The Ras-Raf-mitogen activated protein kinase _MAPK - Novel Agents

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					                                                                       Lung Cancer




                                          Novel Agents in the Treatment of Lung Cancer

                                                                                                                                                      a report by
                                                                              N i k h i l I K h u s h a l a n i , M B , B S and A l e x A A d j e i , M D , P h D

                                                                                                                                  Roswell Park Cancer Institute




                                          Lung cancer remains the number one cause of cancer-             poorer prognosis.4,5 Inhibition of EGFR activity can
                                          related mortality in the world. Despite advances in             be achieved using monoclonal antibodies against the
                                          diagnosis, imaging, staging, and treatment, five-year           receptor, small molecule TK inhibitors, and antisense
                                          survival in this disease is less than 20%. In the US,           oligonucleotides.
                                          approximately 175,000 new cases are expected to be
                                          diagnosed in 2006 with nearly 162,500 deaths from this          Anti-EGFR Monoclonal Antibodies
                                          disease.1 The majority of patients present with advanced
        Nikhil I Khushalani, MB, BS, is
                                          disease, thus limiting the role of potentially curative         Cetuximab (C-225) is a chimeric human–murine
   Assistant Professor, Department of     surgery. Chemotherapy remains the mainstay for                  monoclonal antibody (MoAb) that competitively binds
     Medicine at Roswell Park Cancer      treating metastatic non-small cell lung cancer (NSCLC)          to the extracellular ligand domain of the EGFR with
 Institute, Buffalo, NY. Dr Khushalani
   earned his medical degree at the
                                          with proven benefit in improvement of symptoms and              subsequent inhibition of phosphorylation and
  Topiwala National Medical College,      quality of life, along with prolongation of survival. To        downstream signaling. In the US, it is currently
Bombay, India, followed by residency      date, no specific regimen of chemotherapy has clearly           approved in the treatment of refractory colorectal
    in Internal Medicine at the State
  University of New York at Buffalo.
                                          established superiority over another,2 and the choice is        cancer (either singly or in combination with irinotecan)
     He then finished a fellowship in     largely governed by the patient’s performance status,           and squamous cell carcinoma of the head and neck (in
     Medical Oncology at the Roswell      comorbid conditions and the treating physician’s                combination with radiation or after failure of platinum-
   Park Cancer Institute, Buffalo, NY.
  His areas of interest include novel
                                          preference. Toxicity and relative non-specificity remain        based chemotherapy). Studies in NSCLC are currently
      therapeutics in lung and upper      major drawbacks of chemotherapy in NSCLC.A better               on-going, with early data suggesting a modest response
         gastrointestinal malignancies.   understanding of the molecular signaling pathways in            rate of 4.5% when used after failure of standard therapy.
                                          lung carcinogenesis has led to the exploration of               Interestingly, disease stabilization was seen in nearly
                                          rationally developed novel therapeutic agents.This brief        one-third of patients in this small trial.6 Cetuximab has
                                          review will outline some of these agents under                  also been used in combination with chemotherapy in
                                          investigation in lung cancer.                                   the phase II setting with response rates approaching
                                                                                                          30%.7,8 Results from the Southwest Oncology Group
                                          The process of cellular differentiation, proliferation, and     (SWOG)-0342 trial were recently reported in 225
                                          apoptosis is a tightly regulated one with multiple              patients using cetuximab in combination with
                                          interactions within the cell and the surrounding extra-         carboplatin and paclitaxel, either concurrently or
 Alex A Adjei, MD, PhD, is Professor      cellular matrix. A simplistic schema of intracellular           sequentially (as maintenance therapy).9 Response rates
   and Chair of the Department of         signaling is shown in Figure 1. Disruption of one or            were higher with concurrent therapy (37% versus 25%)
  Medicine and Senior Vice-President
     for Clinical Research at Roswell
                                          more components in these pathways is often specific to          and median overall survival was prolonged (10.5
  Park Cancer Institute, Buffalo, NY.     the malignant phenotype, occurs commonly in                     months versus 8.7 months). These results suggest that
  Before taking up this position, he      NSCLC, and can serve as potential targets for                   further study of cetuximab in NSCLC is of merit and
 was Professor of Oncology and the
  Director of the Phase I and Lung
                                          intervention toward reversal.3                                  a phase III trial is on-going.
 Cancer Programs at Mayo Clinic in
  Rochester, MN. Dr Adjei’s research      Epidermal Growth Factor Receptor                                Panitumumab is a recombinant human immuno-
       is focused on development of
        novel agents for the therapy
                                                                                                          globulin (Ig)G2 kappa MoAb that binds specifically
                     of solid tumors.     The epidermal growth factor receptor (EGFR)                     to the EGFR. It was recently approved in the US for
                                          belongs to a family of receptor tyrosine kinases (TK)           EGFR-expressing chemotherapy-refractory color-
                                          that includes ErB2 (HER2/neu), ErB3, and ErB4.                  ectal cancer. This drug is being evaluated in
                                          Activation of EGFR by ligand binding or by                      combination with chemotherapy and other multi-
                                          mutational conformation leads to TK activity,                   kinase inhibitors in advanced NSCLC. Results should
                                          autophosphorylation, and activation of a cascade of             be forthcoming in the near future. Another selective
                                          cytoplasmic and nuclear signaling eventually                    anti-EGFR MoAb, matuzumab (EMD 72000),
                                          culminating in cell proliferation and survival. EGFR            abrogates ligand-mediated activation and was shown
                                          is often over-expressed in NSCLC and portends a                 to be well tolerated in combination with paclitaxel in


