Incorporation of Pemetrexed (Alimta) Into the Treatment of
`Non-Small Cell Lung Cancer (Thoracic Tumors)
`
`Paul A. Bunn, Jr
`
`Lung cancer is the leading cause of cancer death in the
`United States and throughout the world. The overall
`5-year survival rate for lung cancer is dismal: 14% in the
`United States and even lower in other parts of the
`world. Recent developments in the armamentarium of
`chemotherapeutic agents for lung cancer have shown
`that two-drug combinations improve survival, relieve
`symptoms, and improve quality of life; however, com(cid:173)
`plete response rates are still approximately I % in stage
`IV disease and less than 20% of advanced stage patients
`survive 2 years. Therefore, improved therapeutic
`agents that increase efficacy are sorely needed. Most
`lung cancers overexpress thymidylate synthase and a
`variety of genes involved in cell cycle regulation. Pre(cid:173)
`vious studies have shown that some inhibitors of DNA
`synthesis (eg, gemcitabine) can improve the survival of
`advanced lung cancer patients, especially when com(cid:173)
`bined with other agents such as cisplatin. The multitar(cid:173)
`geted antifolate, pemetrexed (Alimta; Eli Lilly and Co,
`Indianapolis, IN) was developed because it inhibits mul(cid:173)
`tiple enzymes involved in DNA synthesis including thy(cid:173)
`midylate synthase, dihydrofolate reductase, and glyci(cid:173)
`namide ribonucleotide formyl transferase. The early
`studies of pemetrexed showed that the important
`dose-limiting toxicities were myelosuppression, mu(cid:173)
`cositis, and diarrhea, all of which are common with any
`antimetabolite. Subsequent studies described in this
`article will show that these toxicities can be signifi(cid:173)
`cantly reduced by the use of vitamin supplementation
`with folate and 8'2' and that pemetrexed has consid(cid:173)
`erable activity in non-small cell lung cancer and me(cid:173)
`sothelioma.
`Semin Oncol 29 (suppl 9): 17-22. Copyright 2002, Elsevier
`Science (USA). All rights reserved.
`
`L UNG CANCER is the leading cause of cancer
`
`death in both men and women in the United
`States and many developed countries. Lung cancer
`accounts for 28% of all cancer deaths in the
`United States'! The non-small cell lung cancers
`(NSCLCs) (adenocarcinoma, squamous cell carci(cid:173)
`noma, and large-cell undifferentiated carcinoma)
`account for 75% to 80% of all lung cancers.2
`About one third of NSCLC patients present with
`metastatic disease (stage IV) at the time of diag(cid:173)
`nosis, and more than half present with stage IIIB
`orIV.2
`Before 1990, no systemic therapy had been
`proven to increase the survival of these patients.
`Subsequently, cisplatin-based chemotherapy was
`shown to improve survival, increasing median sur(cid:173)
`vival by around 2 months and improving the
`
`I-year survival rate from 15% to 25%.2.3 More
`recently, several new agents including gemcitabine
`(Gemzar; Eli Lilly and Co, Indianapolis, IN), vi(cid:173)
`norelbine, paclitaxel, and docetaxel, were shown
`to be active and some have improved the survival
`of advanced-stage NSCLC patients.2 Two-drug
`combinations combining these agents with one
`another or with cisplatin or carboplatin improved
`survival compared with single-agent cisplatin.4•5
`Randomized trials have shown that several of
`these two-drug combinations have comparable ef(cid:173)
`ficacy.6.7 Nonetheless, even the best of these two(cid:173)
`drug combinations produces responses in fewer
`than half of the patients, with complete responses
`in only 1%, and more than 80% of patients die
`within 2 years of diagnosis.2.7 New agents, espe(cid:173)
`cially those with minimal or little myelosuppres(cid:173)
`sion, are sorely needed.
