Wen Wee Ma, MBBS

Recent therapeutic advances have almost doubled the survival of patients with metastatic pancreatic cancer, and the availability of highly active chemotherapy regimens is making personalized medicine a reality. The role of chemoradiation following induction chemotherapy in locally advanced, unresectable pancreatic cancer was clarified by the LAP 07 study. A major development has been the identification of the group of patients with resectable disease who have a high risk of margin-positive resection (borderline resectable). The use of neoadjuvant therapy in this group has many potential advantages and is currently under active clinical investigation. Tools available for treating pancreatic cancer have certainly multiplied and improved over last few decades, but the long-term survival rate is still dismal; as such, novel treatments and approaches are still urgently needed, and palliative/supportive care is equally important to improve the lives of patients with pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States.

The survival for metastatic disease has doubled over the last 2 decades, though at the expense of increased adverse events (AEs), and the 2-year survival remains approximately 10%.

The advances over the last few years, albeit small compared with other cancers, have provided several more options for patients with pancreatic cancer.

Many anticancer drugs including molecularly targeted agents have been evaluated in randomized trials since the approval of gemcitabine in advanced pancreatic cancer. A major milestone was reported by Conroy et al in the PRODIGE4/ACCORD11 trial that randomized 342 patients with chemotherapyna&iuml;ve metastatic pancreatic cancer to FOLFIRINOX or gemcitabine.

The FOLFIRINOX regimen consisted of oxaliplatin 85 mg/m

as a 46-hour continuous infusion every 2 weeks. Pertinent eligibility criteria included ECOG performance status (PS) 0 or 1 and bilirubin less than or equal to the upper limit of normal range. Patients aged 76 years or older were excluded. The FOLFIRINOX arm achieved a superior median overall survival (OS) of 11.1 months versus 6.8 months in the gemcitabine arm (HR, 0.57;

<.001). The OS of the FOLFIRINOX group at 6, 12, and 18 months were 75.9%, 48.4%, and 18.6% respectively, compared with 57.6%, 20.6%, and 6.0% respectively in the gemcitabine group. The objective response rates were 31% versus 9.4% in the FOLFIRINOX and gemcitabine arms respectively.

The regimen is now a standard for metastatic disease in the first-line setting, though the higher frequency of toxicities such as neutropenia, febrile neutropenia, fatigue, and diarrhea have required dose modification for better quality of life (QoL). Despite the increased toxicity associated with FOLFIRINOX, a follow-up QoL analysis of the ACCORD11 trial showed that the FOLFIRINOX arm had improvement in global health status (GHS) by the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire C30 method, and had longer time to definitive deterioration &ge;20 points than the gemcitabine arm.

The domains that showed improvement included GHS, functioning (physical, cognitive, and social), fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation. A single-institution retrospective report of real-world experience showed that dose reduction occurred in >80% of patients during the first cycle: irinotecan was reduced/omitted in 80%, oxaliplatin in 28%, bolus fluorouracil in 45%, and infusional fluorouracil in 8%.

The analysis showed that comparable efficacy to the PRODIGE

trial was achieved with the ACCORD11 trial even with dose attenuation. In terms of health economics, an analysis by the Ontario health system in Canada showed that FOLFIRINOX was the most cost-effective option for quality life-year gain compared with gemcitabine/capecitabine, gemcitabine/erlotinib, and gemcitabine in patients with metastatic pancreatic cancer.

As such, this regimen is recommended as a first-line option for younger and fit patients with adequate hepatic and other organ reserves, and modification to the published regimen is generally used and accepted to avoid compromising the expected efficacy.

Another milestone soon followed, with the positive results from the Metastatic Pancreatic Adenocarcinoma Trial (MPACT), that randomized 861 patients with metastatic pancreatic cancer to receive nabpaclitaxel plus gemcitabine or gemcitabine.

Nabpaclitaxel is an albumin-bound paclitaxel, which is advantageous in lieu of the Cremaphor formulation of paclitaxel and has significantly lower risk for infusion reactions, and neutropenia, while offering more rapid recovery of neuropathy upon halting the therapy.