24                                                                                                                                  US ONCOLOGICAL DISEASE 2006
                                                              Novel Agents in the Treatment of Lung Cancer

a phase I trial of advanced NSCLC.10 Four of 18               treatment.The development of secondary mutations in
patients in this trial demonstrated a response,               the tumor has been recently recognized as a potential
including one complete response.                              mechanism of acquired resistance.17,18 In several tumor
                                                              specimens examined, a new mutation in exon 20
S m a l l M o l e c u l e R e c e p t o r Ty r o s i n e      leading to substitution of methionine for threonine at
Kinase Inhibitors                                             position 790 (T790M) was identified.This mutation has
                                                              also been identified in tumors from therapy-naïve
Erlotinib and gefitinib are two reversible receptor           patients. This hinders drug binding to the adenosine
tyrosine kinase inhibitors (RTKIs) that are currently         triphosphate (ATP)-binding pocket within the tyrosine
approved for the treatment of advanced NSCLC.These            kinase domain. Some of the newer irreversible EGFR
agents prevent binding of adenosine triphosphate to the       inhibitors have been shown to circumvent this
intracellular tyrosine kinase region and, hence, can          resistance. EKB-569 is an irreversible EGFR tyrosine
abolish downstream signaling even in conditions of            kinase inhibitor with demonstrated activity in vitro in
ligand binding or mutational activation of the EGFR.          gefitinib-resistant NSCLC cell lines. In a phase I study
The enthusiasm for the use of gefitinib after its             in patients with advanced solid cancers, the dose-
accelerated approval in 2003 has been tempered by the         limiting toxicity was diarrhea at the maximum tolerated
lack of demonstrable improvement in survival in the           dose (MTD) of 75 mg.19 One patient with NSCLC had
Iressa Survival Evaluation in Lung Cancer (ISEL) trial.11     stable disease (SD) for 33 weeks. Another structurally
This drug is no longer recommended unless patients are        related novel dual-specific inhibitor, HKI272, that
experiencing benefit from on-going use or when                targets ErB2 and EGFR has been shown to be similarly
utilized under the aegis of a clinical trial. Erlotinib, an   effective in gefitinib-resistant cell lines and is currently
oral EGFR-specific anilinoquinazoline, was evaluated          undergoing phase I testing in human trials.20 In the US,
in BR.21, conducted by the National Cancer Institute          two industry-sponsored trials evaluating canertinib
of Canada Clinical Trials Group. In a 2:1 randomized          (CI1033), a pan-ErB inhibitor, in NSCLC have
placebo controlled design, 731 NSCLC patients were            completed accrual and results should be available
enrolled after failure of standard chemotherapy. The          shortly. For a detailed description of EGFR inhibitors
response rate and overall survival favored the erlotinib      in development, the interested reader is referred to
group (8.9% and 6.7 months) compared with placebo             excellent reviews on this subject.5,21



         The Ras-Raf-mitogen activated protein kinase (MAPK)
         pathway has been implicated in lung carcinogenesis and,
         potentially, the maintenance of the malignant phenotype in
         these tumors.

