Gina Battaglia, PhD

Although EGFR-targeted therapies have led to a survival benefit for patients with nonsmall cell lung cancer (NSCLC), more evidence-based data are still needed to compare the relative values of new versus first- and second-generation therapies, said&nbsp;Edward B. Garon, MD.

According to Garon, however, the pharmaceutical sector is showing willingness to develop therapies for subpopulations in this disease type, having overcome reservations based on uncertain financial rewards of doing so. In addition, the amount of research into resistance mechanisms is increasing, boding well for useful insight into treatment selection.

director of thoracic oncology at the Jonsson Comprehensive Cancer at the University of California, Los Angeles, discussed the role of EGFR-targeted therapies in the treatment landscape of NSCLC.

What are some of the most promising EGFR-targeted therapies approved in the frontline setting for NSCLC?

Osimertinib [Tagrisso] has shown superior progression-free survival [PFS] compared with gefitinib [Iressa] or erlotinib [Tarceva] in the initial management of

mutant nonsmall cell lung cancer. Afatinib [Gilotrif] has also shown a PFS advantage over gefitinib. The magnitude of the benefit appeared greater for osimertinib, although osimertinib and afatinib have not been directly compared. Also, the toxicity profile of osimertinib is generally quite good, while some of the classic EGFR inhibitor toxicities, including dermatologic and gastroenterologic toxicities, have been more problematic with the other agents mentioned above. There are data from 2 trials in Japan showing a PFS advantage of adding bevacizumab [Avastin] to erlotinib. Based on limited follow-up or methodologic issues, we have not yet been able to truly assess whether this regimen improves survival. Although this regimen is not approved in the United States, it is approved in some countries. Dacomitinib [Vizimpro] is the other approved agent. This has significant EGFR inhibitor toxicities, but it represents an impressive improvement over gefitinib with respect to PFS. Dacomitinib also showed a benefit in overall survival. A preliminary survival evaluation of osimertinib looked numerically impressive, but it did not meet the statistical threshold for superiority at this early evaluation. Additional data are awaited.

-rearranged, lung cancer improved the discovery of targeted agents in other types of cancer?

It is hard to convince current trainees of this, but it wasn&rsquo;t long ago that pharmaceutical companies were reluctant to target a subset of a histology, fearing the financial viability of agents targeting restricted populations. We are now seeing more and more biomarker- driven groups being evaluated. In addition, we are starting to see histology-agnostic approvals, where the biomarker, not the location of the primary tumor, is the determinant in the choice of treatment.

How will using new EGFR-targeted agents in the frontline setting change the patterns of resistance and perhaps the sequencing of therapies?

To date, less is known about the resistance to agents other than erlotinib and gefitinib. Impressive PFS has been seen with dacomitinib and the regimen of erlotinib plus bevacizumab followed by osimertinib at the time of progression in those with a T790M mutation. However, it&rsquo;s unclear whether the resistance mechanisms are the same in these alternate regimens as compared with single-agent erlotinib or gefitinib. One change is that in patients treated with osimertinib, there is not substantial selective pressure on the cell to have a T790M mutation. A percentage of patients have a mutation at the C797 binding site at the time of progression on osimertinib, but the majority do not. There is a great deal of ongoing investigation into the resistance seen after frontline osimertinib.

From a scientific and drug development point of view, what are the next steps for EGFR-targeted agents?

Articles

Edward B. Garon, MD,&nbsp;discusses the role of EGFR-targeted therapies in the treatment landscape of NSCLC.

Garon Sheds Light on Next Steps With EGFR-Targeted Agents in NSCLC

Adoptive immunotherapy has shown promising outcomes in early-stage trials for many cancers, but successful approaches in head and neck cancers will require addressing several challenges that are inherent in many solid tumors, such as creating the right homing mechanisms, achieving adequate T-cell infiltration into the tumor, and finding an antigen that will not produce off-tumor effects.

Early data on adoptive immunotherapy in head and neck cancers have shown just modest responses. However, they provide proof-of-concept that such immunotherapy can be effective, and ongoing research on optimizing adoptive immunotherapy in hematologic malignancies will help guide research for head and neck cancer, said Ezra Cohen, MD, associate director, Moores Cancer Center, and professor of medicine, University of California, San Diego, in an interview with

&ldquo;The success has not been as dramatic as we&rsquo;ve seen in leukemia with CD19 chimeric antigen receptors [CARs] or multiple myeloma with B-cell maturation antigen CARs, but the fact that it&rsquo;s been shown to work in some patients demonstrates that at least there&rsquo;s a principle that appears to be true,&rdquo; said Cohen. &ldquo;The question becomes, how do we turn that from an unusual response to an expected response?&rdquo;

Adoptive T-cell therapy for cancer involves harvesting T cells from the patient&rsquo;s blood or tumor, stimulating them to grow and expand in an in vitro culture system, and reinfusing the expanded cells back into the patient with the goal of mediating tumor destruction. Development of T-cell receptors (TCRs) involves introduction of a tumor antigenspecific TCR to genetically modify T cells. These modified T cells use a complex assembly of proximal signaling molecules to achieve highly sensitive recognition of abnormal intracellular antigens, which enables them to initiate a potent, specific immune response against viruses and transformed cancer cells. By contrast, CARs are hybrid receptors formed by linking an extracellular, tumor-specific antibody fragment, a stalk-like region, a transmembrane region, and intracellular signaling domains derived from proximal T-cell signaling machinery (