In an updated analysis, the median OS for the nabpaclitaxel/gemcitabine arm was 8.7 months versus 6.6 months (HR, 0.72; P <.001).

At 36 months, 4% of patients in the study arm were alive compared with none in the gemcitabine arm. The addition of nab-paclitaxel tripled the response rate, with 23% versus 7% (P <.001) in the study and control arms, respectively. The regimen was well tolerated, and the most common grade 3 and above AEs in the study arm were neutropenia, fatigue, and neuropathy. When compared with FOLFIRINOX, Conroy et al reported that the frequency of neutropenia, febrile neutropenia, diarrhea, and fatigue were lower for nab-paclitaxel/gemcitabine, although the risk for thrombocytopenia and neuropathy were higher for nab-paclitaxel/gemcitabine. The nab-paclitaxelrelated neuropathy improved from grade 3 or higher to grade 1 or lower in a median of 29 days upon discontinuation, which potentially allows re-introduction of nab-paclitaxel in a real-world scenario; whereas, neuropathy related to oxaliplatin may be typically prolonged, and a long recovery interval is needed before reintroduction of the therapy in patients treated with FOLFIRINOX.

The MPACT trial enrolled patients with Karnofsky performance-status score 70 or better which, when compared with the ACCORD11 trial that enrolled ECOG performance status 0 to 1, included patients with better ECOG PS 2. The ACCORD11 trial excluded patients age 76 years or older whereas the MPACT trial included patients up to ages 88 years, though the median age was comparable between both. The MPACT trial excluded patients with bilirubin level above the upper limit of normal (ULN) whereas the ACCORD11 trial included patients with higher bilirubin level (1.5 times ULN). Together with the difference in the toxicity profile between both regimens, these factors can help oncologists to personalize their recommendation for patients in the first-line metastatic pancreatic cancer setting.

The availability of two active regimens now offers meaningful options for patients who progress, or become intolerant to first-line treatment. Prior to the ACCORD11 trial, patients who failed first-line gemcitabinecontaining therapy received fluoropyrimidine-based regimens, typically those containing oxaliplatin.

Several retrospective studies showed that FOLFIRINOX was efficacious in second-line setting after failure of gemcitabine-based therapy, with an acceptable safety profile.

Conversely, patients who progressed on FOLFIRINOX in the first-line setting may receive gemcitabine alone or gemcitabinebased combination, provided they have good performance status in the second-line setting. The efficacy of nab-paclitaxel/gemcitabine in the second-line setting and beyond was reported in a single-institution restrospective study.

However, the appropriate sequencing of these regimens in first- and second-line settings to maximize survival has yet to be investigated clinically, and the decisions are currently based on patient&rsquo;s performance status, organ reserves, and preferences. Several randomized trials specifically for the second-line setting and beyond seemed to be promising, including an on-going trial using ruxolitinib (JAK1/2 inhibitor; [NCT02117479, NCT02119663]) and another using nano-liposal irinotecan (MM398; NAPOLI trial)

The management of locally advanced unresectable pancreatic cancer has been similar to metastatic disease with certain extrapolations from that of metastatic disease. The main difference has been the use of chemoradiation in the locally advanced setting, which the role was investigated in several recently reported randomized trials. The LAP 07 trial investigated the use of chemoradiation after an initial systemic chemotherapy, and the results was reported at the ASCO Annual Meeting in 2013.

In this international phase III trial, 442 patients with locally advanced pancreatic cancer started treatment by receiving 4 months of systemic chemotherapy (gemcitabine or gemcitabine/erlotinib), and those who did not progress (269 patients) were then randomized to receive chemoradiation with capecitabine or to continue another 2 months of systemic chemotherapy. The planned interim analysis showed that the median OS achieved in the systemic chemotherapy and chemoradiation arms were 16.5 months versus 15.3 months (HR, 1.03; P = .83), concluding that chemoradiation was not superior to continuing systemic chemotherapy in patients who did not progress after an initial 4 months of systemic chemotherapy.

The role of upfront chemoradiation was investigated in two randomized trials. The ECOG 4201 trial randomized 74 patients with locally advanced pancreatic cancer to systemic gemcitabine therapy and chemoradiation with gemcitabine.

