OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Although lung cancer still causes more deaths than any other type of malignancy not only in the United States but throughout the world, there’s a sense of excitement in the air these days when it comes to helping people with this disease.

The reasons for that spirit of optimism are evident. The pace of discovery in this eld during the past 5 years has been truly breathtaking with the expansion of targeted therapies, where there are now several classes of agents available, and the growth of immunotherapy, which once was considered a poor strategy for this tumor type.

The milestones of this changing landscape are featured throughout this issue of 

Our cover package, “The New First Line in NSCLC: Fresh Views on 3 Fronts,” provides expert insights on the many questions generated by the wealth of new approaches now available to clinicians.

Remarkably, the conversation about which of these therapies to employ in the front line for patients with advanced or metastatic disease is being conducted simultaneously in 3 key areas: EGFR inhibitor therapy, ALK inhibitor treatment, and immunotherapy.

For a taste of the future, we direct your attention to the Clinical Trial Spotlight, titled “Tepotinib Takes Aim at Novel 

Mutation in Lung Cancer Trial.” The ability to sequence the lung cancer genome has resulted in the identification of a 

skipping mutation that seems to respond well to inhibitors directed at this pathway. If this trial and other clinical studies succeed, another group of patients will be able to benefit from biomarker- driven therapy.

Finally, the quest to personalize immunotherapy is the subject of our Precision Medicine in Oncology® offering, “Dual Biomarker Signature Holds Predictive Promise for Response to Anti-PD-L1 Therapy in NSCLC.”

This is a vital undertaking for the academic and industry research establishments. We can’t expect public or private insurers to pay for expensive therapies without a better idea of which patients would most benefit from them—just as we can’t expect patients to forgo a potentially life-altering drug unless there is a high degree of certainty that it would not help them.

As we wind up another year of oncology drug development, there are more reasons than ever to be hopeful. We know, of course, that hundreds of thousands of people worldwide are still dying of this disease. So when there’s forward progress, we like to celebrate—and then keep on pushing for greater advancements.

Thank you for sharing this journey with us.

Articles

A Time for Hope

Significant progress has been made in recent years in understanding the biology and treatment of neuroendocrine tumors (NETs). The latest research indicates that NETs should not be approached and treated as a single disease. Extensive biological differences based on histology, primary site of the tumor, and numerous other factors have been shown to influence prognosis and response to treatment. Thus, these details must be considered when designing clinical trials and developing novel therapies.

: Please highlight some of the main points from your presentation.

, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at the recent 2016 Chemotherapy Foundation Symposium, and shed light on the progress that has been made in this treatment landscape.

: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.

What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?

Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival [OS] as an endpoint, we’re certainly seeing evidence of improvement in outcomes.

The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.

The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.

Are we getting better at diagnosing and managing the treatment of NETs?

The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in OS, which we hope will be confirmed upon final analysis.

Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.

We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.

With sequencing, what are the main questions that we're still trying to answer?

And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.

If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed thera- pies are still an option.

For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice.

Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?

Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?

It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.

There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.

One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future.

There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to—being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.

Significant progress has been made in recent years in understanding the biology and treatment of neuroendocrine tumors.

Expert Discusses Recent Progress in NET Management

The growing incidence of primary liver cancer in the United States poses a great therapeutic challenge. Despite the plethora of new treatment options that have been tested, only a single targeted therapy is approved by the FDA for the treatment of the majority of patients who present with advanced-stage disease. Consequently, survival rates remain comparatively low.

Multiple phase III failures of promising drugs have led to the suggestion that a therapeutic plateau has been reached and that a vastly improved understanding of the molecular mechanisms of liver cancer will be necessary to drive new treatment paradigms.

Genome sequencing studies are helping to advance this goal but have highlighted key treatment challenges. In addition to the extensive heterogeneity both among and within tumors, differences in the underlying disease etiologies can significantly impact the types of potentially targetable events. Moving forward, these challenges need to be addressed in order to improve patient outcomes.

Primary liver cancer is not the most common type of cancer, but it does result in the second most common cause of cancer-related mortality worldwide, indicative of the significant treatment challenge posed by this malignancy. In recent years, the incidence of liver cancer has dramatically increased, particularly in the United States, and rates are expected to double again over the course of the next several decades.