&ldquo;The biggest difference is that CARs depend on a surface-expressed receptor or protein that can be detected by the CAR,&rdquo; said Cohen. &ldquo;It has to be something expressed on the surface of the cancer cell. The TCRs depend on the cancer cell essentially processing a protein and presenting it as a peptide in the context of that cell&rsquo;s major histocompatibility complex.&rdquo;

TCR approaches are appealing for head and neck cancers, particularly those that are virus-related, because they contain antigens that are clearly &ldquo;nonhuman,&rdquo; according to Cohen. A phase I study2 administered ex vivo expanded autologous T cells directed toward the Epstein-Barr virus (EBV) to 22 patients with metastatic EBV-positive nasopharyngeal cancer. Expansion of EBV-specific T cells was successful in 16 patients, who demonstrated a median overall survival (OS) of 523 days. By contrast, the patients who did not have successful T-cell expansion had a median OS of 220 days.

Early research also suggests that adoptive cell therapy could work synergistically with chemotherapy by enhancing the antitumor effect and improve immune function, which is often compromised from chemotherapies frequently used for head and neck cancer. A retrospective study

showed that patients with head and neck squamous cell cancer (HNSCC) who received adoptive cell therapy after radical resection and induction chemotherapy had significantly longer progression-free survival (PFS) and OS than patients who received induction chemotherapy alone (PFS, 56 vs 40 months; OS, 58 vs 45 months). Additionally, the adoptive cell therapy, which involved expansion and profiling of cytokine-induced killer cells (CIKs) from peripheral blood mononuclear cells, increased the cytotoxicity of the CIKs and restored the systemic immunosuppression that occurred after the chemotherapy. The authors also noted that restoring the systemic immunosuppression that occurs with many HNSCC chemotherapy regimens can be particularly valuable for reducing infections and improving patients&rsquo; quality of life during treatment.

Recent preclinical research also suggests that TCRs increase tumor sensitivity to chemotherapy and exhibit cytotoxicity to chemotherapy-resistant tumor cells. In an in vitro study,

adding cytomegalovirus (CMV) pp65 antigen specific cytotoxic T-lymphocytes (CTLs) 5-fluorouracil and cisplatin (CDDP) chemotherapy demonstrated cytotoxicity against oral squamous cell cancer (OSCC) cell lines overexpressing CMVpp65 antigen, and the cytotoxicity of CMVpp65-CTL was the same with CDDP-resistant and -nonresistant OSCC cells. Further, the chemotherapeutic agents sensitized the OSCC cells to CMVpp65-CTL and did not inhibit cytotoxicity or the interferon-&gamma; release response. From these data, the authors concluded that combining TCRs with chemotherapy could be particularly promising for patients who have CDDP-resistant tumors or who cannot tolerate high doses of CDDP.

The rapidly increasing incidence of human papillomavirus (HPV)-positive HNSCC over the past decade has also encouraged recent research efforts toward developing effective HPV-targeted TCRs. Preliminary data from a recently completed phase I/II trial of patients with various metastatic, HPV16-positive, HLA-A*02:01-positive cancers (including oropharyngeal, cervical, anal, and vaginal) showed that administration of a nonmyeloablative conditioning regimen of cyclophosphamide and fludarabine, a single infusion of T cells genetically engineered to express a TCR targeting an HLA-A*02:01-restricted epitope of E6 (E6 TCR T cells), and systemic high-dose aldesleukin yielded partial responses in 2 of 12 patients (both with anal cancer).5 The responders had high levels of E6 TCR T-cell memory 1 month after treatment, and 7% of E6 TCR T cells were detected 10 months after treatment in a resected tumor of the patient who had a 6-month response. By contrast, tumor tissue from a nonresponder had no detectable levels of E6 TCR T cells 3 months after treatment. The researchers plan to recruit up to 18 patients for the dose-escalation portion of the study and enroll at least 41 patients for the phase II portion, provided that a clinical response is observed in at least 2 patients of the first 21 patients in the phase II portion. The primary outcome measures for the study are maximum tolerated dose, objective tumor response rate, and duration of response.

Although Cohen stated that development of adoptive immunotherapy approaches will be more challenging for virus-negative cancers, he suggested that identifying other common neoantigens, such as PIK3CA and HRAS mutations with HNSCC, and the peptides they produce, may be instrumental for developing TCRs that target these mutations. He also noted that finding targets may be somewhat easier for thyroid cancers because they tend to be more homogeneous in their genetic alterations than HNSCCs. &ldquo;More than 50% of papillary thyroid cancers have BRAF mutations, so that could be a good antigen for a T-cell receptor,&rdquo; said Cohen.

Using Biotechnology to Improve Identification of Target Peptides for TCR

In partnership with investigators at MD Anderson Cancer Center, researchers at Immatics US, Inc, developed IMA201 using their proprietary ACTengine approach, which engineers a patient&rsquo;s T cells to express an exogenous TCR targeted to a tumor site identified by their XPRESIDENT target discovery platform. The XPRESIDENT platform improves the identification of target peptides for TCR development by analyzing peptides obtained from samples of tumor tissue and corresponding normal tissue through a combination of quantitative transcriptomics and quantitative HLA peptidomics to identify HLA peptides that are present on cells in tumor tissue and absent on cells in normal tissue.

