lines oftherapy. Although there are occasional contraindications for suchtherapy, it seems highly unlikely that half of these patients would beineligible for therapy. Although one may be critical of the practices ofthe physicians who contributed patients to this study, a recently re-ported randomized trial of oxaliplatin-based chemotherapy, with ei-ther placebo or bevacizumab, also showed that, despite participationin a predefined protocol, treatment with either chemotherapy or bev-acizumab was frequently discontinued before disease progression.5

The authors noted that, “while discontinuation of oxaliplatin withcontinuation of fluoropyrimidine and bevacizumab was permitted,our analysis shows that this course of action was rarely taken.”5 Thisrandomized, controlled trial also suggested that “the duration of bev-acizumab therapy is likely to be important, and that treatment untilPD [progressive disease] may be necessary to maximize the clinicalbenefit derived from bevacizumab therapy.” The data did not, how-ever, permit any conclusion about treatment with bevacizumab be-yond progression.

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Studies must investigate the driving force behind preferences (orlack thereof) for certain drugs in specific indications. Does cost play arole? Marketing? Toxicity? Patient preference? The observations fromthe BRiTE study4 and the study by Saltz et al5 suggest particularpreferences or biases by individual oncologists (or patients) participat-ing in these trials, and thus, we should refrain from overinterpretingthe data until confirmed in prospective, randomized studies.

Regardless of the nuances and limitations of observational stud-ies (see the editorial on this topic by Levine and Julian in this issue ofJournal of Clinical Oncology), the most interesting aspect of the reportby Grothey et al4 of the BRiTE study is the apparent added benefit ofcontinuing bevacizumab (and in most cases, fluorouracil) whilechanging the chemotherapeutic variable (ie, oxaliplatin or irinotecan).How can this drug be effective through multiple lines of therapy? Themechanisms of action (MOAs) of bevacizumab are diverse and com-plex. Proposed MOAs of bevacizumab (and other anti-VEGF thera-pies) include the following: antiangiogenic activity (includinginhibition of new blood vessel growth and vascular regression); vascu-lar constriction; vascular normalization; direct effects on tumor cellfunction; offsetting of effects of chemotherapy induction of VEGFlevels; and inhibition of VEGF repression of dendritic cell function.7

Admittedly, it is difficult to determine the exact MOA in metastaticCRC because no study in humans can adequately address or interro-gate all of the possibilities. However, insights into the MOAs of anti-VEGF therapy can sometimes be obtained from clinical trial results.For example, data on response rates (RRs) would have been informa-tive. A high RR would have suggested that bevacizumab is a chemo-therapy-sensitizing agent through multiple lines of chemotherapy. Incontrast, no increase in RR accompanied by a prolonged overall sur-vival may inform us that this agent is cytostatic in this setting. If thelatter is the case, then one could question whether bevacizumab couldbe used as single-agent maintenance therapy. However, there is noevidence that bevacizumab as a single agent has activity in patientswith metastatic CRC, especially refractory patients, as demonstratedin the Eastern Cooperative Oncology Group 3200 trial.8 Unfortu-nately, without RR data in the current study, we can only speculate onthe MOA of bevacizumab in refractory patients, in whom it may bedifferent from that in chemotherapy-naive patients. It is of note that,in the trial reported by Saltz et al5 in first-line patients, a statisticallysignificant improvement in progression-free survival (the primaryend point) was achieved by the addition of bevacizumab, without anyimprovement in RR.

Recent studies presented at the annual meeting of the AmericanAssociation for Cancer Research provided some insight into themechanisms by which bevacizumab increases the effectiveness ofchemotherapy. In contrast to the normalization hypothesis, wherebybevacizumab leads to a redistribution of tumor blood flow, resultingin increased delivery of chemotherapy to the tumor, Kasman et al9 didnot find any increase in drug uptake in mice bearing human cancerxenografts. Instead, these investigators showed that an antibody toVEGF led to increased vascular damage when combined with chem-otherapy. VEGF activates a number of survival pathways in endothe-lial cells, and Klement et al10 have shown that blockade of VEGFsignaling could sensitize endothelial cells, rather than tumor cells, tothe effects of chemotherapy. Although we typically consider sensitivityor resistance as emanating from tumor cells, we now must considerthe possibility that endothelial cells may also be sensitive or resistant tochemotherapy. It is possible that changing cytotoxic chemotherapy

may expose endothelial cells to a different genotoxic stress and that theaddition of anti-VEGF therapy may serve as a chemotherapy sensitizerto the tumor vasculature through multiple lines of therapy. Of course,the same argument could be made for tumor cells, where VEGFreceptors have been shown to mediate numerous tumor cell func-tions, including survival.11

The BRiTE study, among others, raises interesting questions.For example, what should we use in second-line therapy for meta-static CRC in patients who have experienced progression on abevacizumab-containing regimen? For the sake of discussion, let usassume that a patient has experienced progression on infusional flu-orouracil, leucovorin, and oxaliplatin plus bevacizumab (approxi-mately 60% to 70% of patients in the United States will receive asimilar first-line regimen). On the basis of National ComprehensiveCancer Network guidelines, it would be reasonable to consider anirinotecan-based regimen � cetuximab for such a patient. However,since these guidelines were developed, we have learned that patientswith tumors with mutated KRAS are unlikely to benefit from anti-EGFR MoAB therapy. If this holds true, then cetuximab (or panitu-mumab) should not be considered for patients whose tumors expressmutated KRAS. This limits our options in second- and third-linetherapy yet provides an opportunity to study other biologics in thissetting. It would have been informative if Grothey et al4 had analyzedtumors from the BRiTE study to determine whether bevacizumabbeyond progression is effective in the group of patients with KRASmutations (thus poor candidates for anti-EGFR MoABs). AlthoughKRAS mutational status has not been shown to affect outcome inpatients receiving first-line bevacizumab,12 it is possible that KRASmay have an impact on outcome in refractory patients. Therefore, it isessential to study new approaches for patients who have a mutatedKRAS tumor who have experienced progression on bevacizumab. Forexample, should we study the effects of continued anti-VEGF therapyby tweaking the anti-VEGF approach and using another VEGF-targeted agent, such as sorafenib (an agent designed to target VEGFreceptors and Raf, a downstream mediator of Ras signaling)? There areemerging data on the use of VEGF inhibitors in patients with renal cellcarcinoma, in whom patients refractory to one VEGFR tyrosine kinaseinhibitor may respond to a different tyrosine kinase inhibitor.13