Liver cancer typically manifests as hepatocellular carcinoma (HCC), arising from hepatocytes, which accounts for up to 85% of cases. The next most common form, intrahepatic cholangiocarcinoma (IHCC), is relatively rare in comparison; IHCC originates from the biliary tract epithelial cells in the bile duct or the liver.

The prognosis for most patients is poor, in large part due to a lack of effective surveillance techniques and limited treatment options for patients diagnosed with advanced-stage disease. Among the 30% to 40% of patients diagnosed at an early stage, surgical resection, liver transplantation, and ablative techniques offer a potentially curative option. The vast majority of patients, however, are not eligible for these treatments and advanced liver cancer is also notoriously chemo- and radioresistant, resulting in a 5-year overall survival (OS) rate of less than 10%.

The dearth of effective treatment options for these patients is not for lack of trying, but the highly complex nature of liver cancer is a major impediment to the development of new therapies. It almost always occurs against a background of underlying liver disease: liver cirrhosis is found in 80% to 90% of cases and is widely recognized as a key step in the pathogenesis of liver cancer.

Liver cancer has some of the most well-defined risk factors for any cancer. Although it is most commonly related to infection with the hepatitis B (HBV) and C viruses (HCV), other prevalent risk factors include alcohol consumption and obesity, both of which are growing concerns in developed countries in particular. The dominant risk factors vary according to geographic region and ethnic background, but all create an environment of chronic inflammation and liver damage that often leads to cirrhosis.

Ultimately, permanent damage to the hepatocytes prompts massive compensatory cell proliferation and regeneration, inducing genetic and epigenetic damage to the patient’s genome and fostering a highly carcinogenic environment. The process of hepatocarcinogenesis is a complex, multistep event that is still not fully understood, but several key signaling pathways have been closely linked to it.

The mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathways are the 2 major signaling cascades implicated in HCC development. It is also known to be a highly angiogenic tumor, with a dramatic alteration in arterial vascularity observed in many HCCs.

Thus, the MAPK and PI3K pathways, in addition to the major angiogenic pathways, have been the focus of targeted therapy development for HCC. So far, success has been limited to the multitargeted tyrosine kinase inhibitor sorafenib (Nexavar).

In the 2008 SHARP trial, sorafenib, which blocks components of both the MAPK pathway and VEGF and PDGF receptors that regulate angiogenesis, demonstrated improved OS of almost 3 months, with a manageable toxicity profile in patients with advanced-stage disease. Sorafenib has become standard of care for unresectable, nonablatable, advanced disease; however, in most cases, tumors begin to grow again after less than 6 months.

After multiple phase III failures, hopes are high that regorafenib (Stivarga) will soon join the list of approved therapies. The antiangiogenic multi-kinase inhibitor demonstrated efficacy as second-line therapy for HCC in the phase III RESORCE trial, in which median OS was 10.6 months with regorafenib plus best supportive care compared with 7.8 months for placebo plus best supportive care. This represented a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.50-0.79; 

Genome sequencing studies have begun to identify more of the key molecular drivers of HCC. Thousands of samples have been sequenced and the findings have implicated a number of important cellular processes and pathways in the development of primary liver cancer.

In terms of the types of mutations that are observed, similar to other solid tumors, C:G>T:A transitions are most prevalent. However, in contrast to other tumor types, T:A>C:G transitions and C:G>A:T transversions are also common, which gives HCC a unique mutation signature. Meanwhile, the frequency of mutations is similar to that of other solid tumors, averaging around 4 mutations per megabase, but there is significant variability in the exact number observed from study to study.

Whole-genome and -exome studies have confirmed findings from earlier sequencing studies that 

 is the most frequently mutated oncogene and 

 is the most frequently mutated tumor suppressor gene in HCC. The overall mutation frequency of 

 is 20% to 30%, but these mutations have been shown to be associated with the underlying disease etiology, with fewer 

 mutations observed in HBV-positive tumors. 

 is mutated in 30% to 40% of HCC tumors, overall, but in contrast to 

, it is most frequently associated with HBV-positive disease.

