Advances in Treatment of Non–Small-Cell Lung Cancer

Over the past year, therehave been a number of importantdevelopments in thetreatment of non-small-celllung cancer (NSCLC). Newdata supporting inductionchemoradiation therapyand adjuvant chemotherapywere reported. New combinations including chemotherapeuticagents and targeted biologic agentswere shown to be active in various stages of disease.Developments in Targeted TherapyChemoprevention of NSCLC will increase in importance,as small molecules that target specific receptorsor mutations may prove to be more effective andbetter tolerated than standard therapy; whilechemoprevention is still a very new concept withmany unresolved issues, recent advances in understandingthe molecular biology of lung cancer mayfacilitate development of chemoprevention strategieswith a significant impact on NSCLC incidence andmortality. Targeted biologic therapy has continued tomature as an approach that will ultimately permitindividualization of treatment and patient-specific combinationcocktails. This special supplement to OncologyNews International (ONI) presents a compilationof reports on these and other developments in NSCLCpublished in ONI over the last year.
Targeted biologic agents are under extensive clinicalinvestigation in NSCLC. The HER1/epidermalgrowth factor receptor (HER1/EGFR) tyrosine kinaseinhibitor gefitinib (Iressa) showed activity and producedsymptom improvement in phase II studies butprovided no survival benefit when added to standardchemotherapy in phase III evaluations in chemotherapy-naive patients (see report, beginning on page 6).
However, based on activity observed in a phase IItrial in patients failing platinum-based and docetaxel(Taxotere) chemotherapy (overall 10.6% response rate),gefitinib has received accelerated approval by the USFood and Drug Administration (FDA) as monotherapyin patients with advanced NSCLC previously treatedwith platinum-based and docetaxel chemotherapy.This approval was itself delayed upon receipt of reportsof interstitial lung disease in patients receivinggefitinib in Japan; the FDA concluded that this rare butserious toxicity (approximately 2% incidence in Japanand 0.3% in the US gefitinib expanded-access program,with a mortality rate of 33%) does not outweighthe benefits of treatment in advanced NSCLC (seepage 11).Initial studies of the HER1/EGFR tyrosine kinaseinhibitor erlotinib (Tarceva), which possibly exhibitssome pharmacodynamic properties that are differentfrom gefitinib, indicated activity and durable responsesin patients with advanced refractory NSCLC and inpatients with largely pretreated bronchoalveolar carcinoma.Erlotinib monotherapy is being evaluatedagainst supportive care in a phase III trial in advanced,refractory disease.It was recently announced that phase III trials assessingthe addition of erlotinib to platinum chemotherapyin first-line treatment of advanced disease didnot meet the primary end points of improved survival.Although these findings are disappointing, they werenot unexpected. Clearly, the combination of theseagents with chemotherapy in lung cancer in an unselectpopulation has not shown additive or synergistic activityas seen in the preclinical models. The results alsoreaffirm the need for identifying subsets of patientswho are most likely to respond to treatment with EGFRtyrosine kinase inhibitors and other forms of targetedtherapy (see page 9).In this regard, it is of interest that severity of rash hasbeen correlated with prolonged survival in patientstreated with erlotinib or with the anti-EGFR monoclonalantibody cetuximab (Erbitux). These findings at leastsuggest the possibility of using rash as a biomarker toguide dosing of these agents in order to optimizeresponse. Programs assessing clinical samples toidentify potential predictive and surrogate markersfor response to EGFR inhibitors are underway (seepage 16).New CombinationsIntriguing data on conventional doublets and novelcombinations involving targeted agents have beenreported over the past year. A randomized phase IItrial in chemotherapy-naive patients with advanceddisease indicates that the nonplatinum doublet ofvinorelbine (Navelbine)/gemcitabine (Gemzar) producedresponse rates and survival outcomes similar tocarboplatin (Paraplatin)/paclitaxel (Taxol) treatmentand