Although the 32-month overall survival time of patients receiv-ing bevacizumab beyond progression in this registry is suggestive of apossible benefit for continued bevacizumab beyond first progression,we must keep in mind that this is an observational study and not aprospective randomized trial. There is always a component of investi-gator bias and selection in observational studies. For example, asshown in Table 1 of the article by Grothey et al,4 the percentage ofpatients with an Eastern Cooperative Oncology Group performancestatus of 0 is 50% in the bevacizumab beyond progression groupcompared with 40% in the group who did not receive bevacizumabbeyond progression. A prospective randomized trial (Intergroup Be-vacizumab Continuation Trial/Southwest Oncology Group 0600) isongoing in an attempt to answer the question of whether or not tocontinue bevacizumab (in combination with chemotherapy andcetuximab) after progression on first-line therapy. However, this trialis being modified as a result of the recent data on KRAS mutations andresistance to anti-EGFR therapy, again demonstrating the rapidlyevolving field of therapy for metastatic CRC. Observational studiessuch as the BRiTE registry are important tools that allow us to develop

Ellis and Haller

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new hypotheses, setting the stage for testing these hypotheses in pro-spective randomized trials. Oncologists should continue to individu-alize patient care and adjust their therapies based on data obtainedfrom clinical trials results and US Food and Drug Administrationapprovals. However, there will be circumstances where there are noclinical trial data to answer a specific question, and educated oncolo-gists must fully grasp and interpret available clinical data to supportthe use of drugs to maximize patient benefit, while considering theassociated expense and toxicity.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAlthough all authors completed the disclosure declaration, the followingauthor(s) indicated a financial or other interest that is relevant to the subjectmatter under consideration in this article. Certain relationships markedwith a “U” are those for which no compensation was received; thoserelationships marked with a “C” were compensated. For a detaileddescription of the disclosure categories, or for more information aboutASCO’s conflict of interest policy, please refer to the Author DisclosureDeclaration and the Disclosures of Potential Conflicts of Interest section inInformation for Contributors.Employment or Leadership Position: None Consultant or AdvisoryRole: Lee M. Ellis, ImClone Systems (C); Daniel G. Haller, Genentech(C), Sanofi-Aventis (C) Stock Ownership: None Honoraria: Lee M.Ellis, Genentech; Daniel G. Haller, Roche Research Funding: Lee M.Ellis, Amgen, ImClone Systems, Sanofi-Aventis; Daniel G. Haller, Roche,Bristol-Myers Squibb Co Expert Testimony: None OtherRemuneration: None

AUTHOR CONTRIBUTIONSConception and design: Lee M. Ellis, Daniel G. HallerData analysis and interpretation: Lee M. Ellis, Daniel G. HallerManuscript writing: Lee M. Ellis, Daniel G. HallerFinal approval of manuscript: Lee M. Ellis, Daniel G. Haller

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panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol26:1626-1634, 2008

2. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulinand amphiregulin and k-ras mutation status predict disease control in metastaticcolorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237,2007

3. Lievre A, Bachet JB, Boige V, et al: Kras mutations as an independentprognostic factor in patients with advanced colorectal cancer treated withcetuximab. J Clin Oncol 26:374-379, 2008

4. Grothey A, Sugrue MM, Purdie DM, et al: Bevacizumab beyond firstprogression is associated with prolonged overall survival in metastatic colorectalcancer: Results from a large observational cohort study (BRiTE). J Clin Oncoldoi:10.1200/JCO.2008.16.3212

5. Saltz LB, Clarke S, Diaz-Rubio E, et al: Bevacizumab in combination withoxaliplatin-based chemotherapy as first-line therapy in metastatic colorectalcancer: A randomized phase III study. J Clin Oncol 26:2013-2019, 2008

6. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients withadvanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol22:1209-1214, 2004

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8. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combinationwith oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treatedmetastatic colorectal cancer: Results from the Eastern Cooperative OncologyGroup study E3200. J Clin Oncol 25:1539-1544, 2007

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10. Klement G, Baruchel S, Rak J, et al: Continuous low-dose therapy withvinblastine and VEGF receptor-2 antibody induces sustained tumor regressionwithout overt toxicity. J Clin Invest 105:R15-R24, 2000

11. Dallas NA, Fan F, Gray MJ, et al: Functional significance of vascularendothelial growth factor receptors on gastrointestinal cancer cells. CancerMetastasis Rev 26:433-441, 2007

12. Ince WL, Jubb AM, Holden SN, et al: Association of k-ras, b-raf, and p53status with the treatment effect of bevacizumab. J Natl Cancer Inst 97:981-989,2005

13. Tamaskar I, Garcia JA, Elson P, et al: Antitumor effects of sunitinib orsorafenib in patients with metastatic renal cell carcinoma who received priorantiangiogenic therapy. J Urol 179:81-86, 2008

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