Triplet Combination Chemotherapy and Targeted Therapy Regimens

ABSTRACT: Current agents for the treatment of non-small-cell lung cancer include gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and irinotecan (CPT-11, Camptosar). Experimental agents include pemetrexed (LY231514, Alimta) and tirapazamine. Molecular and biological therapies include angiogenesis inhibitors, epidermal growth factor receptor inhibitors, HER2/neu inhibitors, and inhibitors of ras activation and function. Doublet chemotherapy is currently the standard treatment for advanced non-small-cell lung cancer. In the past 2 years, randomized trials have shown that many of the new two-drug combinations used to treat non-small-cell lung cancer have equivalent efficacy. These combinations produce 1-year survival rates of about 35% and 2-year survival rates of about 15%. Toxicity rates vary but are sufficiently low as to make the development of three-drug combinations feasible. Preliminary studies from several phase I and II trials suggest that triplet therapy can improve survival beyond that of double therapy regimens. [ONCOLOGY 15(Suppl 6):26-32, 2001]

Introduction

Chemotherapy is the cornerstoneof treatment for patients with advanced (stages IIIB and IV) non-small-cell lung cancer.[1] In previous trialsand meta-analyses of randomized trials,[13] cisplatin (Platinol)based therapyhas been shown to prolong survival, relieve symptoms, and improve quality oflife in a cost-effective manner. During the 1990s, the introduction of newchemotherapeutic agents—including the taxanes, gemcitabine (Gemzar),vinorelbine (Navelbine), and irinotecan (CPT11, Camptosar)—led to smallincremental improvements in survival when compared to cisplatin alone orprevious cisplatin regimens.[1,46]

Combining a new agent with cisplatin or carboplatin(Paraplatin) became the most common treatment strategy worldwide. In the past 2years, randomized trials reported that many of these new two-drug combinationshave equivalent efficacy.[7,8] While toxicity rates among the regimens vary,they are sufficiently low, which makes the development of three-drugcombinations feasible. The following explores the development of current andpromising agents for the treatment of advanced non-small-cell lung cancer.

Current Agents

Gemcitabine

Gemcitabine is a new antimetabolite that is incorporated intoDNA and inhibits DNA synthesis.[9] It was shown to produce response rates ofabout 20% in phase II trials in advanced non-small-cell lung cancer.[1,10]Randomized trials compared single-agent gemcitabine with the combination ofetoposide/cisplatin and found equal efficacy but reduced toxicity withsingle-agent gemcitabine. Given the excellent singleagent activity ofgemcitabine, it was logical to combine it with other agents. The combination ofgemcitabine and cisplatin was shown to produce response rates of about 40% inphase II trials[1] with median survival of approximately 1 year. These excellentresults led to randomized trials with this doublet combination and to theincorporation of gemcitabine into triplet combinations.

Paclitaxel

Paclitaxel (Taxol) is a new taxane that works by inhibitingmicrotubule polymerization.[1,11] The initial trials used a 24-hour continuousinfusion schedule, but subsequent studies showed that 3-hour infusions were moreconvenient, less toxic, and equally efficacious.[1] Single-agent paclitaxel wasshown to prolong survival when compared with best supportive care in thetreatment of patients with advanced non-small-cell lung cancer.[12] Itproduced a 32% reduction in the hazard ratio of death in these patients. Inlarge numbers of phase II trials, the overall response rate was 20% to 25%.[1]Many phase II studies showed that paclitaxel/cisplatin or paclitaxel/carboplatinproduced high response rates.[1] In particular, the paclitaxel/carboplatin combination was extremely well tolerated and the toxicity rates, especiallythrombocytopenia, were very low.