An open-label, first-in-human, dose-escalating phase I trial (NCT03247309) was initiated in September 2017 to investigate the safety, tolerability, and clinical activity of IMA201 in patients with HNSCC or nonsmall cell lung cancer (NSCLC) with an HLA-A*02:01 phenotype who have no further options for treatment or who cannot tolerate current treatments (

The primary objective of the study is to assess safety and to identify the maximum tolerated dose. Secondary endpoints include overall response rate (assessed using RECIST criteria and Immune- Related Response Criteria), PFS, and OS. The authors also hope to assess several translational objectives, including the persistence and functionality of IMA201 in vivo, correlative biomarkers for clinical success, and the target expression levels in the tissue.

CAR T-cell therapies have shown remarkable responses in hematologic malignancies, including CAR T cells targeting CD19 in relapsed acute lymphoblastic leukemia (ALL),

and diffuse large B-cell lymphoma or follicular lymphoma.

However, development of CAR T-cell therapies for HNSCC and other solid tumors has been challenging, according to Cohen.

&ldquo;A T cell has to traffic to the cancer and overcome an immunosuppressive microenvironment to kill that tumor cell, even if it&rsquo;s an engineered T cell through a chimeric antigen receptor or TCR,&rdquo; he said. &ldquo;For solid tumors, those T cells may not necessarily have the right homing mechanisms, and part of the education of a T cell is that it learns to home to specific tissue.&rdquo; He also pointed out that the density of solid tumors and the fibrous tissue that makes up many head and neck cancers can prevent T cells from infiltrating the tumor.

Intratumoral Approach With a Multitargeted CAR T-Cell Therapy

To address the challenges of CAR T-cell homing and off-tumor effects, a research group at King&rsquo;s College in London developed a pan-ErbBtargeted CAR T-cell therapy that is injected intratumorally, rather than systemically, for HNSCC. The T4 immunotherapy the team used in a dose-escalation phase I study

involved T cells that were retrovirally transduced to co-express T1E28&zeta; (a CAR coupling a promiscuous ErbB ligand derived from EGF and TGF&alpha; to a fused CD28+CD3&zeta; endodomain) and 4&alpha;&beta; (a chimeric cytokine receptor containing the interleukin (IL)-4R&alpha; ectodomain coupled to the IL-2R&beta; endodomain). The T4 immunotherapy was successfully generated from a 130-mL blood draw, even though 90% of the patients were lymphopenic, and patients were treated in cohorts of 1 x 107, 3 x 107, and 10 &times; 107 T4-positive T cells. The overall disease control rate was 44%, and all 3 patients who received the highest dose had stable disease. Treatment-related adverse events were grade 2 or lower (the most common being tumor swelling, pain, and fatigue), and no dose-limiting toxicities were observed.

The trial is still ongoing, with the study authors planning to investigate the safety and efficacy of higher doses as well as combinations with other immunooncology agents. However, lead author Sophie Papa, PhD, MBBS, MRCP, said that this mechanism of T-cell therapy could also be a promising approach to a regionally directed therapy, such as treatment in the thoracic cavity for mesothelioma or in the abdominal peritoneal cavity for ovarian cancer.

&ldquo;This is, essentially, nontoxic personalized therapy for patients with a very lethal form of cancer that appears to be controlling disease in the majority of patients,&rdquo; said Papa, medical oncologist, Clinical Academic Group, Department of Research Oncology, King&rsquo;s College London, in an earlier interview with T

&ldquo;The future for this is to continue to dose-escalate because we are starting to see signs of more activity in patients in the higher dose level.&rdquo;

Another challenge for CAR T-cell therapy in HNSCC is finding an appropriate antigen to target because many of the antigens on the surface of the tumors are also present on normal cells throughout the body. This can lead to on-target, off-tumor effects that are a common concern when developing CAR T-cell therapies, as was demonstrated when systemically delivered carcinoembryonic antigentargeted CAR T-cell therapy for colorectal cancer led to life-threatening colitis in several patients.

&ldquo;The most highly expressed protein in head and neck cancer is EGFR, but EGFR is expressed at high levels in the liver, skin, and gut,&rdquo; said Cohen. &ldquo;It&rsquo;d be very difficult to get a CAR against EGFR because it would be too toxic.&rdquo;

Tyrosine kinaselike orphan receptor (ROR1) has been identified as a promising target for CAR T-cell therapy because the receptor is produced in solid and hematologic malignancies but not in normal cells, according to Cohen. Additionally, ROR1 expression has been shown to enhance tumor cell growth and survival and promote epithelial&ndash;mesenchymal transition and metastasis,

and high ROR1 expression has been associated with shorter overall survival in triple-negative breast cancer (TNBC), lung adenocarcinoma, and ovarian cancer.

Although the work by Cohen and his colleagues, funded by the California Institute for Regenerative Medicine, is still in the preclinical stages, he anticipates that his ROR1-directed CAR T-cell therapy will be tested in human trials within the next 12 to 18 months. An ongoing phase I clinical trial (NCT02706392) sponsored by the Fred Hutchinson Cancer Research Center in Seattle is investigating a different ROR1-targeted CAR T-cell therapy in patients with advanced, treatment-refractory, ROR1-positive chronic lymphocytic leukemia, mantle cell lymphoma, ALL, NSCLC, or TNBC.

