JANE DE LARTIGUE, PH.D.

FOR 25 YEARS, LYNN Matrisian, Ph.D., M.B.A., was a leader in cancer biology research at the Vanderbilt University School of Medicine in Nashville, Tennessee. She also served as president of the American Association for Cancer Research and as special assistant to the director of the National Cancer Institute at the National Institutes of Health. Then, in 2011, Matrisian’s desire to make a more tangible impact on patients brought her to the Pancreatic Cancer Action Network (PanCAN), where she leads the advocacy group’s scientific and medical affairs teams.

In those roles, Matrisian is committed to helping PanCAN double pancreatic cancer survival by 2020. In an interview with 

®, she described how the group pursues a combination of research, advocacy, patient support and community activity to achieve this goal.

She outlined several of PanCAN’s unique programs, including Know Your Tumor and Clinical Trial Finder. These initiatives use molecular analysis to identify the approximately 25 percent of patients with pancreatic cancer who have genetic alterations treatable with existing drugs, and then guide treatment on the basis of that knowledge. PanCAN’s newest initiative, Precision Promise, aims to improve outcomes through a patient-centric clinical trial and research platform that continuously and rapidly evaluates novel treatment options.

OncLive®: Why has there been such difficulty achieving clinical success with novel drugs in pancreatic cancer?

Matrisian: There are many different reasons, including the fact that it is diagnosed late, so most patients already have metastatic disease, or will soon. We are not good at curing metastatic disease in any cancer type. Another difficult feature is the stroma (the blood vessels and connective tissues supporting a tumor), which is unusually dense and fibrotic and has been shown to increase the tumor’s internal pressure and prevent chemotherapy drugs from getting to its cells. Molecularly, the KRAS gene is mutated 95 percent of the time — and, because it is an oncogene, its mutations can turn normal cells cancerous. But we don’t have a good drug to target this activity, and these mutations prevent some drugs that we do have from working effectively. Finally, it is an immunologically “cold” tumor type, and this has meant that it has not responded to immunotherapy like some other tumor types.

We have had some success in using chemotherapy before surgery, so more patients can have their tumor removed, giving them the best chance for long-term survival. We have had advancements in all the challenging areas I mentioned. A drug has been developed that disrupts the stroma and improves the effectiveness of chemotherapy: PEGPH20.

We’ve discovered that there are molecular alterations in about 25 percent of pancreatic tumors for which a drug exists that is targeted to that alteration, and there are some initial signs that these can be effective for those select patients. Lastly, there is a lot of research ongoing to find immunotherapies that can make a “cold” tumor “hot.”

What are the key pathways and cellular processes being targeted for pancreatic cancer therapy? Therapies are targeting the DNA damage repair pathway, which is often defective in pancreatic cancer, as well as stromal disruption and immunotherapy. In particular, these therapies are focused on the complex interactions between different cell types within the immune system.

In your opinion, what are the most promising current strategies?

I think all of the above are promising. We are particularly excited about targeting hyaluronic acid. PEGPH20 is in phase 3 trials right now, and the phase 2 trials looked good — although it’s the cancer cells themselves that started this whole process, the tumor conscripts neighbors and other cells, and that can drive a tumor to become more aggressive and metastatic and to grow faster.

Hyaluronic acid is part of that stromal response to the tumor. It’s one of the components in your joints that helps give you that ability to bounce back when you walk — that sponginess. But in a tumor, it blocks the blood vessels, and the tumor cells have to adapt in order to survive without having very many nutrients or much oxygen. Also, it keeps drugs designed to kill tumor cells from getting into the tumor.

PEGPH20 delivers the enzyme that breaks down hyaluronic acid in the tumor, which relieves the pressure of collapsed blood vessels and allows circulating drugs to get to the cells. What I really like about the early studies with this drug is that they asked if it worked for all patients or if you had to have a certain level of hyaluronic acid in your tumor before breaking down the acid makes a difference. It turns out that not 100 percent of tumors have a lot of hyaluronic acid. Others have stromal involvement but involving other proteins. I think the phase 2 results were very promising; it’s a molecularly driven approach, and patients are being selected on the basis of whether they are likely to respond.