Docetaxel

Docetaxel (Taxotere) is the second commercially availabletaxane. It has similar single-agent activity compared with paclitaxel,demonstrating objective responses in 20% to 25% of patients.[1] A randomizedtrial also showed that single-agent docetaxel prolonged survival when comparedwith best supportive care.[13] The optimal single-agent dose is unclear,although response rates are about 20% at doses from 60 mg/m² to 100mg/m². Inthe second-line setting, single-agent docetaxel improved survival compared withbest supportive care[14] and compared with ifosfamide (Ifex) or vinorelbine.[15]In these studies, the dose of 75 mg/m² was preferred over 100 mg/m² because itproduced less toxicity with equal efficacy. Docetaxel has also been combinedwith cisplatin, carboplatin, and gemcitabine in two-drug combinations.Randomized trials show these combinations equivalent in efficacy to many othertwo-drug combinations. The toxicity rates may be slightly higher due to a doseof docetaxel that was too high.

Vinorelbine

Vinorelbine was the first of the new agents approved for use inthe United States in the 1990s.[1] Its single-agent activity is also in the 20%range. A randomized trial showed that single-agent vinorelbine was superior tothe combination of fluorouracil (5FU)/leucovorin.[16] Vinorelbine combined withother agents, such as cisplatin, produced high response rates. These studies ledto the development of triplets incorporating vinorelbine.

Irinotecan

Irinotecan is a topoisomerase I inhibitor with considerableactivity in a number of solid tumors including both smallcell lung cancer andnon-small-cell lung cancer.[1] It was originally developed in Japan, wheremost of the trials of this agent have been conducted. Although irinotecan hasbeen combined with many other agents, most two-drug combinations have combinedit with cisplatin. A small number of triplet studies use irinotecan.

Experimental Agents

Pemetrexed Disodium

The multitargeted antifolate pemetrexed disodium (Alimta,LY231514) is a novel antimetabolite that inhibits at least three enzymesinvolved in DNA synthesis, including thymidylate synthase, dihydrofolatereductase, and glycinamide formyl transferase.[17] Pemetrexed has demonstrated abroad range of antitumor activity against human solid tumors in preclinicalmodels. Phase I clinical trials showed activity in mesothelioma, head and neckcancer, and lung, breast, and colon cancers. The primary toxicities werehematologic suppression, skin toxicity, lethargy, nausea, and vomiting.

Phase II trials showed a response rate of 20% in previouslyuntreated patients with advanced non-small-cell lung cancer[18,19] and 16% inpreviously treated patients.[20] Phase I combination studies showed that fulldoses of pemetrexed could be combined safely with cisplatin and gemcitabine;phase II trials showed additive results with response rates of 40% after usingpemetrexed/cisplatin.[21,22] The 1year survival rates in the two studies were49% and 50%, respectively.

An interesting observation made during the early studiesindicated that patients with folate or B₁₂ deficiency documented by highhomocysteine and/or methymalonic acid levels had far greater toxicity thanpatients with low levels.[23] This observation was followed by studies adding B₁₂ and/or folate supplementation. The supplementation markedly increased themaximum tolerated dose of single-agent pemetrexed and reduced its toxicity when administered alone or in combination withother agents. The phase II studies of pemetrexed/cisplatin were completed beforethe observations regarding the effects of vitamin supplementation were known.The ongoing trial of pemetrexed/gemcitabine began without vitaminsupplementation.[24] Subsequently, folate and B₁₂ supplementation were addedhalfway through the 60 patient accrual.

The extremely low rates of severe toxicity observed whenpemetrexed supplemented with folate and B₁₂ was given in combination with otheragents makes it an appealing agent for new triplet combinations for thetreatment of advanced non-small-cell lung cancer.

Tirapazamine

Tirapazamine is a novel chemotherapeutic agent that isespecially toxic for hypoxic cells and that synergizes with cisplatin andradiotherapy.[25] Tirapazamine has activity alone against various solid tumors,but is especially active in combination with radiation and cisplatin. Phase IIstudies showed high response rates with the combination of tirapazamine andcisplatin.[26]

Molecularly/BiologicallyTargeted Therapies

In recent years, a number of molecular and biologic targets forpotential cancer therapeutics have been identified. A number of these agentshave been developed to take advantage of these targets, including humanizedmonoclonal antibodies, tyrosine kinase inhibitors, antisense compounds,ribozymes, gene therapies, and other small molecules with specific targets. Thetargets that have received the most attention in lung cancer include EGF andEGF-receptor (EGFR, HER1, erb-B1), HER2/neu (erb-B2), vascular endothelialgrowth factor (VEGF) and VEGF receptors, and matrix metalloproteinase (MMP)inhibitors. Other targets are being developed.