The trial was terminated early due to poor accrual though an intention-to-treat analysis showed a trend toward better survival in the chemoradiation arm of 11.1 months versus 9.2 months in the chemotherapy arm (

= .017). The 2000-01 FFCD/SFRO study randomized 119 patients to receive induction chemoradiation using fluorouracil and cisplatin or induction gemcitabine. Both groups then received maintenance gemcitabine until disease progression or toxicity.

The median OS was inferior in the chemoradiation group, with 8.6 months compared with 13 months in the chemotherapy group (

= .03), and patients in the chemoradiation arm experienced more grade 3 to 4 toxicities. As such, evidence so far has shown that upfront chemoradiation does not show a clear survival benefit; and, chemoradiation after induction chemotherapy is not superior to continuing systemic chemotherapy in patients who have disease control following induction chemotherapy. Chemoradiation should be considered in situations where local control is needed, including patients who develop local progression following induction chemotherapy, bleeding, poorly controlled pain, or local obstructive symptoms.

The availability of more active combination chemotherapy such as FOLFIRINOX and gemcitabine/nab-paclitaxel may also impact the effect of chemoradiation.

Resectable and Borderline Resectable Disease

Surgical resection remains the only curative modality in pancreatic cancer, and postoperative adjuvant therapy had been shown to confer survival benefit.

Currently accepted standards for adjuvant therapy consist of systemic gemcitabine for 6 cycles (CONKO-001) or systemic gemcitabine with chemoradiation (RTOG 97-04).

Despite that, the recurrence rate remains unacceptably high, and the 5-year survival rate is ~20% for patients with resected disease.

FOLFIRINOX and gemcitabine/nab-paclitaxel are highly active in metastatic pancreatic cancer and are recommended for patients with good performance status. The availability of these regimens allows for personalization of treatment plans according to a patient&rsquo;s performance status, preference, and liver function.

The LAP 07 trials showed that chemoradiation following induction chemotherapy did not add survival benefit in locally advanced, unresectable pancreatic cancer, though chemoradiation should be considered in patients who progress following induction chemotherapy, poorly controlled pain, bleeding, or local obstructive symptoms.

The use of highly active chemotherapy and chemoradiation has the potential of improving surgical outcomes in patients with resectable disease, and the approach is been evaluated in randomized trials.

As such, neoadjuvant, or preoperative, therapy is increasingly used for patients with borderline resectable pancreatic cancer. Borderline resectable disease, in general, refers to localized tumors with high likelihood of margin-positive resection, though the definition varies between various working groups, and readers should refer to the guidelines by the National Comprehensive Cancer Network and Alliance for Clinical Trials in Oncology group for details.

The theoretical advantages of neoadjuvant therapy include: downstaging of disease to improve surgical outcome, selection of patients with aggressive biology who might otherwise not benefit from surgery, and avoidance of therapy initiation delays due to postoperative complications.

The optimal neoadjuvant regimen(s) remains unclear though a number of approaches have been reported and many consist of multimodality approaches incorporating systemic chemotherapy and chemoradiation. The more active combination chemotherapy regimens in metastatic disease (FOLFIRINOX, gemcitabine/nab-paclitaxel) are widely incorporated in an effort to achieve maximal tumor shrinkage prior to surgery.

Currently, the choice of chemotherapy regimen and the incorporation of chemoradiation into a neoadjuvant approach is based on institutional preference given the lack of randomized trial data to support one over the other. Importantly, the impact of neoadjuvant therapy on survival compared with upfront pancreatectomy followed by adjuvant therapy remains to be determined.

Randomized trials are under way to investigate the question of whether or not neoadjuvant therapy will confer a survival benefit. The NEOPAC study is a phase III trial that plans to randomize 310 patients with resectable disease to upfront surgery followed by adjuvant gemcitabine for 6 months or neoadjuvant gemcitabine/oxaliplatin followed by surgery and continuation of the same chemotherapy thereafter.