(1% and 4.7 months), both statistically significant           Va s c u l a r E n d o t h e l i a l
results.12 Further evaluation of trials using these agents    Growth Factor
has demonstrated that response appears to be associated
with certain phenotypes (East Asian descent, never-           The importance of angiogenesis in the process of tumor
smokers, women, and patients with adenocarcinoma)             growth and metastasis has been well recognised for over
and genotypes (EGFR activating mutations and EGFR             two decades. However, its utility as a target for
copy number).13–15 Another reversible EGFR inhibitor,         therapeutic intervention has only recently been
GW572016 (lapatinib), has been evaluated in advanced          exploited. The vascular endothelial growth factor
NSCLC. The drug was well-tolerated, with diarrhea,            (VEGF) and its isoforms are the most commonly
rash, and nausea being the most commonly reported             upregulated angiogenic factors in cancer and their
adverse effects.16 Efficacy results are awaited. On-going     over-expression has generally been linked to a poorer
elucidation of these translational paradigms in cancer        prognosis in lung cancer, among other tumors.22
biology may assist in the rationale selection of therapy
for patients.                                                 Bevacizumab is a recombinant, humanized mono-
                                                              clonal antibody that binds VEGF and prevents its
Despite exhibiting initial sensitivity to gefitinib or        interaction with VEGF receptors Flt-1 (VEGFR-1),
erlotinib, most tumors eventually become resistant to         KDR (VEGFR-2), and Flt-4 (VEGFR-3), thereby


US ONCOLOGICAL DISEASE 2006                                                                                                  25
                                                                                             Lung Cancer



Figure 1: Simplified Scheme of Intracellular Signal Transduction Pathways                                                       histology, those with hemoptysis, and those with brain
                                                                                                                                metastases given apparent risk factors identified in the
                                                                                                                                preceding study. As expected, significant toxicities
                         Extracellular                                                                                          included hemorrhagic adverse events (4.5%) and
                                                                                                                                hypertension (6%) in the experimental arm. Based on
                                            Jak             Src
                                                                                      PI3K          Grb2                        these results, bevacizumab in combination with
                                              p             p
                                                                                         p                                      paclitaxel and carboplatin has received regulatory
                                                p           p                                       SOS
                                                                                                                                approval for the therapy of advanced and metastatic
                                                                                                                                non-squamous NSCLC in the US.
                                                STAT

                                                         STAT
            Src          p                                                                                   Cytoplasm
                  STAT
                                                                                                                                VEGF Trap is partially comprised of the extracellular
     Abl     p
                                                                                                                                domains of VEGFR-1 and -2 fused to the Fc portion of
     STAT
                                                                                Ras           PDK                               human IgG. This drug binds to circulating and tissue-
                                                                                                                                bound VEGF thereby decreasing its availability to bind
                                            p                                                                                   to its naturally occurring receptors. AVE0005 is
                                     STAT                                       Raf           Akt
                                                                                                                                currently being examined in NSCLC to determine its
                                 STAT                                                                                           safety and efficacy. It has been used in advanced solid
                             p
                                                                                MEK          mTOR                 BAD           tumors in combination with oxaliplatin- and
                                                                                                                                irinotecan-based chemotherapy regimens.
                                  p53                                           ERK          p70S6K               p53
                                                                                                                                Another strategy within this pathway involves
                                                                                                                                inhibition of VEGF receptor tyrosine kinase activity. A