In addition to frequent mutations in the 

 gene, genome sequencing studies have revealed that numerous other components of the p53 pathway are mutated or otherwise altered in HCC. For example, the p53-activating kinases ATM and RPS6KA3 have also been reported to be significantly mutated, although not at the frequency of the 

The p53 protein is a tumor suppressor whose broad function is to maintain genome stability by regulating a number of different cellular processes, including DNA repair and the cell cycle. One result of inactivating mutations in 

, therefore, is a loss of cell cycle regulation.

It turns out that dysregulation of the cell cycle at the molecular level may be a characteristic of HCC, as numerous other cell cycle alterations have been detected. These include amplification of the cyclin D1 gene 

 and deletion of negative regulators of the cell cycle, such as 

. Overall, more than 70% of HCCs are thought to have alterations in the component genes of the p53 pathway or the cell cycle.

 gene encodes the beta-catenin protein, a central mediator of the beta-catenin or Wnt pathway within the cell. Vital for embryonic development, this signaling cascade has myriad roles in adult cells, reflected by its frequent association with cancer.

 gene, other components of Wnt signaling are also frequently mutated in HCC. These predominantly involve the 

 genes, which negatively regulate the beta-catenin protein through posttranslational modification. It is estimated that more than 65% of HCCs show Wnt signaling-related alterations, strongly implicating this pathway in the development of HCC and presenting a potential therapeutic target.

The most common mutation overall in HCC is not an activating or inactivating mutation in an oncogene or tumor suppressor, but a mutation in a non-coding part of a gene. Specifically, more than half of all HCCs display mutations in the promoter region of the telomerase reverse transcriptase (

Normal cells are only able to undergo a finite number of cell divisions before they enter a senescent state, in which they no longer divide or grow. In large part, this is regulated by the length of caps on the end of the DNA, known as telomeres, which get progressively shorter with each division.

Cancer cells have acquired the capacity to maintain their telomeres. which allows them to achieve “immortality,” with an unfettered ability to grow and divide. The vast majority of cancers do this by reactivating the telomerase enzyme that is responsible for adding telomere sequences to the end of the DNA. The 

 gene encodes the catalytic core of this enzyme.

, a recent study looked at mutations in other noncoding regions of the HCC genome. A significant number of mutations were observed in 29 regions, implicating 6 long intergenic noncoding RNA genes, among them 

 genes; and 9 untranslated regions (UTRs; the area just upstream of the start of a protein-coding sequence that has an important role in protein translation), including those of the 

 promoter mutations represent the most commonly mutated genes in HCC, a second group of genes has been identified in genome sequencing studies. Individually, these genes are far less frequently mutated in HCC samples, but collectively they impact several key pathways.

Most numerous in this group are mutations in genes that affect chromatin remodeling. When the cell is not actively dividing, the DNA is wound tightly around histone proteins to form chromatin. Chromatin remodeling alters the way the DNA is packaged and controls the accessibility of genes for transcription, thereby regulating gene expression.

Overall, alterations in genes regulating chromatin are observed in half of all HCCs. Most often, these are inactivating mutations in genes that make up the SWI/SNF chromatin remodeling complex, including 

, in addition to less frequent mutations in other components, such as 

 mutations were observed more often in HCV-associated HCC, while 

 mutations occurred more commonly in alcohol-related cases.

Another HCC group contains a large number of genes that are mutated in less than 10% of samples. This “long-tail effect,” in which the vast majority of significantly mutated genes occurs at low frequencies, is common across tumor types, particularly in those with substantial mutational heterogeneity. It represents one of the most significant issues limiting the development of targeted therapy.

Interestingly, among HCCs, this group of mutations appears to be made up of many genes involved in growth factor signaling. This could help to explain the apparent promise of targeting growth factor signaling pathways in HCC, but the difficulties experienced in achieving success in the clinic thus far.

Alterations in drug target kinases are rare and mutations in growth factor signaling are mostly represented by those in the 

 genes are rare and, when mutations are observed, they typically are not the same types of mutations commonly observed in other tumor types.

 gene amplification and protein overexpression is also rare in HCC, yet the EGFR, RAS, and PI3K pathways have all been demonstrated to play a role in the development of HCC. Exactly how they are involved, however, remains unclear, although there are suggestions they may be activated in other ways.