Angiogenesis Inhibitors

It is well established that tumors need new blood vessels toproliferate, and that the process of new blood vessel formation (angiogenesis)is different in tumors when compared with normal tissues that often requireproteins such as VEGF for tumor vessel growth.[27] Thus, angiogenesis became atarget for cancer therapeutics, which differed from the usual target in thatsurrounding tissues—rather than the tumor cell—became the target. Manydifferent agents that inhibit angiogenesis have been developed and have enteredclinical trials.[28] These include MMP inhibitors, natural products, receptortyrosine kinase inhibitors directed at the VEGF receptor, monoclonal antibodiesdirected at VEGF and its receptors, ribozymes directed at VEGF receptors, and avariety of miscellaneous agents.

Many of these antiangiogenic agents have undergone phase I andII testing in humans with advanced lung cancer and several have been studied inphase III trials. Although a thorough review of all of these studies is beyondthe scope of this article, the preliminary results of several trials will bediscussed briefly. Genentech has evaluated a humanized monoclonal antibodydirected at VEGF. Phase I trials showed the product had a serum half-life of 2to 3 weeks and was largely nonimmunogenic.[29] Thus, phase II trials in lungcancer were developed using intravenous infusion given every 3 weeks.

Several MMP inhibitors were entered into phase III trials aftersafe doses were established in phase I studies. These were done without thecompletion of phase II trials. Studies were conducted in both small-cell lungcancer and non-small-cell lung cancer. Several MMP inhibitors were studied intrials in which small-cell-lung cancer patients who had entered into remissionafter chemotherapy or chemoradiotherapy were randomized to receive maintenanceMMP inhibitor or placebo. Unfortunately, there is no evidence to date thatsurvival was improved, and it is possible that survival was compromised by oneof these agents, Bay 9366.

EGF Receptor Inhibitors

The overexpression of dominant oncogenes is not one of theearlier events in the pathogenesis of lung cancer, but the majority of invasivecancers have overexpression of one or more dominant oncogenes.[30] Several ofthe dominant oncogenes encode for growth factors or growth factor receptors. Theepidermal growth factor receptor (EGFR) is encoded by the erb-B1 oncogene, whichis sometimes referred to as HER1.[31] Two growth factors bind to EGFR: EGF andtransforming growth factoralpha (TGF-alpha).

Overexpression of EGFR occurs in the vast majority of squamouscell lung cancers and the majority of large cell carcinomas andadenocarcinomas.[32] Using a monoclonal antibody, expression can be assessed inparaffin blocks. Several types of new agents that interfere with the EGFRfunction have been developed. Among these are monoclonal antibodies to EGF andto EGFR. The anti-EGFR antibody that has the most clinical study is thehumanized antibody, C225.[33] This antibody combined with radiation therapy andcisplatin has produced high response rates in patients with advanced refractoryhead and neck cancer, for which phase III randomized trials are in progress.Phase I trials of EGFR in combination with gemcitabine/cisplatin and withpaclitaxel/carboplatin for several cancer types are also in progress.

Another type of EGFR inhibitor are EGFR-directed small moleculetyrosine kinase inhibitors. Several such compounds are in development bydifferent pharmaceutical companies. The compound that has been studied the mostin lung cancer is the oral agent Iressa (ZD1839),[34] which has completed phaseI trials. Objective responses were observed in about 7 of 70 patients at dosesthat ranged from 250 to 700 mg/d.

A major advantage of this approach is the nonoverlappingtoxicities and mechanism of action of these agents. Phase I combination studieswith chemotherapeutic agents and eventual phase III randomized trials withchemotherapy with or without Iressa are planned.