Cohen also noted that the incidences of cytokine release syndrome observed with CAR T-cell therapy for hematologic malignancies may be a concern for HNSCC and other solid tumors, but he was optimistic that these will become less common as researchers learn how to predict them. &ldquo;We&rsquo;ve learned to anticipate those in hematologic malignancies,&rdquo; said Cohen. &ldquo;By the time we&rsquo;re treating solid tumors in head and neck cancer with CARs, hopefully that won&rsquo;t be as much of a concern.&rdquo;

Once effective CAR T-cell therapies are developed for head and neck cancer, resistance will likely be the next major concern, according to Cohen.

&ldquo;We&rsquo;d love to have that as a real-time concern,&rdquo; he said. &ldquo;The reality is that for cancer to become resistant to a therapy, that therapy has to work in the first place. [Resistance] is almost certainly going to happen, and it&rsquo;s going to happen through loss of expression of that receptor, specific clones that eventually grow out, and highly immunosuppressive microenvironments that develop.&rdquo;

Cohen noted that the research on resistance mechanisms to CAR T-cell therapies in hematologic malignancies will help guide research in solid tumors. While CD19-targeted CAR T-cell therapy has been shown to yield a 90% response rate in patients with relapsed ALL, it also led to CD19 epitope loss in 10% to 20% of patients.

Further research has shown that disease relapse was associated with the development of alternative splicing variants of the CD19 protein that were still functional in promoting B-cell proliferation.

Thus, researchers are currently working on designing approaches that tackle these resistance mechanisms, such as designing new antibodies that recognize alternative epitopes in the CD19 domain, forcing the cell to produce a full-length CD19, or co-expression of CARs.

&ldquo;If you become more sophisticated with your engineering and begin to coexpress CARs or have more than 1 target, you can begin to get around that initial resistance and hopefully eliminate every cancer cell so that resistance never develops,&rdquo; said Cohen.

Although adoptive immunotherapy approaches are still in the infancy stages for head and neck cancer, Cohen was optimistic that they would soon play a role in treatment, possibly in conjunction with checkpoint inhibitors, for patients with chemotherapy-refractory disease and eventually in the first-line recurrent metastatic setting.

&ldquo;I have no doubt that we will see T-cell engineering in head and neck cancer later this year or early next year,&rdquo; said Cohen. &ldquo;We&rsquo;ll begin to see the first CARs and more TCRs. We&rsquo;ll find a way to make them work in solid tumors, and I think they&rsquo;ll eventually work quite well. It&rsquo;s just a matter of getting there.&rdquo;

Harris DT, Kranz DM. Adoptive T cell therapies: a comparison of T cell receptors and chimeric antigen receptors.

2016;37(3):220-230. doi: 10.1016/j.tips.2015.11.004

Smith C, Tsang J, Beagley L, et al. Effective treatment of metastatic forms of Epstein-Barr virusassociated nasopharyngeal carcinoma with a novel adenovirus- based adoptive immunotherapy.

2012;72(5):1116-1125. doi: 10.1158/0008-5472.CAN-11-3399.

Jiang P, Zhang Y, Archibald SJ, Wang H. Adoptive cell transfer after chemotherapy enhances survival in patients with resectable HNSCC.

2015;28(1):208-214. doi: 10.1016/j.intimp.2015.05.042.

Nishio-Nagai M, Suzuki S, Yoshikawa K, et al. Adoptive immunotherapy combined with FP treatment for head and neck cancer: an in vitro study.

2017;51(5):1471-1481. doi: 10.3892/ijo.2017.4142.

Hinrichs CS, Doran SL, Stevanovic S, et al. A phase I/II clinical trial of E6 T-cell receptor gene therapy for human papillomavirus (HPV)-associated epithelial cancers.

2017;35(suppl; abstr 3009). meetinglibrary.asco.org/record/152695/ abstract.

XPRESIDENT. Immatics US, Inc, website. immatics.com/x-president.html. Accessed March 26, 2018.

Blumenschein GR, Bourgogne A, Reinhardt C, et al. Phase I trial evaluating genetically modified autologous T cells (ACTengine IMA201) expressing a T-cell receptor recognizing a cancer/germline antigen in patients with squamous NSCLC or HNSCC.

2018;36(suppl 5S; abstr TPS78). meetinglibrary.asco.org/ record/156705/abstract.

Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia.

2014;371(16):1507-1517. doi: 10.1056/NEJMoa1407222.

Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma.

2015;373(11):1040-1047. doi: 10.1056/ NEJMoa1504542.

Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas.

2017;377(26):2545-2554. doi: 10.1056/ NEJMoa1708566.

Papa S, Adami A, Metoudi M, et al. T4 immunotherapy of head and neck squamous cell carcinoma using pan-ErbB targeted CAR T-cells.

2017;77(suppl 13):abstr CT118. doi: 10.1158/1538-7445.AM2017-CT118.

Early trial results show potential for T-cell therapy in head and neck cancer. Targeted Oncology website. targetedonc.com/news/early-trial-results-show-potentialfor- car-tcell-therapy-in-head-and-neck-cancer. Published April 20, 2017. Accessed March 26, 2018.

Parkhurst MR, Yang JC, Langan RC, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis.

2011;19(3):620-626. doi: 10.1038/mt.2010.272.

Zhang S, Chen L, Cui B, et al. ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth.

2012;7(3):e31127. doi: 10.1371/journal.pone.0031127.

Cui B, Zhang S, Chen L, et al. Targeting ROR1 inhibits epithelialmesenchymal transition and metastasis.

2013;73(12):3649-3660. doi: 10.1158/0008-5472.CAN-12-3832.