Patients with tumor involvement of portal/superior mesenteric veins (>180&deg;), abutment of major visceral arteries, or distant metastases are excluded. The study has completed enrollment and results have not been reported (NCT01521702). NEPAFOX is an ongoing randomized multicenter phase II/ III study that plans to enroll patients with resectable or borderline resectable pancreatic cancer (NCT02172976).

Eligible patients will be randomized to receive surgery followed by 6 cycles of gemcitabine adjuvant treatment (24 weeks) or 6 cycles of FOLFIRINOX neoadjuvant treatment (12 weeks) and surgery followed by 6 cycles FOLFIRINOX adjuvant treatment (12 weeks). The primary endpoint is OS at 24 months, and secondary endpoints include progression-free survival (PFS), perioperative morbidity and mortality, R0 resection rate, pathological complete remission, and prevalence of iron deficiency anemia.

Patients with pancreatic cancer are afflicted with many debilitating complications unique to this disease, and optimal palliation requires a multidisciplinary approach.

Biliary obstruction is common in pancreatic cancer and can lead to infection and fatigue. Prompt diagnosis, initiation of antibiotics and access to interventional GI endoscopists will help prevent treatment delays and avoid or shorten hospitalization. Cachexia and malnutrition (from the cancer and pancreas insufficiency) are significant in this disease, and pancreas enzyme supplementation and nutrition counseling are often needed. Patients with pancreatic head lesions may also suffer from varying degrees of gastric outlet obstruction and may benefit from promotility agents, and severe cases will require stenting or placement of PEG or feeding tubes. Pain and poor prognosis associated with this disease can often lead to depression and may adversely impact the patient&rsquo;s functioning and social relationships. Comanagement by dedicated palliative care team and social worker/psychologist will significantly improve the patient&rsquo;s quality of life.

Though outcomes for patients with pancreatic cancer seems to have improved at a glacial rate, the impact of recent therapeutic advances is significant. Patients with metastatic disease now have access to several active chemotherapy regimens, and their treatment path can be tailored according to the patient&rsquo;s performance status and preference for efficacy versus impact of the toxicities on quality of life. Several promising therapies are currently undergoing clinical evaluation including an irinotecannano-liposomal formulation that is under regulatory review in the United States.

The role of chemoradiation following induction chemotherapy in locally advanced pancreatic cancer was clarified in the LAP 07 trial. The identification and pre-operative use of highly active chemotherapy regimens with/without chemoradiation in patients with borderline resectable disease has spared patients with micrometastatic or aggressive disease the morbidity of surgery and chemoradiation, though the impact of neoadjuvant therapy on survival is just starting to be evaluated in randomized trials.

American Cancer Society. Cancer Facts & Figures 2015. Atlanta; 2015.

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.

Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ ACCORD 11 randomized trial.

. 2012;31(1):23-29. doi:10.1200/ JCO.2012.44.4869.

Gunturu KS, Yao X, Cong X, et al. FOLFIRINOX for locally advanced and metastatic pancreatic cancer: single institution retrospective review of efficacy and toxicity.

Tam VC, Ko YJ, Mittmann N, et al. Cost-effectiveness of systemic therapies for metastatic pancreatic cancer.

Vaccaro V. Metastatic pancreatic cancer: is there a light at the end of the tunnel?

Hoff Von DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

Ma WW, Hidalgo M. The winning formulation: the development of Paclitaxel in pancreatic cancer.

Goldstein D, El-Maraghi RH, Hammel P, et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial.

Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial.

Assaf E, Verlinde-Carvalho M, Delbaldo C, et al. 5-fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma.

Lee MG, Lee SH, Lee SJ, et al. 5-Fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with advanced pancreatic cancer who have progressed on gemcitabine-based therapy.

Umemura A, Nitta H, Sasaki A, Takahara T, Hasegawa Y, Wakabayashi G. Modified FOLFIRINOX for locally advanced and metastatic pancreatic cancer patients resistant to gemcitabine and S-1 in Japan: a single institutional experience.

Bertocchi P, Abeni C, Meriggi F, et al. Gemcitabine plus nab-paclitaxel as second-line and beyond treatment for metastatic pancreatic cancer: a single institution retrospective analysis.