HER2/neu Inhibitors

Another dominant oncogene is HER2/neu (erb-2).[35] This oncogeneis most frequently overexpressed in adenocarcinomas. The most extensive datahave been developed in breast cancers that overexpress HER2/neu in about 30% ofcases. The frequency of overexpression in adenocarcinoma of the lung is slightlylower at about 20%.[36] Gene amplification also occurs less often in lung cancercompared with breast cancer.[37]

Trastuzumab

Trastuzumab (Herceptin) is a humanized monoclonal antibody thatbinds to HER2/neu.[38] In breast cancer, trastuzumab produces objectiveresponses in just fewer than 20% of HER2/neu- positive cases. In combinationwith chemotherapy, trastuzumab produces objective responses in a higherproportion of cases than chemotherapy alone or trastuzumab alone. Combinationstudies with trastuzumab and chemotherapy in lung cancer are in progress inHER2/neu positive cases.

Inhibitors of ras Activationand Function

Another dominant oncogene frequently altered in non-small-celllung cancer is ras, which is mutated in about 20% of patients.[39] Mutated rasimparts a poor prognosis. There are many ways of inhibiting ras. Because of itscritical role in cell signaling, ras activation may have a role in patientswithout mutated ras as well as in those with mutated ras. The ras inhibitorsthat have received the most study to date are the farnesyl transferaseinhibitors.[40] Several of these agents have completed phase I trials. Furtherphase II and III trials of these agents in patients with advanced non-small-celllung cancer are eagerly awaited.

Doublet Chemotherapy Combinations

The standard treatment for advanced non-small-cell lung canceris doublet chemotherapy. Even though meta-analyses have shown that cisplatin(alone or in combination) improved survival in advanced non-small-cell lungcancer patients,[2] little evidence has shown that two-drug combinations such asvindesine (Eldisine)/cisplatin and etoposide/cisplatin improved survival beyondthat of cisplatin alone. Even less evidence indicated that triplet combinationswere superior in efficacy to doublet combinations, although they invariablyproduced more toxicity.[1]

The inability to show that twodrug combinations were superiorto cisplatin changed with the availability of new chemotherapeutic agents in the1990s. The combinations of cisplatin/vinorelbine and cisplatin/gemcitabine wereshown to be superior to cisplatin alone.[4,6] In randomized trials, efficacy ofthe twodrug combination of gemcitabine/cisplatin was equivalent to that ofolder threedrug regimens, such as MIC (mitomycin[Mutamycin]/ifosfamide/cisplatin)[41] and new twodrug regimens, such asdocetaxel/cisplatin, paclitaxel/cisplatin, and paclitaxel/carboplatin.[8]

Gemcitabine in Combination

Early gemcitabine combination trials often used a 4weekschedule with gemcitabine administered on days 1, 8, and 15. With this schedule,the day-15 drug doses were often omitted because of low blood counts on thisday. More recent trials gave gemcitabine on days 1 and 8 of a 3-weekschedule.[42] These 3-week schedules generally allowed for greater planned drugdelivery with less toxicity. Combinations of gemcitabine with cisplatin orcarboplatin are among the most commonly used regimens around the world. Therelatively low toxicity profile of gemcitabine alone and in combination makesthis a logical part of threedrug combinations.

Vinorelbine in Combination

Randomized trials have shown that the combination ofvinorelbine/cisplatin was not only superior to cisplatin alone, but also tovinorelbine alone and to the combination of vindesine/cisplatin.[43] Therandomized trial of the Southwest Oncology Group showed that thevinorelbine/cisplatin combination had equivalent activity compared withpaclitaxel/carboplatin.[7] Although the toxicity rates were a little higher,the costs were lower. Vinorelbine has also been combined with gemcitabine anddocetaxel and has been used in many triplet combinations.