resulted in reduced hematologic toxicity (see page19). The combination of erlotinib and the angiogenesisinhibitor bevacizumab (Avastin) has shown goodactivity (25% response) and a very encouraging safetyprofile in a phase I/II study in patients with recurrent/metastatic disease (see page 14).Similar good activity of a combination of cetuximaband docetaxel has been reported in a phase II trial inpatients resistant to second-line chemotherapy (seepage 12). In addition, interim results of a comparativephase II trial in chemotherapy-naive patients indicatethat the addition of cetuximab to a standard cisplatin/vinorelbine regimen resulted in improved responserate (53% vs 32%) compared with the standard regimen,with no major increase in toxicity (see page 17).Adjuvant TherapyThe International Adjuvant Lung Cancer Trial hasdemonstrated that cisplatin-based adjuvant chemotherapyresults in significant improvements in 5-yearoverall survival (4.1% absolute benefit) and diseasefreesurvival (5.1% absolute benefit) in patients undergoingcomplete surgical resection for NSCLC. Thetrial involved 1,867 patients who received a cisplatinbaseddoublet (with etoposide, vinorelbine, vinblastine,or vindesine [Eldisine], depending on study site),or placebo following surgery. Grade 4 toxicity occurredin 23% of the adjuvant group. These dataargue strongly for a role of adjuvant therapy in NSCLC.Further investigation will be needed to define patientselection criteria and optimal adjuvant regimens (seepage 5).Induction TherapyFindings of the Intergroup Trial 0139 indicate thatconcurrent chemotherapy, radiation, and surgical resectionresults in improved progression-free survival comparedwith chemotherapy/radiation therapy alone. Inthis trial, 429 patients with T1-3, pN2, M0 diseaseunderwent two cycles of induction therapy with cisplatin/etoposide and daily radiation and then were randomizedto surgery or continued radiation therapy, bothfollowed by two additional cycles of chemotherapy.Median progression-free survival was significantly prolonged(13.4 vs 11.8 months) in the surgery arm. However,no difference in overall survival was observed. Inthe surgery arm, significantly more patients are alivewithout progression and significantly more have diedwithout progression. An important finding in this trial isthat downstaging of disease from N2 to N0 occurred ina significant proportion of patients, and that N0 statuswas associated with a marked improvement in survival(53% at 3 years) (see page 27).Docetaxel in First-LineTreatment With CisplatinDocetaxel was approved for use in combinationwith cisplatin as first-line treatment in patients withunresectable locally advanced or metastatic NSCLC.The approval was based on a phase III trial in 1,218patients showing significantly improved overall survivalwith this combination compared with the standardregimen of cisplatin/vinorelbine (10.9 vs 10.0 months);survival in a third study arm receiving carboplatin/docetaxel was similar to that in the cisplatin/vinorelbinearm (see page 10).Looking ForwardThe coming year will bring additional advances intargeted therapy in NSCLC and other cancers. Informationabout novel combinations and schedules willbecome available. Ongoing investigations aimed atcharacterizing patients who respond best to theseinterventions will yield results that will ultimately enabletargeting of therapy to appropriately selectedpatient subsets. With the FDA approval of gefitinib foruse in patients with advanced NSCLC who havereceived prior platinum-based and docetaxel treatment,we have a demonstration of clinical benefitusing the HER1/EGFR inhibition approach. More successof this approach and other targeted approachesis to follow.The greatest excitement in NSCLC research is tocombine multiple agents in a patient-specific way;unlike chronic myelogenous leukemia, there is mostlikely not a single mutation that drives all cases ofNSCLC, hence there can be no Gleevec (imatinibmesylate) for this disease-rather, treatment will requirea cocktail of agents based on a patient's particularmolecular phenotype.Roy S. Herbst, MD, PhD
Associate Professor of Medicine
Chief, Section of Thoracic Medical Oncology
Department of Thoracic/
Head and Neck Medical Oncology
University of Texas M. D. Anderson Cancer Center
Houston, Texas