Hoff Von D, Li CP, Wang-Gillam A, et al. NAPOLI-1: randomized phase 3 study of MM-398 (NAL-IRI), with or without 5-fluoracil and leucovorin, versus 5-Fluorouracil and Leuvorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy.

Hammel P, Huguet F, Van Laethem JL, et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: final results of the international phase III LAP 07 study.

Loehrer PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial.

Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study.

Tempero MA, Malafa MP, Behrman SW, et al. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines.

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Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.

Regine WF, Winter KA, Abrams R, et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-Year analysis of the U.S. intergroup/RTOG 9704 phase III trial.

Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial.

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MacKenzie S, Zeh H, McCahill LE, et al. A pilot phase II multicenter study of nab-paclitaxel (Nab-P) and gemcitabine (G) as preoperative therapy for potentially resectable pancreatic cancer (PC).

Katz MHG, Shi Q, Ahmad SA, et al. Preoperative modified FOLFIRINOX (mFOLFIRINOX) followed by chemoradiation (CRT) for borderline resectable (BLR) pancreatic cancer (PDAC): Initial results from Alliance Trial A021101.

Heinrich S, Pestalozzi B, Lesurtel M, et al. Adjuvant gemcitabine versus Neoadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter phase III study (NEOPAC study).

Hozaeel W, Pauligk C, Homann N, et al. Randomized multicenter phase II/III study with adjuvant gemcitabine versus neoadjuvant/adjuvant FOLFIRINOX in resectable pancreatic cancer: The NEPAFOX trial.

Articles

Recent therapeutic advances have almost doubled the survival of patients with metastatic pancreatic cancer, and the availability of highly active chemotherapy regimens is making personalized medicine a reality.

Current Management of Pancreatic Cancer

Wen Wee Ma, MBBS, associate professor of oncology, Department of Medicine, Roswell Park Cancer Institute, discusses the utility of CA 19-9 in patients with pancreatic cancer.

CA 19-9 is a cancer marker that can be measured in the blood and is elevated in 60-70% of patients with pancreatic cancer

High levels of CA 19-9 in a patient who does not otherwise have clinical features of pancreatic cancer is not helpful in obtaining a diagnosis

CA 19-9 is primarily used in monitoring treatment response

Videos

The Utility of the CA 19-9 Test in Patients With Pancreatic Cancer

Wen Wee Ma, MBBS, associate professor of oncology, Department of Medicine, Roswell Park Cancer Institute, discusses interrupting the FGFR signaling pathway in pancreatic cancer.

The recent MPACT trial represents a major milestone in improving the survival of patients with stage IV pancreatic cancer

The microenvironment (consisting of white blood cells, macrophages, collagens, connective tissues, and fibroblasts) in pancreatic cancer plays a major role in treatment resistance

The fibroblast growth factor receptor (FGFR) signaling pathway is active in cancer cells in promoting proliferation, growth, and blood vessel formation

Interrupting this pathway can cause cancer cells to undergo apoptosis

A clinical trial is underway looking at dovitinib and gemcitabine-based chemotherapy for patients with advanced or metastatic pancreatic cancer

Interrupting the FGFR Signaling Pathway in Pancreatic Cancer

Assistant Professor, Department of Medicine,

Anaplastic Lymphoma Kinase as Therapeutic Target

Gene translocations account for most oncogenic

alterations discovered to date. Crizotinib is an efficacious treatment for patients with non-small cell lung cancer (NSCLC) harboring

translocation, but resistance eventually develops during therapy. LDK378 is a highly selective and potent inhibitor of ALK, and has demonstrated preclinical antitumor activity against tumors with acquired crizotinib resistance. In a phase I trial, LDK378 induced tumor response in 70% of patients with crizotinib-resistant NSCLC and gained Breakthrough Therapy designation from the FDA. Phase III studies evaluating LDK378 in crizotinib-na&iuml;ve and crizotinib-resistant NSCLC are currently under way.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Structurally, the intracellular kinase domain shares close homology to that of insulin receptor (InR; 46%), insulin-like growth factor receptor- 1 (IGF-1R; 47%), and leukocyte receptor tyrosine kinase (LTK; 79%).

was first implicated with the discovery of nucleophosmin (NPM1)-ALK fusion protein in anaplastic large cell lymphoma (ALCL).

alterations had been identified, including

mutations/amplification in neuroblastoma, and

rearrangements is approximately 3% to 5% of the overall NSCLC patient population.

alterations have also been reported in other cancer types including brain, breast, colon, ovarian, prostate, and esophageal.