`
`PRECLINICAL TRIALS OF PEMETREXED
`
`The multi targeted antifolate pemetrexed (AI(cid:173)
`imta; Eli Lilly and Co) possesses mechanisms of
`action that inhibit multiple enzymes involved in
`DNA synthesis, including thymidylate synthase,
`dihydrofolate reductase, and glycinamide ribonu(cid:173)
`cleotide formyl transferase. Pemetrexed inhibited
`the growth of a large panel of human cancer cells
`lines, including lung cancer cells in vitroS and in
`vivo in athymic nude mice. 9 Combination studies
`showed additive or synergistic growth inhibition
`when pemetrexed was combined with several es(cid:173)
`tablished chemotherapeutic agents such as gemcit-
`
`From the Lung Cancer Program and Department of Medicine,
`University of Colorado Cancer Center and University of Colorado
`Health Sciences Center, Denver, CO. Supported in part by Na(cid:173)
`tional Cancer Institute grant nos. CA 46934 and CA 58187 and
`Ea Lilly and Company, Indianapoas, IN.
`Dr Bunn has received research grant support and honoraria and
`has served as a member of the speakers' bureau for Ea Lilly and
`Company.
`Address reprint requests to Paul A. Bunn Jr, MD, University of
`Colorado Health Sciences Center, Box B188, 42001 E. 9th Ave,
`Denver, CO 80262.
`Copyright 2002, Elsevier Science (USA). All rights reserved.
`0093-7754/02/2903-0904$35.00/0
`doi: 10 .1053/sonc.2002.34268
`
`Seminars in Oncology, Vol 29, No 3, Suppl 9 Gune), 2002: pp 17-22
`
`17
`
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`Sandoz v. Eli Lilly, Exhibit 1078-0001
`
`

`
`18
`
`PAUL A. BUNN, JR
`
`Table I. Tumor Growth Delay by Alimta, Cisplatin,
`Gemcitabine, Paclitaxel, and the Combinations in
`Human A549 Adenocarcinoma Cells in Athymic Mice"
`
`Therapy
`
`Average Growth Delay (days)
`
`Pemetrexed
`Gemcitabine
`Cisplatin
`Paclitaxel
`Alimta and Cisplatin
`Alimta and Gemcitabine
`Alimta and Paclitaxel
`
`8
`7
`6
`7
`18
`17
`15
`
`abine, cisplatin, and paclitaxel (Table 1).9 For
`example, when compared with the control growth
`of A549 tumors, pemetrexed produced an average
`growth delay of 8 days. The combination of pem(cid:173)
`etrexed with cisplatin, gemcitabine, or paclitaxel
`increased the average growth delay to 15 to 18
`days (see Table 1).
`
`PHASE I TRIALS OF PEMETREXED
`
`Phase I trials of pemetrexed explored several
`schedules including an every 3-week schedule,lo a
`weekly schedule,ll and a daily for 5 consecutive
`days every-3-week schedule.12 Objective responses
`were seen with several schedules, including four
`partial responses (two each in advanced pancreatic
`and colorectal cancers) and six minor responses
`(colorectal cancer) on the every-3-week sched(cid:173)
`ule.1° This schedule was also the most convenient
`and produced consistent toxicity. The dose-limit(cid:173)
`ing toxicity (DLT) on this schedule developed at a
`dose of 700 mg/m2
`, and the recommended phase II
`dose was 600 mg/m2.1o Dose-limiting toxicities
`consisted of myelosuppression, mucositis, and di(cid:173)
`arrhea. Skin toxicity developed in a minority of
`
`patients. The pre- and postadministration of dec(cid:173)
`adron daily for 3 days around the pemetrexed dose
`seemed to reduce the frequency of skin toxicity.