What are the most significant challenges and hurdles to effective new treatments for pancreatic cancer?

The challenges include getting more patients with pancreatic cancer on clinical trials so we can test new approaches and see if they work, learning which patients are most likely to respond to what therapies, and getting all physicians across the United States to use best practices in treatment and supportive care so all patients get state-of-the-art care.

PanCAN’s Patient Central, Clinical Trial Finder and Know Your Tumor initiatives are designed to improve clinical trial enrollment. Patient Central, our Patient Registry and research publications contribute to education efforts. We coordinate efforts so that we can use the information from patients with pancreatic cancer most effectively and efficiently to figure out the best treatments for future patients.

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A leader of the Pancreatic Cancer Action Network, which aims to double survival rates by 2020, outlines treatment strategies that could lead to success.

On the Double: Improving Survival Rates in Pancreatic Cancer

In the hopes of recreating the successes achieved in other solid malignancies, researchers have evaluated many types of targeted therapy for the treatment of advanced gastric cancer. Regulatory approval of Herceptin (trastuzumab) in 2010 was a step forward, but only a minority of patients is eligible for the human epidermal growth factor receptor 2 (HER2)-targeting antibody therapy.

Success with other targeted agents has been lukewarm, particularly those directed against the epidermal growth factor receptor (EGFR), which has shown no benefit in clinical trials to date and, more recently, MET inhibitors, which also have missed their mark after a promising start.

More recently, studies evaluating Cyramza (ramucirumab), an antiangiogenic therapy that targets the vascular endothelial growth factor receptor 2 (VEGFR2), have translated into a survival benefit in the second-line setting and resulted in regulatory approval last year. Other targeting strategies are also beginning to make headway, and the first reports of immune checkpoint inhibition in gastric cancer emerged in 2014.

Valuable insights have been gathered from both failures and successes; improved molecular characterization of gastric cancer and biomarker identification have emerged as pressing needs. As we enter an era of unprecedented clinical trial activity in gastric cancer, with thousands of patients enrolled or set to be enrolled in large, randomized phase 3 trials of novel targeted agents, we may finally be on the path to changing the course of this disease.

Gastric cancer is a major health problem around the world; it is among the five most common types of cancer, with nearly 1 million new diagnoses annually, and was the third-leading cause of cancer-related mortality in 2012, with more than 700,000 deaths annually, according to the World Health Organization.

Surgical resection is the only cure for gastric cancer and, combined with recent improvements in postoperative adjuvant chemotherapy, there have been significant gains in survival for patients with early-stage disease. However, gastric cancer is an insidious disease, often asymptomatic in the early stages, meaning that a vast majority of patients present when the cancer is more advanced and inoperable.

For patients with unresectable, locally recurrent, or metastatic disease, chemotherapy is standard of care (SOC) and a wide variety of combinatorial chemotherapeutic regimens have been developed, but a common feature is their poor efficacy in advanced disease. Thus, these patients have a poor prognosis, with a median survival ranging from 10 to 14 months in advanced diseased.

Advanced gastric cancer represents an enormous unmet medical need and substantial resources have been committed to trying to reproduce the success of targeted therapies in other advanced solid malignancies. But, despite some regulatory approvals, this has proved to be far from straightforward in gastric cancer.

Its molecular complexity is the most challenging feature of gastric cancer, presenting a barrier to the identification of targetable genetic aberrations. While other solid malignancies are often driven by a defining oncogene and its associated signaling pathways, gastric cancer may be driven by many such essential pathways, with distinct tumor biology for different molecular and histological subtypes.