Chien HP, Ueng SH, Chen SC, et al. Expression of ROR1 has prognostic significance in triple negative breast cancer.

2016;468(5):589-595. doi: 10.1007/s00428-016-1911-3.

Zhang H, Qiu J, Ye C, et al. ROR1 expression correlated with poor clinical outcome in human ovarian cancer.

Liu Y, Yang H, Chen T, et al. Silencing of receptor tyrosine kinase ROR1 inhibits tumor-cell proliferation via PI3K/AKT/mTOR signaling pathway in lung adenocarcinoma.

2015;10(5):e0127092. doi: 10.1371/journal.pone.0127092.

Karachaliou N, Gimenez-Capitan A, Drozdowskyj A, et al. ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer patients with the EGFR T790M mutation.

2014;3(3):122-130. doi: 10.3978/j. issn.2218-6751.2014.03.02.

Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy.

2015;5(12):1282-1295. doi: 10.1158/2159-8290.CD-15-1020.

Adoptive Immunotherapy Makes Inroads in Head and Neck Cancers, But Challenges Remain

Reactivation of the tumor suppressor gene

) reverted colorectal cancer cells back to normal intestinal tissue in mice, according to a recent preclinical study.

on June 18, 2015, and suggest a novel mechanism for treating colorectal cancer through the Wnt pathway, which is central to proliferation, migration, and survival in various types of cells.

Colorectal cancer is the second leading cause of death in developed countries,

and &ldquo;[current] treatment regimes for advanced colorectal cancer involve combination chemotherapies that are toxic and largely ineffective,&rdquo; said Scott Lowe, senior study author from Memorial Sloan Kettering Cancer Center, in a press release. According to the researchers, modulating gene activity may provide a new avenue for more durable, less toxic cancer therapies.

Up to 90% of colorectal tumors contain a mutation in

lead to excess activity of the Wnt signaling pathway, leading to uncontrolled cell proliferation in the colon. However, completely blocking Wnt signaling would be &ldquo;severely toxic&rdquo; to normal intestinal cells, according to Lowe.

Lead author Lukas Dow, PhD, of Weill Cornell Medical College stated in an interview with

reactivation in the current study was to &ldquo;dampen,&rdquo; not eliminate, the activity of the Wnt pathway so that the tumor cells behaved similarly to normal intestinal cells.

&ldquo;We were looking for ways to re-engage this natural tumor suppressor mechanism,&rdquo; said Dow.

Restoring function to mutated genes has been challenging because the resulting excess gene activity can cause problems to normal cells. To circumvent this difficulty, Dow and his colleagues used a mouse model of colorectal cancer in which

was directly and reversibly suppressed using a doxycycline-regulated small hairpin (sh)RNA.

suppression in the mice activated the Wnt pathway and led to development of adenomas in the colon and small intestine. Reactivation of Apc normalized Wnt activity, halted proliferation of tumor cells, and restored normal function in the intestinal cells after 4 days. The adenomas regressed and reintegrated into normal tissue within 2 weeks, a response that was sustained 6 months later.

Although the results from Dow and his colleagues suggest a relatively durable response, he notes that the shorter overall lifespan of the mouse must be accounted for when predicting long-term response in humans. Furthermore, tumor cells often develop resistance to initially effective therapies over time, and this acquired resistance is a common problem with current methods of cancer treatment.

&ldquo;We don&rsquo;t know the types of resistance mechanisms that may arise from [modulating the Wnt pathway], said Dow. &ldquo;We intend to predict that [in future research]. We need to understand what types of [mechanisms] might allow for resistance of these tumors if we were to target the Wnt pathway with a therapy,&rdquo; said Dow.

Although the researchers induced selective

that lead to colorectal cancer vary in humans. The mutations in humans tend to cluster around a similar region within the gene, but Dow stated that even slight variations in human

mutations could potentially affect the rate of tumor progression and response to therapy. According to Dow, understanding this relationship will be important for developing effective therapies targeting

&ldquo;In human colorectal cancer, there are lots of different types of mutations that can occur in the gene,&rdquo; said Dow. &ldquo;For technical reasons, researchers haven&rsquo;t been able to recreate these mutations in mouse models [in the past], and that&rsquo;s something we&rsquo;re actively doing right now.&rdquo;

New methods published in the past few years allow creation of mice that express specific types of gene mutations that occur in human cancer. According to Dow, these methods can be used to inspect the different types of

mutations, and ultimately their &ldquo;functional consequence.&rdquo;

mutations are relatively unique to colorectal tumors. Nevertheless, Dow indicated disruption of the downstream Wnt pathway can occur in multiple tumor types, including lung, breast, and liver cancer, but through mutations in different modulators of the pathway. He stated that understanding why certain mutations tend to develop in particular tumor types may help develop specific therapies that regulate the Wnt pathway.

Furthermore, understanding how tumor growth and progression is regulated in the 10% of colorectal tumors that do not have

mutations could provide information for development of individualized therapies.

&ldquo;Up to 90% of human colon cancers have mutations in

, but that means that 10% don&rsquo;t,&rdquo; said Dow. &ldquo;There are many ways for a cell to become a tumor [cell] without mutations in

. We think they are almost all dependent on the Wnt pathway, but we have not tried to modulate the pathway much [in the clinical setting].&rdquo;

Dow LE, O&rsquo;Rourke KP, Simon J, et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer.

http://meyercancer.weill.cornell.edu/news/2015-06-18/single-gene-turns-colorectal-cancer-cells-back-normal-tissue-mice

Jemal A, Bray F, Center MM, et al. Global cancer statistics.