`The severity of nausea and vomiting were mild,
`even without steroids. Toxicities encountered dur(cid:173)
`ing early phase II trials with the dose of 600 mg/m2
`every 3 weeks led to a subsequent decrease in the
`recommended phase II dose to 500 mg/m2
`•
`
`PHASE II TRIALS OF PEMETREXED IN
`ADVANCED NON-SMALL CELL
`LUNG CANCER
`
`Two studies evaluated the role of pemetrexed in
`patients with advanced NSCLC who had not re(cid:173)
`ceived prior chemotherapy. The results are sum(cid:173)
`marized in Table 2. In these respective trials that
`were conducted in Canada13 and South Africa/
`Australia,14 similar results were produced. In the
`Canadian trial, Rusthoven et aP3 used the initial
`dose of 600 mg/m2
`• After the first three patients
`had been enrolled, the dose was reduced to 500
`mg/m2 in the remaining 30 patients. This was
`based on the combined toxicity of 12 patients
`enrolled onto this study and a Canadian phase II
`study of pemetrexed in advanced colorectal can(cid:173)
`cer.1 5 The objective response rate was 23% among
`30 patients evaluable for response (all 33 assess(cid:173)
`able for toxicity), and the median survival was 9.2
`months. The most frequent severe toxicity was
`grade 3/4 neutropenia, which developed in 39% of
`the patients. In the South African/Australian trial,
`Clarke et al14 used a dose of 600 mg/m2 in all 59
`patients. The objective response rate was 16%
`among 57 evaluable patients. Median survival was
`7.2 months, and 32% of the patients were alive at
`1 year. The toxicity rates were similar to the Ca(cid:173)
`nadian trial despite the slightly higher dose of
`pemetrexed. Overall, the response rate was 19.5%
`
`Table 2. Summary of Phase II Studies of Single-Agent Pemetrexed in Advanced Non-Small Cell Lung Cancer
`
`Study
`
`Dose
`
`600/500
`
`Rustoven et al 13 (Canada)
`Clarke et al '4
`(Australia/South Africa)
`600
`* Percentage of patients alive at I year.
`t Percentage of patients.
`
`No. of
`Patients
`(Evaluable)
`
`33 (30)
`
`59 (57)
`
`Objective
`Response.
`n (%)
`
`7 (23)
`
`9 (16)
`
`Median
`Survival
`(mos)
`
`9.2
`
`7.2
`
`I-Year
`Survival
`(%)*
`
`25
`
`32
`
`Grade 3/4
`Neutropenia
`(%)t
`
`39
`
`42
`
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`
`PEMETREXED IN LUNG CANCER
`
`19
`
`Table 3. Phase II Trial of Pemetrexed in Second-Line Therapy of Advanced Non-Small Cell Lung Cancer'·
`
`Group
`
`No. of
`Patients
`
`45
`Prior cisplatin
`No cisplatin
`33
`* Percentage of patients alive at I year.
`t Percentage of patients.
`
`Objective
`Response.
`n (%)
`
`4 (9)
`5 (15)
`
`Median
`Survival
`(mos)
`
`6.1
`4.1
`
`I-Year
`Survival
`(%)*
`
`19
`24
`
`Grade 3/4
`Neutropenia
`(%)t
`
`35
`
`in these two trials and the median survival was
`between 7.2 and 9.2 months. The results are sim(cid:173)
`ilar to the most active agents, including gemcitab(cid:173)
`ine, paclitaxel, and docetaxel.
`An additional trial evaluated the role of pem(cid:173)
`etrexed in patients with advanced NSCLC who
`had progressed during or within 3 months of com(cid:173)
`pleting prior chemotherapy.16 The results of this
`trial are summarized in Table 3. Among the 78
`evaluable patients in this trial, 44 had received
`therapy that included a platinum agent, and 33
`had not. The objective response rate was higher in
`the platinum-naive patients (15% v 9%). Overall,
`the objective response rate was 9% (compared
`with a 19% response rate observed in previously
`untreated patients). Survival results were also ex(cid:173)
`cellent, with median survivals of 6.1 and 4.1
`months in the respective platinum-pretreated and
`platinum-naive groups. Results are similar to the
`phase II results reported with docetaxel in the
`second-line setting. Pemetrexed was well tolerated
`in this group, with 35% of patients experiencing
`grade 3/4 neutropenia. The excellent results noted
`in this trial led to the institution of an ongoing
`phase III randomized trial comparing pemetrexed
`to docetaxel in NSCLC patients who had previ(cid:173)
`ously received chemotherapy.