In recognition of its complexity and poor prognosis, The Cancer Genome Atlas (TCGA) chose gastric/esophageal cancer as one of more than 20 cancers that scientists would map as part of a federally funded project launched in 2010. Investigators from major academic institutions throughout the United States and several other nations, including South Korea and Australia, used six molecular platforms to analyze 295 primary gastric adenocarcinomas. Last year, Adam J. Bass, of the Dana-Farber Cancer Institute, and colleagues reported their findings in 

The team identified four major genomic subtypes: tumors that tested positive for the Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. The distribution of the subtypes differed depending on the region of the stomach, as did the tumor’s molecular profile.

Notably, the genomically stable subtype was composed mostly of diffuse-type tumors, a particularly deadly type of gastric cancer that metastasizes rapidly for which there currently is no effective treatment. The study identified novel 

 mutations or alterations involving activating proteins in the pathway in approximately 30 percent of samples in this subgroup, providing a potentially novel target for this form of gastric cancer.

Researchers hope the analysis will provide a springboard for stratifying patients for treatment and discovering new agents for testing.

All members of the HER family of receptor tyrosine kinases, whose members include HER1 (or EGFR), HER2, HER3 and HER4, are expressed in gastric cancer and represent promising targets. HER2 is overexpressed or amplified in 8 percent to 34 percent gastric cancer cases, with rates varying depending on histologic subtype and location, and targeting the aberration has met with success.

Herceptin, which proved so potent in HER2-positive breast cancer patients, was evaluated as first-line therapy in HER2-positive gastric cancer. It was ultimately approved for this indication in 2010, following the pivotal phase 3 TOGA trial, in which Herceptin added to cisplatin and fluoropyrimidine extended overall survival (OS) by two months compared with chemotherapy alone, with no difference in toxicity profile. As a result, this combination has become SOC for HER2-positive advanced or metastatic disease.

Several other HER2-targeting agents are also being evaluated in clinical trials, including Perjeta (pertuzumab) and Kadcyla (T-DM1). Analogous to the CLEOPATRA trial in breast cancer, the ongoing phase 3 JACOB trial is evaluating the combination of Perjeta, Herceptin and chemotherapy (

). Meanwhile, the phase 3 GATSBY trial is comparing Kadcyla with taxane chemotherapy in advanced gastric cancer (

). Herceptin also continues to be investigated in gastric cancer, including in the phase 3 HELOISE trial in combination with cisplatin and capecitabine (

Not all HER2-targeting agents have had such clear-cut success. The dual HER2/EGFR inhibitor Tykerb (lapatinib) has been evaluated in both the first (LOGiC) and second-line (TyTAN) settings. Both trials found no overall survival benefit upon addition of Tykerb to standard chemotherapy. However, the LOGiC trial did suggest that Asian patients and those under age 60 years might benefit. The TyTAN trial, which enrolled 261 Asian patients with HER2-amplified cancers, observed statistically significant improvements in OS and progression-free survival (PFS) among a prespecified subgroup of patients with strong HER2 positivity.

Despite the success of HER2-targeting agents, only a minority of patients are HER2-positive and even among those who are, not all respond to Herceptin. A second member of the HER family, EGFR, is overexpressed in 27 percent to 64 percent of gastric cancers and has been associated with more aggressive histology and poorer prognosis.

None of the EGFR-targeted therapies tested to date (both monoclonal antibodies and tyrosine kinase inhibitors) have shown a survival advantage and, in some cases, have even proved potentially detrimental.

However, none of the failed phase 3 trials were carried out in biologically selected patient populations. Retrospective analyses of very small subgroups of patients in the EXPAND trial of Erbitux (cetuximab) suggested patients with high EGFR expression may derive benefit from this drug. Biomarker analyses are ongoing in the hope that they may help researchers identify a potential benefit of these agents.

In addition, trials of several novel EGFR agents are still ongoing. Of particular note, the phase 3 ENRICH trial of nimotuzumab in combination with irinotecan in the second-line setting is preselecting patients with high EGFR expression (

). The results of this trial could seal the fate of EGFR-targeted therapy in gastric cancer.