Paclitaxel in Combination

In studies comparing new doublets to older doublets, randomizedtrials showed that the combination of paclitaxel with cisplatin was superior inefficacy and toxicity when compared to etoposide/cisplatin.[5] It was equallyefficacious but less toxic and associated with better quality of life comparedwith teniposide (Vumon)/cisplatin.[44] To determine whether a platinum compoundis necessary in two-drug combinations, the Hellenic Group comparedpaclitaxel/carboplatin to paclitaxel/gemcitabine.[45] Both regimens were welltolerated and efficacy was equivalent. Randomized trials showed that thepaclitaxel/carboplatin combination was equivalent in efficacy to four othertwo-drug combinations and less toxic and more convenient.[7,8]

Other Combinations

Randomized trials of irinotecan/cisplatin have shown thecombination to be equivalent or slightly superior compared with irinotecan aloneor vindesine/cisplatin.[46,47] The observation that tirapazamine plus cisplatinproduced high response rates in phase II trials led to a phase III randomizedtrial comparing the combination of tirapazamine/cisplatin with cisplatinalone.[26] This trial showed that the combination had a higher response rate,longer survival, and increased toxicity. Because of some irregularities with thetrial data, the US Food and Drug Administration (FDA) has not yet approvedtirapazamine. Further studies are in progress.

Summary

In summary, current doublet chemotherapy combinations remain thestandard therapy for patients with advanced non-small-cell lung cancer. Thesedoublet combinations produce 1-year survival rates of about 35% and 2-yearsurvival rates of about 15%. Although these results are superior to earlierresults, improved therapies are clearly needed.

Triplet Chemotherapy Combinations

The most straightforward way to improve current doublets wouldbe to add new agents with nonoverlapping mechanisms of action and toxicity. Manysuch triplet combinations have now completed phase I and phase II testing. Table1 provides a summary of the results of these phase I and II trials.

Paclitaxel/Gemcitabine/Carboplatin (or Cisplatin)

The combination of paclitaxel/gemcitabine/carboplatin (orcisplatin) was reported in the largest number of trials. Early studies from theUniversity of Colorado Cancer Center and from the Sarah Cannon Cancer Centershowed that full doses of each agent could be delivered.[48,49] The phase IIresponse rates were higher than the two groups reported with thepaclitaxel/carboplatin doublet. The -1 and 2-year survival rates were slightlyhigher. Furthermore, other groups also reported excellent results with thistriplet combination. In the 10 trials of this triplet combination, the overallresponse rate was 52%; 1year survival rates ranged from 42 to 53 weeks.

These excellent phase I and II results led to several randomizedtrials. The results of these randomized trials are summarized in Table1.[5052]Unfortunately, these randomized trials are too small to make firm conclusionsabout the results. However, the studies reported superior response rates andlonger survival in patients receiving the triplet combination.

The study from the Response Oncology Group compared the tripletwith the paclitaxel/carboplatin doublet,[50] while the South Italy Groupcompared the paclitaxel/gemcitabine/cisplatin triplet with thegemcitabine/cisplatin doublet and with a triplet ofvinorelbine/gemcitabine/cisplatin.[51,52] Both triplets produced equivalentresults that were superior to the doublet results.

Gemcitabine/Vinorelbine/Cisplatin

The next most frequently studied triplet regimen,gemcitabine/vinorelbine/cisplatin, was reported in five trials (Table2). Theoverall response rate was 50% with 1year survival rates of about 53%. Theseresults also led to a randomized trial (summarized in Table1).[51,52] Thisrandomized trial reported by the South Italy Oncology Group compared twodoublets (gemcitabine/cisplatin and vinorelbine/cisplatin) with thegemcitabine/vinorelbine/cisplatin triplet. The worst results were obtained withthe vinorelbine/cisplatin arm and the best results were observed in the tripletarm. Unfortunately, the arms were not always the same in this study, which wastoo underpowered to draw meaningful conclusions. Based on these three randomizedtrials that all showed superiority for a triplet combination, a large,welldesigned trial is sorely needed.