                                                                                                                                number of these agents inhibit the kinase activity of
                                                                                                                                multiple receptors. Selected agents are shown in Table
                                                           p                                                                    1. Vatalanib (PTK787/ZK222584) is one such oral
                                                                  STAT
                                                                         STAT                                                   small molecule TK inhibitor with multi-targeted
                                                                                  p
                                                                                                                                activity against VEGFR-2, c-kit, platelet derived
                                                                                                 ↑ VEGF                         growth factor receptor (PDGFR), and Flt-3. In a phase
                                                                                                 ↑ CYCLIN D1/D2                 II trial in the second-line setting in advanced NSCLC
                                                                                                 ↑ MYC                          using a dose of 1,250mg/d, a disease stabilization rate
                                                                                                                                of 33% was obtained (one partial response, 17 SD) at
Ligands bind to the extracellular domain of membrane receptors that are then phosphorylated, leading to activation of           week 12 and median survival was 7.2 months.25
cytoplasmic second messengers, which sequentially activate transcription factors in the nucleus. Receptor and non-receptor      Common adverse reactions included nausea, vomiting,
tyrosine kinases are shown in this figure.
PI3K = phosphoinositide-3-kinase, MEK = mitogen-activated protein kinase kinase, ERK = extracellular signal-regulated kinase,   and dizziness.
also known as MAP kinase, BAD = pro-apoptotic protein of the Bcl-2 family, Src = serine-threonine kinase homolog of the Rous
sarcoma virus oncogene, p70S6kinase = 40S ribosomal protein S6 kinase, STAT = signal transducer and activator of
                                                                                                                                Sunitinib is another small molecule multi-RTKI that
transcription, Akt = RAC-alpha serine/threonine-protein kinase or protein kinase B, mTOR = mammalian target of rapamycin.
From Adjei AA, Hidalgo M, “Intracellular signal transduction pathway proteins as targets for cancer therapy”, J Clin Oncol      targets VEGFR,1–3 stem-cell factor receptor (KIT),
(2005);23(23): pp. 5386–5403. Reprinted with permission from the American Society of Clinical Oncology.                         platelet derived growth factor receptors (α and β),
                                                                                                                                RET, and FLT3. Socinski et al. reported a 9.5%
                                                                                                                                response rate (and 43% SD rate) to this agent after
                                                       inhibiting endothelial cell proliferation and reducing                   failure of platinum-based chemotherapy in patients
                                                       microvessel density. Following encouraging results                       with stage IIIB or stage IV NSCLC.26 Median overall
                                                       seen with the addition of bevacizumab to                                 survival was 24 weeks. There were three hemorrhage-
                                                       conventional chemotherapy (carboplatin and                               related deaths believed to be secondary to treatment.
                                                       paclitaxel) in a randomized phase II setting,23 ECOG                     Given this promising activity in a largely treatment-
                                                       launched a randomized placebo-controlled phase III                       refractory population, additional trials of sunitinib in
                                                       trial (ECOG 4599), results of which were presented at                    combination with other agents, including targeted
                                                       the 2005 annual meeting of the American Society of                       therapy are on-going.
                                                       Clinical Oncology (ASCO).24 Patients receiving the
                                                       combination of bevacizumab, paclitaxel, and                              Dual VEGFR/EGFR Inhibitors
                                                       carboplatin had a significantly improved response rate
                                                       (27% versus 10%), overall survival (12.5 months versus                   ZD6474 (vandetanib) is an oral small molecule
                                                       10.2 months) and one-year and two-year survival rates                    inhibitor of VEGFR, EGFR, and RET tyrosine kinase
                                                       (52% versus 44% and 22% versus 17%) compared with                        activity. Theoretically, abrogating more than one
                                                       those receiving chemotherapy only. Of note, this trial                   pathway of carcinogenesis may lead to greater anti-
                                                       excluded patients with tumors of squamous cell                           tumor activity, a concept that may be important in a