A different receptor tyrosine kinase, the MET or hepatocyte growth factor receptor (HGFR), has also provoked significant interest in gastric cancer. Overexpression of MET is estimated to occur in 50 to 60 percent of cases and is associated with poorer prognosis.

Until recently, several MET-targeting agents were in late-stage clinical development, but have been plagued by a string of disappointments. Most recently, all clinical trials of rilotumumab in advanced gastric cancer have been halted, following a planned safety review of the phase 3 RILOMET-1 study of rilotumumab in combination with epirubicin, cisplatin and capecitabine. An increase in the number of deaths was observed and the company reported that protocol-defined futility criteria would likely have been met at a March 2015 analysis. Also, recently reported results from a trial of tivantinib monotherapy (phase 2) in Asian patients with metastatic gastric cancer reported only modest efficacy.

Roche is continuing its development of the MET antibody MetMab (onartuzumab) in gastroesophageal cancer. The phase 3 MetGastric trial is designed to evaluate onartuzumab in combination with mFOLFOX6 versus placebo plus the same chemotherapy regimen in approximately 600 patients; the study is ongoing although it is not recruiting new participants (

Currently, the therapeutic avenue proving most promising in gastric cancer is antiangiogenic targeting, though even this got off to a somewhat rocky start. Angiogenesis has long been thought to be a promising target for cancer therapy, given its role in supporting tumor growth and metastasis. The vascular endothelial growth factor receptor (VEGFR) pathway is a central regulator of angiogenesis and thus has been the focus of efforts to target this process. All VEGFRs and their VEGF ligands are overexpressed in gastric cancers (36 to 40 percent) and are associated with tumor aggressiveness and poor prognosis.

Avastin (bevacizumab) is a major player in antiangiogenic therapy and has gained regulatory approval for the treatment of other solid malignancies. It was studied in the first-line setting for advanced gastric cancer in the phase 3 AVAGAST and AVATAR trials. Both studies failed to show an overall survival benefit, though there were significant improvements in several secondary endpoints, including overall response rate (ORR), PFS and one-year survival in the AVAGAST trial.

Bevacizumab targets the ligand VEGF-A, but inhibitors of VEGFR have also been examined, including Sutent (sunitinib), which continues to be studied, but has proved disappointing to date. These VEGFR inhibitors, however, were multitargeted tyrosine kinase inhibitors and did not solely inhibit VEGFRs. Ramucirumab is a monoclonal antibody that specifically targets VEGFR2.

Following positive results from the phase 3 REGARD study, ramucirumab was approved in April 2014 as a single agent for second-line treatment of patients with gastric or gastroesophageal junction (GEJ) cancer whose disease progressed after first-line platinum and/or fluoropyrimidine-containing combination therapy. This was followed in November 2014 by approval for combination of ramucirumab with paclitaxel on the basis of the phase 3 RAINBOW trial.

In the REGARD trial, ramucirumab monotherapy led to a significant improvement in OS (5.2 months versus 3.8 months), PFS (2.1 months versus 1.3 months), ORR (3.4 percent versus 2.6 percent), and disease control rate (49 percent versus 23 percent). Although rates of hypertension were higher in the ramucirumab arm, ramucirumab treatment was not associated with higher rates of other toxicities. There was no increase in the risk of thromboembolic events, fistula formation, or gastrointestinal perforation, as seen for other antiangiogenic agents.

The RAINBOW trial confirmed the efficacy of ramucirumab in the second-line setting and demonstrated its efficacy and tolerability in combination with standard chemotherapy, with significant improvements in OS (9.6 months versus 7.4 months), PFS (4.4 months versus 2.9 months) and ORR (28 percent versus 16 percent) observed. Patients in the combination arm also reported a reduction in pain and other improvements in quality of life. Side effects were manageable and included neutropenia, leukopenia and hypertension. Clinicians are currently developing algorithms to guide in decision making with regard to monotherapy versus combination therapy.