Other Triplet Combinations

Triplets with other combinations of new agents are alsosummarized in Table 2. Overall these results were quite similar to the twotriplet regimens discussed above. There is no reason to anticipate that thesetriplets should be superior. Thus, randomized trials with these triplets shouldawait the results of randomized trials using the more studied regimens discussedabove.

Phase I and II trials using the newest agents, tirapazamine andpemetrexed, in triplet therapy are just being reported or planned. The threedrug combination oftirapazamine/paclitaxel/carboplatin showed that itcould be delivered safely. The Southwest Oncology Group is planning a randomizedtrial comparing paclitaxel/carboplatin with paclitaxel/carboplatin/tirapazamine.Randomized trials with a pemetrexed triplet will await the results of phase Iand II trials.

Doublet Chemotherapy Plus Biologic Combinations

Another approach to creating triplet combinations is to addmolecularly targeted agents to standard chemotherapy doublets. Phase I, II, andIII trials of some such triplet combinations have been completed. After phase Itrials showed that anti-VEGF antibodies could be safely administered withstandard chemotherapy doublets such as paclitaxel/carboplatin, a randomizedphase II trial was conducted.[53] Two arms received anti-VEGF concurrently withchemotherapy. One of these arms received a dose of 7.5 mg/kg as an intravenousinfusion every 3 weeks and the other arm received a dose of 15 mg/kg given inthe same schedule. Patients on the chemotherapy alone arm were allowed to crossover to anti-VEGF at the time of tumor progression.

Interestingly, the group that received the highest dose ofanti-VEGF had the longest time to progression, the highest response rate, andthe longest survival. However, the group receiving the lowdose anti-VEGF hadthe shortest time to progression and survival. The survival of all three groupswas longer than expected from historical comparisons with median survivals of11.7 months, 14.7 months, and 17.7 months in the lowdose, chemotherapy alone,and highdose anti-VEGF arms, respectively. It is not certain why the lowdosearm had the worst outcome and if the excellent survival of all three arms wasdue to the administration of the anti-VEGF or some unknown factors.

Toxicity

Unexpected toxicity occurred on the two arms that received theanti-VEGF concurrently with the chemotherapy. This toxicity was severeintrapulmonary hemorrhage and hemoptysis that occurred in six patients and wasfatal in four. These patients tended to have central squamous tumors that bleedinto the bronchus from the pulmonary arteries perhaps due to tumor shrinkage.Additional studies are needed to sort out this toxicity and to determine therole of anti-VEGF in the excellent outcome.

Randomized trials evaluating MMP inhibitors have also beencompleted. In advanced non-smallcell lung cancer, several trials randomizedpatients to receive chemotherapy alone or chemotherapy plus an MMP inhibitor.

Randomized phase III trials with the MMP inhibitor AG3340 wereundertaken with the combination of carboplatin/paclitaxel with or withoutAG3340 and with the combination of gemcitabine/cisplatin with or without AG3340.Although the results of these studies are unknown, the former study was closedat an interim point, apparently because there was no benefit. Thus, there havebeen no positive trials to date. Other MMP inhibitors that inhibit differentMMPs are still in early development. Randomized trials with trastuzumab, Iressa,C225, and other biologic agents are planned but have not yet been completed.

Conclusions

The optimal therapy for advanced non-small-cell lung cancerhas undergone rapid evolution during the past decade from best supportive careto single-agent cisplatin and then to doublet chemotherapy regimens. Currently, oneof several doublet chemotherapy combinations is the standard therapy forpatients with advanced non-small-cell lung cancer. Although survival isimproved considerably over best supportive care, more than 50% of patientssuccumb within 1 year and more than 80% by 2 years.

New treatment strategies must be employed to achieve furtherprolongation of survival. One strategy is to combine additional approved orexperimental agents to standard chemotherapy doublets. This strategy hasstrong rationale, and preliminary studies suggest that triplet therapy canimprove survival beyond that of doublet regimens. Additional randomized trialsare necessary to confirm early observations.

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