`
`PHASE I TRIALS OF CISPLATIN PLUS
`PEMETREXED
`
`The preclinical synergy between pemetrexed
`and cisplatin combined with the activity of each
`agent in NSCLC made it logical to test the com(cid:173)
`bination. A phase I trial evaluated the schedule of
`pemetrexed and cisplatin given every 3 weeks. 17
`When both drugs were administered on day 1, the
`dose-limiting toxicity was neutropenia. Mucositis,
`nausea/vomiting, and diarrhea were also observed,
`but were well controlled with supportive measures.
`
`The maximum tolerated dose was pemetrexed 600
`mg/m2 with cisplatin 100 mg/m2
`• Objective re(cid:173)
`sponses were noted in this phase I trial, including
`one patient with NSCLC and five patients with
`mesothelioma. The recommended doses for phase
`II trials were pemetrexed 500 mg/m2 and cisplatin
`75 mg/m2
`, both given on day 1 every 3 weeks.
`
`PHASE II TRIALS OF PEMETREXED PLUS
`CISPLATIN
`Two phase II trials l8,19 evaluating the combina(cid:173)
`tion of pemetrexed plus cisplatin in previously
`untreated patients with advanced NSCLC were
`conducted using pemetrexed 500 mg/m2 and cis(cid:173)
`platin 75 mg/m2 given every 3 weeks. The results
`are summarized in Table 4. In the study from
`Canada, Shepherd et aP8 reported an objective
`response rate of 45% among 29 evaluable patients.
`A similar response rate (39%) was noted among 36
`patients in a European trial by Manegold et al:19
`Median survival in the two studies was 8.9 and
`10.9 months, and approximately 50% of patients
`were alive at 1 year in both trials. The 33% and
`59% rates of grade 3/4 neutropenia were higher
`than with either single agent, but were of shorter
`duration and were relatively well tolerated. There
`were no septic deaths. These response and survival
`rates are as good as those reported in phase II trials
`by any "standard" two-drug combination.2
`
`PHASE III TRIAL OF PEMETREXED PLUS
`CISPLATIN VERSUS CISPLATIN IN
`MESOTHELIOMA
`
`Based on the finding of responses to pemetrexed
`plus cisplatin in mesothelioma patients in the
`phase I setting, a randomized phase III trial com(cid:173)
`paring cisplatin with pemetrexed plus cisplatin has
`been completed. The results, which should be
`available in 2002, are eagerly awaited.
`
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`
`20
`
`PAUL A. BUNN, JR
`
`Table 4. Phase II Trials of Cisplatin Plus Pemetrexed in Previously Untreated Advanced Non-Small Cell Lung Cancer
`
`Study
`
`No. of
`Patients
`(Evaluable)
`
`Shepherd et al '8 (Canada)
`31 (29)
`Manegold et al '9 (Europe)
`36 (36)
`* Percentage of patients alive at I year.
`t Percentage of patients.
`
`Objective
`Response.
`n (%)
`
`13 (45)
`14 (39)
`
`Median
`Survival
`(mos)
`
`8.9
`10.9
`
`I-Year
`Survival
`(%)*
`
`49
`50
`
`Grade 3/4
`Neutropenia
`(%)t
`
`33
`59
`
`PHASE I TRIALS OF PEMETREXED PLUS
`GEMCITABINE
`
`The preclinical synergy noted between pem(cid:173)
`the
`etrexed and gemcitabine combined with
`known clinical activity of each agent in advanced
`NSCLC provided a rationale to test these two
`drugs in combination. Adjei et apo at the Mayo
`Clinic used two different schedules in a phase I
`trial. In the first cohort (n = 35), gemcitabine
`1,000 and 1,250 mg/m2 was given on days 1 and 8,
`with pemetrexed 200 to 600 mg/m2 given 90 min(cid:173)
`utes after gemcitabine on day 1. Cycles were re(cid:173)
`peated every 3 weeks. In the second cohort (n =
`21), gemcitabine was also given on days 1 and 8,
`but pemetrexed was administered on day 8; cycles
`were also given every 3 weeks. The schedule on
`which pemetrexed was delivered on day 8 pro(cid:173)
`duced less hematologic toxicity than the schedule
`with day 1 pemetrexed administration, permitting
`a higher gemcitabine dosage in this schedule. The
`days 1 and 8 gemcitabine maximum tolerated dose
`was 1,250 mg/m2 combined with pemetrexed 500
`mg/m2 on day 8, every 3 weeks. Overall, there
`were 13 objective responses: NSCLC (3), colorec(cid:173)
`tal cancer (3), cholangiocarcinoma (2), ovarian
`carcinoma (2), mesothelioma (1), breast cancer
`(1), and adenocarcinoma of unknown primary site
`(1). The recommended dose for the phase II study
`was gemcitabine 1,250 mg/m2 days 1 and 8 and
`pemetrexed 500 mg/m2 (90 minutes after gemcit(cid:173)
`abine) on day 8, every 3 weeks.