For example, mutations were observed in the 

 gene, which encodes the ERBB receptor feedback inhibitor 1, a protein that inhibits the kinase activity of EGFR and HER2. Thus, this mutation may remove that inhibitory activity and drive activation of these pathways. In addition, mutations in the 

 genes that could activate the mTOR protein have also been reported.

More than 80% of HCCs are associated with HBV or HCV infection, with HBV being most common worldwide. Since these are DNA viruses, one of the ways in which they drive HCC development is by integrating their viral DNA into the host genome. In a manner similar to other types of genetic damage, this can alter the expression and function of host genes and induce genomic instability.

Several genome sequencing studies have begun to examine the consequences of HBV integration. Among the hundreds of integration sites that have been identified, there is a significant overrepresentation of coding or promoter regions, suggesting that HBV integration confers a growth advantage by regulating host gene expression.

Cell Cycle, Adhesion, and Oxidative Stress

The most common integration sites involve the 

 genes, strongly implicating telomere stability and the cell cycle in the development of HCC. These integration events were shown to significantly increase the transcription and expression of these genes. In addition, the number of HBV integration sites was significantly associated with more aggressive disease and poorer prognosis.

Other categories of mutations that have been identified include dysregulation of the cell cycle at the G1/S checkpoint through inactivation of the 

 genes, and aberrations in genes that regulate adhesion molecules involving the epithelial cells (EpCAM).

Wide-Ranging Implications of Heterogeneity

Additonally, there is oxidative stress resulting from an imbalance between the generation of reactive oxygen species and the body’s ability to neutralize them or repair the resulting damage. When this occurs, cells orchestrate an adaptive response that functions to counter the effects and restore balance.

By unraveling the genomic alterations underlying HCC, a picture of significant heterogeneity has emerged, with only a few common driver mutations identified in the majority of patients and a plethora of genes that are infrequently mutated.

Studies have also shown that HCC develops through clonal evolution, resulting in significant heterogeneity even within the same tumor. Although the majority of abnormalities are found across multiple regions of a single tumor, representing a common genetic basis for tumor development, each tumor region also acquires independent mutations.

Heterogeneity has important implications for the development of new drugs and is likely one of the principal reasons that genomic findings have not, as of yet, translated into any significant therapeutic progress. It also impacts the development of biomarkers if these molecular alterations are not identified uniformly across or within tumors as this may lead to differential responses to therapy.

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The growing incidence of primary liver cancer in the United States poses a great therapeutic challenge.


Mutational Complexity Reflects Treatment Challenges for Hepatocellular Carcinoma

Gastroesophageal cancer (GEC) is a complex disease, encompassing cancers with different histological and molecular subtypes. Growing insight into the molecular biology of GEC is poised to change the treatment landscape for this disease, although many questions remain unanswered.

 recently assembled a distinguished panel of experts to discuss the evolving treatment paradigm for advanced GEC. In addition to discussing the complex epidemiology of GEC, the Peer Exchange panel reviewed findings from studies of emerging therapeutic regimens.

Classes of targeted agents that have shown promise for GEC include monoclonal antibodies, antiangiogenic agents, and immunotherapy drugs. Some targeted therapies, such as trastuzumab (Herceptin) and ramucirumab (Cyramza), have already been approved for certain types of GEC.

To add context to recent developments in managing GEC, it helps to understand the different cancer subtypes and their geographic distribution. Although GEC is rare in the United States, it is relatively common in Asian countries.

Ian Chau, MD, FRCP, noted that gastric cancer is the third most common cause of cancer death in Asia and the second most common cause if esophageal cancer is included.

Esophageal cancer is divided into 2 histological subtypes: squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Whereas ESCC is the predominant subtype in Asia and developing countries, EAC accounts for most US cases of esophageal cancer.

During the past several years, the incidence of EAC, which primarily affects the lower esophagus (the gastric junction), has been increasing in Western countries, including in the United States.

 “A lot of it is because of gastroesophageal reflux disease, and that might be related to obesity, which is becoming more and more common in the Western world,” Chau said.