Other antiangiogenic therapies continue to be evaluated in gastric cancer and this has once again become a promising avenue of research.

Among the most interesting of the other novel targets under study for gastric cancer are the immune checkpoint inhibitors, which boost the patient’s antitumor immune response by targeting proteins involved in an inhibitory signaling network that dampens down cytotoxic T-cell activity.

The first data on immune checkpoint inhibition in gastric cancer were presented at the 2014 European Society for Molecular Oncology meeting for Keytruda (pembrolizumab), an inhibitor of programmed death 1 (PD-1). Updated data from the gastric cohort of the phase I KEYNOTE-012 demonstrated an ORR of 22.2 percent and 33.3 percent, respectively, by central and investigator review, in findings presented at the 2015 Gastrointestinal Cancers Symposium. Side effects were similar to those reported for Keytruda in other studies, with very few grade 3 or higher. Keytruda is now being evaluated in the phase 2 KEYNOTE-059 study as monotherapy and in combination with chemotherapy in recurrent or metastatic gastric cancer (

The heterogeneity of gastric cancer may have limited the success of targeted therapy to date. Many trials have likely broadly applied a one-size-fits-all approach, in large part due to the lack of validated biomarkers available to guide patient selection.

Researchers have increasingly recognized the importance of tissue collection from both positive and negative trials to aid in biomarker discovery and numerous biomarker studies are now ongoing. In the AVAGAST study of Avastin, researchers successfully collected tissue and serum samples from more than 90 percent of study participants, and identified two candidate biomarkers.

Technological advancements are also allowing improved molecular characterization of gastric cancer, which is aiding in biomarker discovery and the identification of novel therapeutic targets, including those suggested by the TCGA analysis.

In the hopes of recreating the successes achieved in other solid malignancies, researchers have evaluated many types of targeted therapy for the treatment of advanced gastric cancer. 

Targeting Gastric Cancer: Recent Advances Generate Fresh Hopes After Many Frustrations

Josh D. Lauring, of Johns Hopkins Medicine, is interested in identifying the genetic changes that drive breast cancer growth in order to determine novel therapeutic targets for drug development and ultimately improve outcomes for patients with breast cancer.

His focus includes the PI3K pathway, the most highly dysregulated cell-signaling network in breast cancer.

“The PIK3CA gene, encoding one of the major PI3K proteins, is mutated in approximately 30 percent of breast cancers, with even higher rates in the estrogen receptor [ER]-positive and HER2-amplified subtypes,” Lauring said. “Several other PI3K pathway proteins, such as PTEN, Akt and PIK3R1 are also mutated.”

Lauring details efforts to develop breast cancer therapies by targeting the pathway.

Which PI3K-targeting strategies are proving most promising and in which types of breast cancer?

 Currently, the only FDA-approved drug targeting the PI3K pathway for breast cancer is everolimus (Afinitor). This drug targets the mTOR protein, which is a major downstream target of the PI3K pathway. Everolimus has been most extensively studied in ER-positive breast cancer, where it provided a large progression-free survival [PFS] benefit when added to the aromatase inhibitor exemestane (BOLERO-2 trial) or tamoxifen (TAMRAD trial2) in women whose cancer had progressed after initial hormonal therapy.

Studies using PI3K inhibitors or Akt inhibitors, which target the pathway above the level of mTOR, are mostly still ongoing, often in combination with hormonal therapies. The PI3K inhibitor pictilisib provided a modest but nonsignificant PFS benefit when combined with fulvestrant in women with aromatase inhibitor-resistant ER-positive breast cancer in the recently reported FERGI phase II trial, however.