`
`PHASE II TRIAL OF PEMETREXED PLUS
`GEMCITABINE
`
`Based on the results of the phase I combination
`trial described previously, an international phase II
`trial of pemetrexed plus gemcitabine was con(cid:173)
`ducted in North America (John Hopkins Univer-
`
`sity, University of Colorado, Denver) and Europe
`(Institut Gustave-Roussy, Villejuif, France),21 In
`the initial phase of this study, the pemetrexed dose
`was 500 mg/m2 given on day 8, the gemcitabine
`dose was 1,250 mg/m2 administered on days 1 and
`8, and there was no vitamin supplementation.
`When data from other clinical studies indicated
`that daily administration of 350 to 600 f.Lg of folic
`acid and vitamin B12 every 9 weeks could reduce
`the toxicity of pemetrexed, and data from a pre(cid:173)
`clinical study suggested that this could potentially
`be achieved without reducing effectiveness (see
`below), the study was modified to provide folic
`acid and vitamin B12. The final study results are
`not yet available. However, the study had a two(cid:173)
`stage design with an early stopping rule if the
`response rate was less than 20%, and the study
`completed the planned accrual.
`
`EFFECTS OF FOLATE AND BI2 STATUS
`ON PEMETREXED TOXICITY
`
`Analysis of many earlier pemetrexed studies
`showed that pretreatment folate and B12 status of
`patients were highly correlated with toxicity,22 In
`these studies, folate status was assessed by serum
`homocysteine levels, and B12 status by serum
`methylmalonic acid levels. Patients with high ho(cid:173)
`mocysteine levels (associated with folate defi(cid:173)
`ciency) had significantly higher rates of severe
`myelosuppression, mucositis, and febrile neutrope(cid:173)
`nia compared with patients with lower homocys(cid:173)
`teine levels. There was also a correlation between
`low methylmalonic acid levels and increased tox(cid:173)
`icity. Subsequently, data from a randomized trial
`comparing pemetrexed plus cisplatin with cispla(cid:173)
`tin alone in mesothelioma patients showed an
`excess of toxic deaths and severe toxicity on the
`pemetrexed plus cisplatin arm. Preclinical data
`
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`
`PEMETREXED IN LUNG CANCER
`
`21
`
`Table 5. Toxicities in Trials of Pemetrexed With and Without Vitamin Supplementation 2'.25
`
`Toxicity
`
`Drug-related death
`Grade 4 neutropenia
`Grade 4 thrombocytopenia
`Grade 3/4 diarrhea
`Grade 3/4 mucositis
`Any grade 4 hematologic or grade 3/4 nonhematologic*
`
`No Folic Acid/B 12
`(n = 394). %
`
`+ Folic Acid/B 12
`(n = 196). %
`
`4.2
`28
`6
`5
`5
`33
`
`1.4
`9.0
`1.0
`4
`0.5
`12
`
`P Value
`
`.006
`
`.0017
`
`* Toxicities include grade 4 neutropenia. grade 4 thrombocytopenia. grade 3/4 mucositis. grade 3/4 diarrhea. and grade 3/4 infection.