In 2014, the Cancer Genome Atlas (TCGA) completed a molecular evaluation of 295 gastric adenocarcinomas and proposed 4 major subtypes of gastric cancer

Epstein-Barr virus—associated tumors, most of which contain 

 mutations, have excessive DNA hypermethylation, and overexpress JAK2, PD-L1, and PD-L2

Microsatellite unstable tumors, which can also have 

 mutations and commonly overexpress HER2 or EGFR

Genomically stable gastric cancers, characterized by 

Tumors with chromosomal instability, including 

 mutations and RTK-RAS, VEGFR, and p110 amplifications

​The TCGA analysis and subsequent studies carried out by other research groups have identified several potential therapeutic targets in GEC. Approved therapies already exist for some of these targets, but must still be validated in patients with GEC. Researchers are also investigating whether novel targeted agents alone or in combination can prolong survival and reduce the unwanted toxicities of systemic chemotherapy.

Immune checkpoint inhibitors prevent cancer cells from initiating a signaling cascade that ultimately blunts the response of activated T cells to the cancer. “The whole concept of immunotherapy is where you get your own immune system to attack the tumor,” said Johanna C. Bendell, MD, who served as moderator for the Peer Exchange discussion.

The first checkpoint inhibitors were approved to treat advanced melanoma, and subsequently for lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, and bladder cancer.

 Checkpoint inhibitors are currently being studied in a host of other cancer types, including GEC. Most target PD-1, a protein that binds to PD-L1 and PD-L2.

“If you look at the mutational burden of the tumors that have been historically studied and targeted with checkpoint inhibitors, such as melanoma and subtypes of lung cancer, gastric cancer is actually very close to the mutational burden on that spectrum,” said Yelena Y. Janjigian, MD. She said this is because the gastrointestinal mucosa is often subjected to repeated DNA damage (and repair) due to chronic inflammation or 

Nivolumab is a PD-1 inhibitor approved in the United States for melanoma and several other cancers. The CheckMate-032 study evaluated the safety and efficacy of nivolumab in 59 heavily treated patients with advanced or metastatic gastric or gastroesophageal junction cancer.

 These patients have few options and a poor prognosis.

According to data presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, the overall response rate (ORR) was 12% and median overall survival (OS) was 7 months. In the subset of patients with PD-L1—positive tumors, the ORR was 18%.

More recently, Bristol-Myers Squibb, which manufactures nivolumab, publicized preliminary data from the ONO-4538-12 study, which was a phase III trial evaluating nivolumab in Asian patients with unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer. The ORR was 14%, which increased to 27% in a subset analysis of patients with PD- L1—positive disease,

“I think what impresses everybody the most [about checkpoint inhibitors] is these durable responses that can even go on for years,” Bendell said. Despite this, Chau noted that it can take weeks for checkpoint inhibitors to take effect and advised caution when selecting patients for immunotherapy. Janjigian agreed that checkpoint inhibitors are probably not the best option for patients who are presenting with obstructive symptoms or peritoneal carcinomatosis.

Combining checkpoint inhibitors may increase the risk of toxicities. Janjigian said in her experience, combining a PD-1 inhibitor with a checkpoint inhibitor that targeted CTLA-4 was associated with a higher response rate, but also an increase in grade 3/4 toxicities. “Instead of febrile neutropenia and neuropathy, these patients get potentially life-threatening immune processes,” she said.

After disappointing results from the AVAGAST first-line trial of the VEGF inhibitor bevacizumab, it was unclear whether antiangiogenic agents had a role in GEC.

 The panel discussed how AVAGAST’s multinational population may have contributed to the trial’s failure to meet its primary endpoint. “Asians really don’t seem to derive any benefit from bevacizumab, either in progression-free survival [PFS] or OS, whereas the Pan-Americans seem to have some benefits,” Chau said.

In contrast to AVAGAST, both the phase III RAINBOW and REGARD trials observed significant benefits with the VEGF/HER2 inhibitor ramucirumab in patients with GEC.8 The study findings prompted the FDA to approve ramucirumab for GEC.

Manish Shah, MD, highlighted differences between the protocols for AVAGAST and the ramucirumab trials. “RAINBOW and REGARD were second-line studies...Also, the proportion of patients from Asia were limited in those studies.” Subgroup analyses of RAINBOW data associated ramucirumab with superior PFS relative to placebo in Japanese and Western cohorts. But only the Western population experienced improvement in OS. Shah said modeling suggests that using a higher dose of ramucirumab might improve survival outcomes.