Accumulating evidence points to PIK3CA mutation as a biomarker that predicts less responsiveness to HER2-targeting drugs in HER2-positive breast cancer, so there is great interest in determining whether adding PI3K pathway inhibitors can improve responses to HER2-targeted therapies. Everolimus had only a modest 1-month PFS benefit when combined with trastuzumab (Herceptin) in metastatic HER2-positive breast cancer, but trials combining HER2-targeted agents with PI3K or Akt inhibitors are underway, and some promising responses have been seen in early-phase trials. Thus far, we have not seen evidence of robust activity of single-agent PI3K-Akt-mTOR inhibitors against triple-negative breast cancer, but this may require combining these drugs with chemotherapy, which is being studied.

Are these agents likely to be most effective in combination with other drugs and, if so, what are the most rational combinations?

Much research has shown that the PI3K pathway participates in complex crosstalk with other important signaling pathways in cells and that PI3K signaling involves regulatory feedback loops. Blockade of PI3K can lead to feedback activation of growth factor receptors such as IGF1R, EGFR, HER2 and HER3. Sustained signaling from these receptors can bypass PI3K blockade by activating alternative pathways such as the MAPK pathway.

Mutations in MAPK pathway genes such as KRAS can also lead to resistance to PI3K inhibitors, and researchers have shown that co-targeting PI3K and MAPK can overcome such resistance. This approach is under study clinically, but it has been a challenge to inhibit both of these major pathways in patients without undue toxicity.

Additional trials are combining various kinds of PI3K inhibitors with drugs targeting upstream growth factor receptors, such as HER2, or the estrogen receptor. Because PIK3CA mutations are highly enriched in ER-positive and HER2-positive breast cancer, and because these signaling pathways involve PI3K, such approaches are rational.

Using a less biased approach, Jeffrey A. Engelman’s group [at Massachusetts General Hospital] recently used a combinatorial drug screen to identify synergy between PI3K inhibitors and Cdk4/6 inhibitors in PI3K inhibitor—resistant, PIK3CA-mutant breast cancer cells. The Cdk4/6 inhibitor palbociclib (Ibrance) has already shown very promising PFS benefit in ER-positive breast cancer combined with letrozole [its approved FDA indication], and studies of another Cdk4/6 inhibitor LEE001 are ongoing, so there will likely be interest in combining these drugs with PI3K pathway inhibitors.

How significant is the development of biomarkers, and which biomarkers seem to have the most significant potential?

Biomarkers are essential to understanding how best to use PI3K-targeting drugs in the clinic. Many of us had assumed that mutational activation of the pathway would predict for inhibitor benefit, in the same way that EGFR mutations predict for responsiveness to EGFR kinase inhibitors in lung cancer. Mutations could then be used as predictive biomarkers to select patients who would benefit from PI3K inhibitors.

It is becoming clear, however, that while mutations in the pathway may enrich for responsiveness in some settings, they are not strictly predictive in a positive or negative way. In fact, a study by Hope Rugo and colleagues of a subset of patients from the BOLERO-2 trial of everolimus and exemestane suggested that the patients with the fewest genetic alterations in the growth factor receptor and PI3K pathways derived the most benefit from everolimus. Some researchers have developed gene expression signatures that may reflect PI3K pathway activation better than mutation alone.

These and various proteomic biomarkers are also being evaluated in ongoing preclinical and clinical studies, but much work remains to identify robust predictive biomarkers for PI3K pathway inhibitor benefit. An exploratory analysis of the recently reported FERGI trial combining the PI3K inhibitor pictilisib with fulvestrant showed a doubling of PFS with the addition of pictilisib in the subset of patients whose tumors expressed both the estrogen and progesterone receptors [PR]. Whether combined ER/PR positivity will identify a subset of patients who are particularly likely to benefit will need to be determined prospectively in future studies.

JANE DE LARTIGUE, PH.D.

On the Double: Improving Survival Rates in Pancreatic Cancer

Targeting Gastric Cancer: Recent Advances Generate Fresh Hopes After Many Frustrations

The Evolving Challenges of Targeting PI3K in Breast Cancer

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