`
`also became available that suggested that folate
`supplementation might reduce toxicity without re(cid:173)
`ducing efficacy.23 These data led to the institution
`of folic acid and B12 supplementation in all ongo(cid:173)
`ing trials, including the mesothelioma trial. As
`shown in Table 5, folic acid and B12 supplemen(cid:173)
`tation has produced a highly significant reduction
`in the rate of severe toxicity (c. Niyikiza, personal
`communication, January 2002).24 Vitamin supple(cid:173)
`mentation is now standard in all pemetrexed trials.
`This supplementation is especially important in
`countries that do not require dietary supplemen(cid:173)
`tation, as required in the United States.
`
`PHASE I TRIAL OF CARBOPLATIN PLUS
`PEMETREXED
`
`The excellent results obtained with pemetrexed
`plus cisplatin, coupled with the greater conve(cid:173)
`nience and reduced toxicity profile of carboplatin,
`led Calvert et aF5 to conduct a phase I trial of
`pemetrexed plus carboplatin. All patients accrued
`to this trial had mesothelioma and were chemo(cid:173)
`therapy-naive. The maximum tolerated dose was
`reported to be pemetrexed at 500 mg/m2 and car(cid:173)
`bop latin dosed to an area under the concentra(cid:173)
`tion-time curve (AUC) of 6 (based on the Calvert
`Formula with 51Cr_EDTA estimation of glyci(cid:173)
`namide ribonucleotide formyl transferase), each
`administered on day 1 of a 3-week cycle; the
`dose-limiting toxicity was reversible myelosuppres(cid:173)
`sion. The recommended dose for phase II trials was
`pemetrexed 500 mg/m2 and carboplatin at an
`AUC of 5. These were given on a 3-week schedule
`with both drugs administered on day 1. No vita(cid:173)
`min supplementation was used in this trial. Inter(cid:173)
`estingly, the results in the mesothelioma patients
`were superior to the best reported in any historical
`
`series from this patient group. The overall response
`rate was 40% among 25 evaluable patients. No
`patients progressed during the first three cycles of
`therapy, and the median survival rate was 13
`months.
`
`SINGLE-AGENT PEMETREXED IN
`MESOTHELIOMA
`
`Scagliotti et aF6 evaluated single-agent pem(cid:173)
`etrexed in 62 chemotherapy-naive patients with
`malignant pleural mesothelioma. Pemetrexed 500
`mg/m2 was administered by 10-minute intravenous
`infusion on day 1, every 3 weeks. After 21 patients
`had enrolled, vitamin supplementation (low-dose
`folic acid/vitamin Bn) was added to therapy to
`reduce the toxicity of pemetrexed. Nine patients
`achieved a partial response, for an overall response
`rate of 14.5%. To date, median duration of re(cid:173)
`sponse is 10.8+ months, median time-to-progres(cid:173)
`sive disease is 5,4 months, median survival time is
`10.7 months, and the I-year survival rate is 25%.
`
`CONCLUSIONS
`
`Pemetrexed is an active agent for NSCLC
`and mesothelioma. Single-agent responses occur
`in approximately 20% of chemotherapy-naive
`NSCLC13,14 and 14.5% of chemotherapy-naive
`mesothelioma patients.26 The survival results in
`the phase II single-agent pemetrexed studies in
`these diseases are as high as those produced by
`other known agents. The combination of pem(cid:173)
`etrexed plus cisplatin produces higher response
`rates in both NSCLC than is observed for either
`single agent, and the survival rates are superior to
`those reported in historic series with other doublet
`therapies. The rates of toxicity from pemetrexed
`are related to the dose and folate and B12 status of
`
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`
`22
`
`PAUL A. BUNN, JR
`
`the patient. Irrespective of the serum folate and
`B12 level, vitamin supplementation with daily oral
`folate and intramuscular B12 every 9 weeks mark(cid:173)
`edly reduces the toxicity of pemetrexed and may
`permit greater drug delivery. The results of ran(cid:173)
`domized trials will provide greater insight into the
`role of pemetrexed in the therapy of advanced
`NSCLC and mesothelioma.
`
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`
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