Chau praised REGARD as “the first randomized controlled trial that shows an antibody against VEGF has a survival advantage.” He also praised the drug’s safety profile, which was highly favorable in both studies. Although ramucirumab is typically given with paclitaxel, Chau said that because data established ramucirumab as effective monotherapy, he feels comfortable discontinuing paclitaxel if a patient develops neuropathy. Bendell said that based on the favorable findings, she would like to see a trial of ramucirumab plus chemotherapy in the first-line setting.

Apatinib is a novel VEGF-HER2 inhibitor and was evaluated in a phase III trial of Chinese patients with chemotherapy-refractory GEC.

 The apatinib arm had significantly longer median OS than the placebo group and longer PFS. Shah said the findings of the Chinese study, combined with the results of RAINBOW and REGARD, support a role for VEGF inhibition in GEC.

Janjigian predicted that combination regimens are the future paradigm for GEC due to its molecular complexity. “Because of the nature of the epithelium and where the tumor is located, it will be important to find combinations of targeted agents that will help us control the tumor if we ever want to move away from cytotoxic chemotherapy,” she said.

Several experts on the panel are currently conducting clinical trials that combine targeted agents. Janjigian is involved in a trial that is evaluating the HER2 inhibitor trastuzumab with a PD-1 inhibitor in patients with GEC.

Bendell, Chau, and their colleagues are conducting a phase I trial that pairs the PD-1 inhibitor pembrolizumab with ramucirumab in patients with solid tumors, including GEC.

 Chau explained the rationale behind the combination: “Preclinical evidence says that if you give a tumor low-dose antiangiogenic therapy, you change it from an immunosuppressive environment to a much more immunosupportive environment.”

Safety data they presented at the 2016 ASCO Annual Meeting shows “the 2 drugs [together] are very safe—hardly any grade 3/4 toxicity or even grade 2 toxicities,” said Chau. The study is being expanded to include patients naïve to cytotoxic chemotherapy, and they hope to present efficacy data next year.

As the session ended, Shah expressed appreciation for how much progress researchers have made. “In the last 10 years, we have 5 new drugs that have been approved [for GEC],” he said. The panelists acknowledged that despite the tremendous progress, GEC remains a difficult disease to treat and much more needs to be done.

Shah said improving outcomes and patients’ quality of life will depend on “learning to sequence the drugs and combine them in a smarter way to understand the molecular profiles and to be proactive in terms of managing the patient’s side effects.”

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Le DT, Bendell JC, Calvo E, et al. Safety and activity of nivolumab monotherapy in advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): results from the CheckMate-032 study. 

Opdivo (nivolumab) Demonstrates overall survival benefit in patients with unresectable advanced or recurrent gastric cancer in phase III study [press release]. Princeton, NJ: Bristol-Myers Squibb; November 10, 2016. http://news.bms.com/press-release/bmy/opdivo-nivolumab-demonstrates-overall-survival-benefit-patients-unresectable-advan. Accessed November 28, 2016.

Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. 

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Javle M, Smyth EC, Chau I. Ramucirumab: successfully targeting angiogenesis in gastric cancer. 

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Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. 

. 2016;34(13):1448-1454. doi: 10.1200/JCO.2015.63.5995.

Herbst RS, Bendell JC, Isambert N, Calvo E, Santana-Davilla R, Cassier P, Perez-Garcia J, Yang J, Rege J, Ferry D, Mi G, Chau I. A phase I study of ramucirumab (R) plus pembrolizumab (P) in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma (UC): phase Ia results [ASCO abstract 3056]. 

Gastroesophageal cancer (GEC) is a complex disease, encompassing cancers with different histological and molecular subtypes. Growing insight into the molecular biology of GEC is poised to change the treatment landscape for this disease, although many questions remain unanswered.


Targeted Therapy Makes Inroads in Gastroesophageal Cancer

Tepotinib (MSC2156119J), an investigational small molecule that targets a recently identified aberration in the 

 gene, is moving forward rapidly in clinical development for patients with non—small cell lung cancer (NSCLC) who harbor the mutation, raising hopes that a more specific attack on the signaling pathway will lead to a new therapy for a significant subgroup of individuals with the disease.

The drug is being evaluated in a single-arm phase II trial for patients with stage IIIB/IV lung adenocarcinomas who have progressed after prior chemotherapy and whose tumors test positive for the 

 exon 14 skipping mutation (NCT02864992). The study, which was launched in July, aims to enroll 60 patients.