Brannon AR, Vakiani E, Sylvester BE, et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions.

Reactivation of the tumor suppressor gene adenomatous polyposis coli (Apc) reverted colorectal cancer cells back to normal intestinal tissue in mice, according to a recent preclinical study.

Activation of Apc Reverted Colorectal Cancer Cells Back to Normal Tissue

On February 13, 2015, the FDA approved lenvatinib (Lenvima) for treatment of locally recurrent or metastatic differentiated thyroid cancer (DTC) that is refractory to radioactive iodine therapy (RAI).

The approval gives clinicians a therapy to treat a common form of advanced thyroid cancer that is often resistant to conventional treatment.

R. Michael Tuttle, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center in New York City, discussed the results of the phase III SELECT trial that led to the approval of lenvatinib and how this agent will influence future treatment of advanced thyroid cancer.

Lenvatinib is a tyrosine kinase inhibitor (TKI) that potently inhibits activity of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3), as well as fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor alpha (PDGFR&alpha;), KIT, and RET. According to Tuttle, the multitargeted nature of lenvatinib and other TKIs is beneficial in targeting a broad patient population that may have distinct mutations in their tumors.

&ldquo;If [the patient] fails to respond to one [TKI] inhibitor, you can just move onto the next one,&rdquo; said Tuttle. &ldquo;Even though [the drugs are] in the same group of kinase inhibitors, [the receptors] they inhibit can be different.&rdquo;

Mutations within the tumor itself also likely play a role in the effectiveness of lenvatinib. Before choosing a drug to use, Tuttle&rsquo;s institution performs sequencing of the tumor to predict whether or not a particular agent may be effective.

&ldquo;We have found 351 mutations, all of which have a targetable drug to use against that mutation,&rdquo; said Tuttle. &ldquo;We&rsquo;re trying to be smarter about which one of these drugs to use.&rdquo;

However, Tuttle also indicated that all potent VEGF inhibitors, including lenvatinib, tend to produce hypertension and proteinuria, which will have to be followed in ongoing safety analyses. Furthermore, lenvatinib likely interacts with other targets that are not fully understood, which may explain differences in toxicity profile, tolerability, and activity among patients.

was a phase III, multicenter, randomized, double-blind, placebo-controlled study that investigated the efficacy of lenvatinib in patients with progressive RAI-refractory DTC. A negative RAI scan with structural disease was a straightforward indication of RAI-refractory disease and fulfilled the inclusion criteria for the trial. However, patients also qualified if they had a positive RAI scan with evidence of progression within 12 months of RAI therapy or a cumulative RAI activity greater than 600 mCi with the last RAI dose administered at least 6 months prior to study entry.

According to Tuttle, these last 2 inclusion criteria were important considerations for identifying refractory disease. He indicated that even though some of the lesions were &lsquo;RAI-avid,&rsquo; the RAI therapy was not sufficient to halt progression of the disease in these patients. Furthermore, patients who required treatment with high doses of radioactive iodine were likely to be refractory to RAI. Therefore, both of these groups of patients should be considered RAI-refractory and thus, candidates for lenvatinib, Tuttle suggested.

A total of 261 patients received lenvatinib (24 mg/day in 28-day cycles), and 131 received placebo with an opportunity to receive lenvatinib upon disease progression. The median age among all patients was 63 years, and 99% of them had metastasis (89% in the lungs, 52% in the lymph nodes, 39% in the bone, 18% in the liver, and 4% in the brain).

Patients who received lenvatinib had a median progression-free survival (PFS) of 18.3 months, which was significantly longer than the 3.6 months in the placebo group. Objective response rates (the sum of the partial and complete response rates) were 65% for the lenvatinib-treated group versus 2% for the placebo group. Tuttle noted that these substantial differences between the treatment and placebo groups highlights the effectiveness of lenvatinib in treating patients with rapidly progressing, treatment-refractory thyroid cancer.

&ldquo;The patients in this trial are probably the sickest you&rsquo;d find in practice,&rdquo; said Tuttle. &ldquo;It makes the PFS data in the treatment group that much more impressive.&rdquo;

The most common adverse reactions (AEs) associated with lenvatinib included hypertension, fatigue, diarrhea, decreased appetite, and proteinuria. Hypertension was particularly common, occurring in 73% of patients on lenvatinib and required dose reductions in 13% of patients. Therefore, Tuttle emphasized the importance of normalizing the patient&rsquo;s blood pressure before lenvatinib treatment and monitoring it at weekly or biweekly intervals.

Tuttle also emphasized that many patients who will take lenvatinib are likely to have health complications and take other drugs unrelated to their thyroid cancer diagnosis. Therefore, the oncologist must be aware of patients&rsquo; changing clinical status when monitoring their response to lenvatinib and adjust the dosage accordingly if an AE occurs.

&ldquo;It&rsquo;s important to see the big picture when treating these patients,&rdquo; said Tuttle.

Tuttle also indicated that lenvatinib is intended to be a &lsquo;static agent,&rsquo; and patients should continue to take it as long as it is effective and does not result in serious AEs. However, dose interruptions from AEs is common and a single occurrence of an AE should not preclude usage permanently, Tuttle said.