Crizotinib (PF-02341066) is an oral ATP-competitive small-molecule inhibitor against MET kinase and also potently inhibits ALK signaling, and the agent induced apoptosis and tumor regression in a preclinical

The first-in-human crizotinib study initially focused on enrolling patients with

-positive (rearranged) tumors. The study was then amended to enrich enrollment in

-positive NSCLC in the expansion phase following observation of encouraging efficacy in two

-positive patients with NSCLC during dose escalation.

In the expansion phase, 143 evaluable patients with ALK-positive NSCLC were enrolled to receive crizotinib 250 mg twice daily on an every-28-day cycle, which induced tumor response in 87 patients (60.8%), including 3 complete responses and 84 partial responses.

The median duration of response was 49.1 weeks. The most common grade 3 or 4 adverse events (AEs) were neutropenia, elevated alanine aminotransferase, hypophosphatemia, and lymphopenia. Crizotinib was compared with cytotoxic chemotherapy (pemetrexed or docetaxel) in the phase III PROFILE 1007 trial in patients with

-positive, locallyadvanced or metastatic NSCLC with one prior platinum- based treatment, and the agent demonstrated superior progression-free survival (PFS; 7.7 months vs 3.0 months;hazard ratio [HR]=0.49;

<.001) and response rate ([RR], 65% vs 20%;

<.001).11 The success of crizotinib demonstrated the feasibility in targeting oncogenic

signaling using a small-molecule inhibitor, which led to an interest in developing other potent

inhibitors, particularly those that can overcome acquired resistance to crizotinib.

LDK378 is a highly-selective potent ALK inhibitor optimized from Novartis&rsquo; previous lead compound TAE684.

In kinase assays, LDK378 potently inhibited ALK (IC

s of 3.17 &mu;M). Other kinases that were inhibited by LDK378 below 100 nM, were IGF-1R, InR, and STK22D with IC50&rsquo;s 8, 7, and 23 nM respectively. However, the potent biochemical inhibition of IGF-1R and InR were not reproducible in cellular kinase assay. LDK378 also did not affect insulin levels or glycemic control in a mouse model, with multiple dosing at pharmacologically active dosages tested, which was consistent with results from the cellular kinase assay. In a preclinical cancer model, tumor regression in xenografts derived from NCI-H2228 carrying

fusion gene and correlates with inhibition of STAT3 phosphorylation. LDK378 was also efficacious in NCI-H2228 that was induced to become resistant to crizotinib that carried the

C1156Y mutation found in crizotinib-relapsed patients.

As such, LDK378 is an attractive potential treatment option in both crizotinib-na&iuml;ve and crizotinib-resistant

In the phase I trial, LDK378 administered orally once daily continuously every 21 days was evaluated in patients with advanced cancers harboring a gene alteration in

who previously progressed on standard therapy or for whom there was no effective therapy.

Anticancer effect was observed at 400 mg daily and above, and the maximum tolerated dosage was determined to be 750 mg daily. LDK378 was rapidly absorbed upon ingestion with Tmax of 5 to 6 hours and a half-life of about 36 hours.

When the results were presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting, 131 patients harboring an alteration in the

-rearranged NSCLC, had been enrolled and received LDK378 at dosages of 50 mg to 750 mg once daily.

Eighty-eight evaluable patients with NSCLC were treated with LDK378 at 400 mg to 750 mg daily. The overall response rate (ORR) was 70%, and the ALK inhibitor was efficacious in the 64 patients who were crizotinib-resistant, achieving an ORR of 73%. The median PFS among the 123 evaluable patients with NSCLC was 8.6 months (95% CI, 4.3-19.3 months). The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%), and fatigue (31%). The most common Grade 3 or 4 AEs were diarrhea (7%), and elevated alanine aminotransferase and aspartate aminotransferase (12% and 6% respectively). Interestingly, responses were also observed in patients with untreated metastases in the central nervous system, suggesting that the drug penetrates the bloodbrain barrier.