An estimated 3% to 4% of patients with NSCLC are believed to harbor the skipping mutation, about the same frequency as the incidence of 

 rearrangements, said Paul K. Paik, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center who is the global principal investigator on the trial. He led one of the first research teams to identify the mutation as a potential therapeutic target in lung cancer last year.

“It’s an unmet need for those patients, which translates worldwide to quite a large number of people,” considering the prevalence of lung cancer, said Paik in an interview with 

. An estimated 1.8 million individuals are diagnosed globally with lung cancer each year.

Paik noted that MET signaling has been the subject of active research in lung cancer for years in patients with a high expression of the MET protein or amplification of the gene, or for individuals with 

-mutant disease with a higher MET expression, possibly due to a resistance mechanism.

To target MET, investigators have tried 2 strategies: monoclonal antibodies directed against the MET receptor or its ligand and tyrosine kinase inhibitors.

 However, results have been mixed. In addition, there are 2 multikinase inhibitors approved by the FDA, crizotinib (Xalkori) and cabozantinib (Cometriq/Cabometyx), which among other receptors also target MET.

Now, the focus has shifted to the exon 14 skipping mutation as an alteration that appears predictive for response to MET inhibitors, Paik said. Notably, investigators believe these alterations are mutually exclusive with mutations in 

 that would be targeted by less speci c agents.

Last year, Paik and colleagues described 4 case studies in which patients ranging in age from 65 to 90 years with advanced lung cancer with exon 14 skipping mutations received either crizotinib or cabozantinib. One patient with a 5-cm liver metastasis experienced a complete response after 4 weeks of daily cabozantinib therapy, while 2 others achieved partial responses with crizotinib.

Paik said this study helped lay the groundwork for tepotinib, which specifically targets MET. He said the agent inhibits MET more potently than crizotinib and, because of its specificity, appears to have fewer adverse effects. The appropriate dosing was established in phase I testing.

Patients treated with the drug have experienced fewer of the adverse events typical of the MET-targeting class of drugs, such as gastrointestinal side effects, liver function laboratory abnormalities, and peripheral edema, according to Paik. “In terms of tolerability in the phase I experience it’s a very well-tolerated drug,” he said.

Specifically, the mutation is as its name implies: exon 14 is spliced out—or skipped&mdash;during the processing of RNA.

 “There is a normal mechanism to delete out portions of the RNA and the protein. These alterations end up deleting out in a deleterious way this one section of the RNA and subsequently the protein,” said Paik.

“That section is very important,” he continued. “It has the key amino acid that allows the cell to target that receptor for degradation so when that part is deleted out, the receptor is stabilized, the turnover rate is decreased, and we think that is why there is increased dependence on that protein.”

At present, the exon 14 alteration is detected through DNA sequencing that includes noncoding regions (introns), which are starting to be incorporated into testing panels, said Paik. He said investigators are conducting the testing on tissue samples during the trial but will be studying participants’ blood draws to see whether similar results can be obtained from circulating DNA.

Although Paik’s study zeroes in on the exon 14 alteration, tepotinib also is being evaluated in a more broadly MET-positive population in a phase I/II trial (NCT0198255). In that study, patients with locally advanced or metastatic NSCLC are being randomized to receive either tepotinib plus gefitinib or platinum plus pemetrexed.

Tepotinib is being developed by Merck KGaA, Darmstadt, Germany, and operates in the United States as EMD Serono, Inc.

Tepotinib, an investigational small molecule that targets a recently identified aberration in the MET gene, is moving forward rapidly in clinical development for patients with non–small cell lung cancer who harbor the mutation, raising hopes that a more specific attack on the signaling pathway will lead to a new therapy for a significant subgroup of individuals with the disease.

Vol. 17/No. 24 | Oncology Live®

A Time for Hope

Expert Discusses Recent Progress in NET Management

Mutational Complexity Reflects Treatment Challenges for Hepatocellular Carcinoma

Targeted Therapy Makes Inroads in Gastroesophageal Cancer

Tepotinib Takes Aim at Novel MET Mutation in Lung Cancer Trial

Patient-Friendly Policies Extend to Decision Making