&ldquo;We don&rsquo;t give up on it,&rdquo; said Tuttle. &ldquo;We want to keep patients on a dose as long as we can, because that is probably the best way to treat them.&rdquo;

Factors to Consider When Prescribing Lenvatinib

Tuttle indicated that serious AEs may require a patient to take a lower dose (for example, a decrease from 24 mg to 20 mg after the first occurrence of an AE) but that the dose can be titrated back up as long as it is tolerable for the patient.

Tuttle stated that identifying whether the patient is truly refractory to RAI is important, because incorrect or inappropriate methods of test administration can falsely identify patients as refractory. Tuttle indicated that radioactive iodine is still preferable for patients who respond to it because it has been used successfully for a longer time than has lenvatinib.

Patients who take lenvatinib should also have progressive disease and the drug is not recommended for those who have no or very slow progression. One of the clinical challenges, according to Tuttle, is determining when a clinician should administer lenvatinib during disease progression. Generally, other methods of management, such as surgery and external beam radiation, are preferred for disease that is localized in the neck area, according to Tuttle. Other contraindications for lenvatinib include rising thyroglobulin levels, tumors that can be surgically resected, or use in those patients who have a single metastasis that can be targeted with external beam radiation.

&ldquo;[Tyrosine kinase inhibitors] are great drugs,&rdquo; said Tuttle. &ldquo;But if I can keep patients off of them for as long as possible, that is what I would like to do.&rdquo;

U.S. Department of Health and Human Services. FDA News Release: FDA approves Lenvima for a type of thyroid cancer. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm434288.htm. Accessed March 6, 2015.

Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630.

Approval of Lenvatinib for Advanced Thyroid Cancer: Clinical Implications

According to a recent descriptive analysis of the Veterans Administration (VA) Corporate Data Warehouse, veterans who reported Agent Orange exposure had higher rates of thyroid cancer compared to the overall national VA health care patient population.

Lead investigator Karen T. Le, MD, an endocrine fellow at Cedars Sinai Medical Center and VA Greater Los Angeles Healthcare Center in Los Angeles, California, presented these findings on March 6, 2015, at The Endocrine Society&rsquo;s 97th Annual Meeting in San Diego, California.

The incidence of thyroid cancer nearly tripled between 1975 and 2009 (from 4.9 to 14.3 per 100,000 people). Although improved methods of detection have contributed in part to this increase, Le and her colleagues hypothesize that the VA patient population may have additional risk factors, such as Agent Orange exposure, that may contribute in part to increased prevalence of thyroid cancer.

US soldiers used Agent Orange, a mixture of two herbicides (2,4,5-trichlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid) that was contaminated by the toxin 2,3,7,8-tetrachlorodibenzodioxin (TCDD) during manufacturing, to destroy foliage hiding North Vietnamese troops during the Vietnam War. According to Le, TCDD is a known carcinogen, and Agent Orange exposure has been associated with numerous forms of cancer, including Hodgkin&rsquo;s disease, non-Hodgkin&rsquo;s lymphoma, and soft tissue sarcomas.

However, the relationship between thyroid cancer and Agent Orange exposure in the veteran population has not been clarified. Le and her colleagues performed a descriptive analysis of the VA Corporate Data Warehouse database from all U.S. Veterans Health Administration (VHA) health care sites from October 1, 1999, to December 31, 2013.

She and her colleagues used the 193 diagnosis code from the The International Classification of Diseases, 9th Revision (ICD-9) to identify 19,592 veterans who had been diagnosed with thyroid cancer over the 14-year study period, of which 42% were Vietnam era veterans. Self-reported exposure to Agent Orange was significantly higher in patients with thyroid cancer (10.0%) than in those in the general VHA population (6.2%).

&ldquo;We will need further studies to determine whether this is a cause-and-effect relationship between Agent Orange exposure and thyroid cancer,&rdquo; said Le. &ldquo;But we wanted [this study] to increase awareness of the possible correlation.&rdquo;

The prevalence rate in veteran men (1:1023) was similar to that of the U.S. general population in 2011 (1:1219). The veteran women had a lower prevalence rate (1:1114) than their nonveteran counterparts in 2011 (1:350). However, Le noted that the small number of female veterans (14% of the total cohort) may have biased the results and limited the ability to draw conclusions.

&ldquo;The VA [database] is a very male-dominated compilation of patients, so when it comes to any type of female correlation, we have to be very careful with our analyses,&rdquo; said Le.

Although the relationship between Agent Orange exposure and thyroid cancer seems plausible, Le indicated that more studies in different populations are needed to confirm this association. For example, Le stated that she and her colleagues are investigating whether farm workers who work with herbicides have a higher incidence of thyroid cancer and whether the characteristics of those patients are similar to the ones in the VA database. However, she indicated that Agent Orange exposure is limited to Vietnam era veterans and farm workers who were accidentally exposed, which may limit the generalizability of the association.

According to Le, veterans may be eligible to receive special health care benefits and services if they suffer from conditions, such as non-Hodgkin&rsquo;s lymphoma and certain respiratory cancers, linked to Agent Orange exposure during their military service. Although the results from this study alone would not be sufficient to establish such benefits for thyroid cancer, she hopes they increase awareness about the possible link between Agent Orange exposure and thyroid cancer.

Although the current study did not investigate the relative proportions of thyroid cancer types, which was partially due to the highly confidential nature of the VA database, Le stated that one of the next goals for her and her colleagues is to analyze different cohorts and the histological subtypes associated with Agent Orange exposure, as well as the overall survival trends and treatments among these subtypes.