Approximately 3% to 5% of patients with NSCLC harbor

translocation and eventually develop resistance to crizotinib treatment.

LDK378 is a highly selective and potent inhibitor of ALK but not MET, and demonstrated efficacy in both crizotinib-na&iuml;ve and crizotinib-resistant

LDK378 received Breakthrough Therapy designation by the FDA in March 2013, which speeds the development for the treatment of patients with

-rearranged metastatic NSCLC who progressed on or were intolerant of crizotinib therapy.

The impressive clinical efficacy of LDK378 during this early-phase study led to the designation of Breakthrough Therapy by the FDA in March 2013 for the treatment of patients with

-positive metastatic NSCLC who progressed during treatment with or were intolerant to crizotinib.

The designation was intended to expedite the development and review of drugs that treat serious and life-threatening conditions and that have demonstrated substantial improvement over existing therapies on at least one clinically significant endpoint.

Despite the initial response, many patients with

-rearranged NSCLC eventually become refractory to crizotinib treatment, and several mechanisms of acquired crizotinib-resistance have been discovered. A third of the acquired resistance may be due to secondary mutations in the

tyrosine kinase domain or amplification of the

mutations identified from patients with crizotinib-treated NSCLC include

. The other third bypass the ALK inhibition by activating compensatory signaling pathways such as EGFR, KIT, or KRAS, whereas the mechanisms for the last third have not yet been determined. In addition to developing LDK378 as monotherapy in crizotinib-na&iuml;ve and -resistant

-rearranged NSCLC (ClinicalTrials.gov Identifier NCT01828099, NCT01828112), efforts are also under way to develop rational LDK378-based combination therapies, including combination therapy with the heat-shock protein 90 inhibitor AUY922 (NCY01772797).

Wellstein A. ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers.

Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin&rsquo;s lymphoma.

Mano H: ALKoma: a cancer subtype with a shared target.

Palmer RH, Vernersson E, Grabbe C, et al. Anaplastic lymphoma kinase: signalling in development and disease.

Marsilje TH, Pei W, Chen B, et al. Synthesis, structure-activity relationships and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) Inhibitor LDK378 currently in phase 1 and 2 clinical trials.

Schoppmann SF, Streubel B, Birner P: Amplification but not translocation of anaplastic lymphoma kinase is a frequent event in oesophageal cancer.

Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.

Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma.

Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

Camidge DR, Bang Y-J, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.

Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.

Chen J, Jiang C, Wang S: LDK378: A promising anaplastic lymphoma kinase (ALK) inhibitor.

Li N, Michellys P-Y, Kim S, et al. Activity of a potent and selective phase I ALK inhibitor LDK378 in naive and crizotinib-resistant preclinical tumor models. Available at: http://mct.aacrjournals.org/cgi/content/meeting_ abstract/10/11_MeetingAbstracts/B232. Accessed December 3, 2013.

Shaw AT, Mehra R, Kim D-W, et al. Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. Abstract ASCO 2013. Available at: http://meetinglibrary.asco.org/content/111102-132. Accessed December 3, 2013.

Shaw AT, Cambidge DR, Felip E, et al. Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. Ann Oncol. 2012;l23:ix152-ix174.

Huang D, Kim D-W, Kotsakis A, et al. Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment.

LDK378 is a highly selective and potent inhibitor of ALK, and has demonstrated preclinical antitumor activity against tumors with acquired crizotinib resistance. In a phase I trial, LDK378 induced tumor response in 70% of patients with crizotinib-resistant NSCLC.

Wen Wee Ma, MBBS | Authors

Articles

Current Management of Pancreatic Cancer

The Utility of the CA 19-9 Test in Patients With Pancreatic Cancer

Interrupting the FGFR Signaling Pathway in Pancreatic Cancer

LDK378: A Promising Next-Generation ALK Inhibitor