26                                                                                                                                                     US ONCOLOGICAL DISEASE 2006
                                                             Novel Agents in the Treatment of Lung Cancer

molecularly heterogeneous tumor. In phase I studies, a       Table 1: Selected Multiple Receptor Tyrosine Kinase Inhibitors
dose of 300mg/day was established as the maximum
tolerated dose with diarrhea, rash, and asymptomatic         Drug             Target                Doses studied         Clinical toxicity
QTc prolongation being the most common side effects          Vandetanib       EGFR and VEGFR-2      Up to 900–1,800mg/    Diarrhea
of ZD6474. Two phase II studies of ZD6474 (alone or          (ZD6474)         TK inhibitor          twice a day           Nausea/vomiting
in combination with chemotherapy) in nearly 300                                                                           Constipation
patients with refractory NSCLC have demonstrated an                                                                       Fatigue
improvement in progression-free survival compared                                                                         Anorexia
with gefitinib or docetaxel.27,28 Randomized trials in the                                                                Rash
therapy-naïve as well as refractory NSCLC population         Sorafenib        Raf and VEGFR         200–800mg             Diarrhea
are currently on-going. Other agents in this class           (BAY 439006)     kinase inhibitor      twice/day             Skin rash
include AEE788 and XL647.29                                                                                               Hand-foot-syndrome
                                                                                                                          Dyspnea
The Ras-Raf-mitogen Activated Protein                                                                                     Fatigue
K i n a s e P a t h w ay a s a Ta r g e t                    Sunitinib        PDGFR, VEGFR, KIT,    50mg daily            Fatigue/asthenia
                                                             (SU11248)        FLT-3                 four weeks on,        Nausea/vomiting
The Ras-Raf-mitogen activated protein kinase                                                        two weeks off         Diarrhea
(MAPK) pathway has been implicated in lung                   Vatalanib        VEGFR-1, KDR,         1,000mg/day for       Nausea/vomiting
carcinogenesis and, potentially, the maintenance of the      (PTK787)         VEGFR-2 PDGFR-β,      14 days or            Headache
malignant phenotype in these tumors. As a result,                             c-kit                 150–750 mg            Hypertension
numerous approaches to inhibiting this pathway in                                                   alternate days
lung cancer have been explored in the last decade.           AEE788           VEGFR,EGFR,           Up to 100mg daily     Diarrhea
Inhibition of raf kinase and MEK is currently                                 HER-2/neu                                   Skin rash
under investigation.                                         Axitinib         VEGFR-1, KDR,         Up to 20mg            Hemoptysis
                                                             (AG-013736)      VEGFR-2 PDGFR-β,      twice daily           Hypertension
Raf Kinase Inhibitors                                                         c-kit                                       Proteinuria
                                                             Pazopanib        VEGFR-1, KDR,         800mg daily           Diarrhea
The Raf family consists of serine/threonine kinases          (GW786034)       VEGFR-2 PDGFR-β,                            Fatigue
downstream of Ras, which play an important role in                            c-kit
proliferative signal transduction from the extracellular     AMG 706          VEGFR-1, KDR,         25mg daily
stroma to the cell nucleus. Sorafenib is a novel bi-aryl                      VEGFR-2 PDGFR-β,
urea that was initially developed as a specific inhibitor                     c-kit
of the RAF/MEK/ERK pathway. Subsequent studies
have shown this compound to also inhibit several other       as extracellular-related kinase or ERK) classically occurs
TKs involved in tumor progression, including                 downstream of, but can be independent of, Ras and Raf.
VEGFRs, PDGFR, Flt-3, and c-kit.30 Gatzemeier et al.         Inappropriate oncogenic activation of this pathway is a
reported a 59% SD rate with single-agent sorafenib           feature of many neoplasms. CI-1040 is an orally active
(400mg orally twice daily) in advanced refractory            difluorobenzamide that exhibited highly selective,
NSCLC, although there were no partial responses.31           nanomolar inhibition of MEK in pre-clinical studies.
Patients with SD had a progression-free survival of
23.7 weeks versus 11.9 weeks for all evaluable subjects.     This was the first MEK inhibitor to undergo clinical
Diarrhea, hand–foot syndrome and fatigue were the            testing. Based on promising findings in phase I studies,
most commonly reported side effects of this drug,            a broad phase II study was performed in patients with
which is currently approved in the US for metastatic         breast, pancreatic, colorectal, and NSCLC. Eighteen
renal cell carcinoma. There was no adverse impact of         patients with NSCLC previously treated with one
sorafenib on patient-reported outcomes in function           systemic chemotherapy regimen were enrolled. No
and symptom response.At least two phase III studies of       objective responses were documented in these 18
this compound either singly or in combination with           patients.Three patients maintained disease stability for
chemotherapy in lung cancer are currently on-going in        three, three, and 10 months, respectively. The median
Europe and North America.                                    TTP was 4.2 months, and median survival was 5.2
                                                             months. Interestingly, 70% of NSCLC tumor samples
MEK Inhibitors                                               overexpressed p-ERK at baseline, indicating that the
                                                             MEK pathway is activated in these tumors. Poor
The only known substrate for MEK (or mitogen-                pharmacokinetics were felt to have contributed in
activated protein kinase kinase) is MAP kinase.              large part to the lack of efficacy of CI-1040 in phase
Sequential activation of MEK and MAPK (also known            II studies.32


US ONCOLOGICAL DISEASE 2006                                                                                                                   27
                                 Lung Cancer



     Based on the above, and because of the documented          reported drug adversities.34 A confirmed partial
     activation of the MEK pathway in NSCLC, MEK is             response lasting over 12 months was observed in a
     still felt to be a valid target for lung cancer therapy.   patient with NSCLC. Results from trials of other
     Phase I studies of two second-generation MEK               mTOR inhibitors in lung cancer are eagerly awaited.
     inhibitors, PD0325901 and ARRY-142886/AZD6244
     are on-going.33                                            Conclusions

     mTOR Inhibitors                                            In a disease where pharmacologic progress has been
                                                                generally stunted with a plateau in chemotherapy
     The mammalian target of rapamycin (mTOR) is a              options, the availability of rationally developed targeted
     member of the family of phophatidylinositol kinases        drugs is indeed encouraging. In the investigation of
     and plays an important role in the regulation of           these newer biologic agents we may need to
     translation initiation. Rapamycin, temsirolimus,           incorporate novel surrogate end-points of activity
     everolimus, and AP23573 are inhibitors of mTOR             and/or efficacy, thus changing paradigms in the
     currently under investigation. In a recently reported      treatment of lung cancer. Future trials need to focus on
     phase I study of temsirolimus, asthenia, nausea,           the optimal method to incorporate these agents into
     cutaneous toxicity, and mucositis were the commonly        clinical practice. ■


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