&ldquo;I think it will be really helpful to get that data to shine some more light on the [mechanism behind Agent Orange exposure and development of thyroid cancer],&rdquo; said Le.

Le KT, Sawick MP, Want MB, et al. High Prevalence of Agent Orange Exposure Among Thyroid Cancer Patients in the National VA Healthcare System. Database. Presented at: The Endocrine Society&rsquo;s 97th Annual Meeting (ENDO 2015); March 5-8, 2015; San Diego, CA. Abstract FRI-040.

According to a recent descriptive analysis of the VA Corporate Data Warehouse, veterans who reported Agent Orange exposure had higher rates of thyroid cancer compared to the overall national VA health care patient population.

Exposure to Agent Orange Associated With Increased Prevalence of Thyroid Cancer in Veterans

According to a recent retrospective cohort analysis of a large national database, patients with a history of breast cancer have a higher risk of developing thyroid cancer than do the general population, particularly if they receive adjuvant radiation therapy.

Lead investigator Jennifer H. Kuo, MD, assistant professor of surgery at Columbia University, New York City, presented these findings on March 5, 2015, at The Endocrine Society&rsquo;s 97th Annual Meeting in San Diego, California.

&ldquo;There should be a greater awareness [of the link between the cancers] so patients can be treated appropriately in a timely manner,&rdquo; said Kuo.

Although several single-institution studies have proposed an increased risk of thyroid cancer in patients with a history of breast cancer, analysis of a population-based sample across multiple institutions had not been performed previously. The retrospective analysis by Kuo et al1of the National Cancer Institute&rsquo;s Surveillance, Epidemiology, and End Results 9 (SEER 9) investigated data in patients diagnosed with breast and/or thyroid cancer from 1973 to 2011.

This study included data on 707,678 patients with breast cancer and 49,663 patients with thyroid cancer. Of these, 1526 patients had developed thyroid cancer after a diagnosis of breast cancer. These patients were compared with patients who developed only breast or only thyroid cancer, respectively.

Although Kuo indicated that multiple factors likely play a role for the association between the 2 cancers, she stated that adjuvant radiation therapy for breast cancer probably contributes to future development of thyroid cancer. A greater proportion of patients who developed thyroid cancer after breast cancer received adjuvant radiation therapy compared with those with breast cancer only (47.9% vs 44.0%,

Patients who subsequently developed thyroid cancer also had smaller breast cancer tumors (15.0 &plusmn; 0.52 mm vs 18.0&plusmn;0.03 mm,

<.001), and a greater percentage had invasive ductal carcinoma (7.6% vs 5.5%,

= .002) than did patients with breast cancer only. According to Kuo, patients with smaller tumors generally tend to receive lumpectomy followed by adjuvant radiation therapy, while patients who have larger tumors often have a mastectomy (which does not require adjuvant radiation therapy).

&ldquo;The pendulum has definitely swung toward breast conservation therapy [for treatment of breast cancer], and that has only been made possible with radiation therapy,&rdquo; said Kuo.

The researchers also found that patients with thyroid cancer and a history of breast cancer had a greater incidence of tall-cell variant papillary, oxyphilic variant follicular, or anaplastic thyroid cancers. Kuo stated that these more aggressive forms of thyroid cancer are often associated with previous radiation exposure.

According to Kuo, the median interval between the diagnosis of breast and thyroid cancers (5.0 &plusmn; 0.1 years) is consistent with general findings on radiation-induced cancers, which further supports a potential link between radiation therapy for breast cancer and subsequent development of thyroid cancer. However, according to Kuo, this link does not suggest a need for alternatives to current indications for radiation therapy in breast cancer.

&ldquo;I don&rsquo;t think it&rsquo;s a big enough argument to make against adjuvant radiation therapy [for treatment of breast cancer],&rdquo; said Kuo.

Although the study did not investigate the contribution of systemic factors, Kuo pointed to the possible influence of estrogen in both cancers. She indicated that hormones, particularly estrogen, are likely involved in development of breast cancer and that some literature supports a link between estrogen and incidence of thyroid cancer.

Kuo plans to investigate whether tamoxifen, a common therapeutic agent used for 5 years after breast cancer diagnosis, is associated with an increased risk of thyroid cancer. Although Kuo indicated the mechanism responsible for a potential link is unclear, she suggested it may be related to estrogen.

&ldquo;We do know tamoxifen is estrogen related, and there is evidence to suggest that estrogen increases the incidence of thyroid cancer,&rdquo; said Kuo.

According to Kuo, the study results indicate that patients with a history of breast cancer should receive a dedicated thyroid examination every year for the first 5 years after breast cancer diagnosis, particularly if they had received radiation therapy for breast cancer. Furthermore, Kuo indicated that researchers must have an improved understanding of the etiology behind the rising incidence of thyroid cancer following breast cancer to improve diagnosis and treatment.

Kuo JH, Chabot JA, Terry MB, et al. Increased Incidence of Thyroid Cancer Among Breast Cancer Survivors: An Analysis of the SEER-9 Database. Presented at: The Endocrine Society&rsquo;s 97th Annual Meeting (ENDO 2015); March 5-8, 2015; San Diego, CA. Abstract THR-049.

Patients with a history of breast cancer have a higher risk of developing thyroid cancer than do the general population, particularly if they receive adjuvant radiation therapy.