Danielle Bucco

SOME OF TODAY’S MOST effective and least grueling treatments for gastrointestinal (GI) cancers come in the form of targeted drugs, which work when disease is driven by specific genetic mutations. Some immunotherapies, too, work best on cancers that express certain genetic alterations.

But before doctors can treat a cancer with this kind of personalized medicine, they must ask for next-generation sequencing or other tests of the tumor tissue so that they know which mutations an individual tumor expresses. The next step should be choosing the medications most likely to bring about a response based on the tumor’s genomic profile.

To offer help in matching a cancer’s genetic alterations with the most appropriate medications, the American Society of Clinical Oncology (ASCO) provides its 2016 document “

Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer

”. The recommendation is a joint consensus by ASCO, the Association for Molecular Pathology and the College of American Pathologists.

Also helpful is guidance that ASCO released in 2006 and updated in 2009; specific to GI cancers,

 spell out the use of tumor biomarkers to prevent, screen, treat and keep a close watch on these conditions.

“It is important that the guidelines are followed so that, ideally, every patient has that fundamental baseline treatment,” explains Shirley Michelle Shiller, D.O. In an interview during the 2017 OncLive® State of the Science Summit™ on Gastrointestinal Cancers, Shiller, a pathologist at Baylor Scott & White Health in Dallas, discussed progress in precision medicine for patients with GI cancers. 

OncLive®: Can you discuss some of the highlights of the ASCO guidelines?

Shiller: The guidelines are intended to help direct clinicians, especially those who may be in more remote areas, as to what any patient should receive in terms of treatment. Some (genetic) alterations, such as KRAS mutations, indicate that a patient would not respond to select therapies (such as EGFR inhibitors), and (this) helps direct the therapy to a more meaningful and efficacious treatment.

Can you discuss the current role of liquid biopsies that can identify mutations by examining cancer cells or their DNA that are found in blood or urine?

That is an emerging technology. The plasma-based testing we know the most about is in the lung cancer space, but it has opportunity in colon cancer, so some people are starting to use it there.

The detection rate is lower in plasma versus in a solid tumor, and that is largely based on our experience: We have more experience testing solid tumors. When you move into the liquid space, there are some sensitivity issues that we are working on, as well as the other variables that you cannot control as much. For example, when you draw blood, it is not certain that the tumor is shedding at that time or that the mutations you hope to detect are shedding enough of a quantity to be detected.

What role will liquid biopsies play in the future of this treatment landscape?

I am certain that they will play a role in all cancers. Ultimately, we will understand how to utilize the information in terms of an initial diagnosis on the tumor, but what might be more relevant are the biomarkers. Once we know what we are looking to monitor, then we can watch those patterns prior to a patient presenting with a recurrence (or drug resistance, and in a much less invasive way than with repeated tissue biopsies).

Some (pharmaceutical) companies are hoping to detect cancer before an actual lesion is even present. That is very far in the research future, but I believe that will become reality at some point.

What impact has precision medicine had on treatment thus far for these patients?

We are having growing pains because some of the testing can be more expensive than a routine blood test or chemistries. However, the information is very important if you are contemplating what therapy to give patients. We are in a power struggle with third-party payers as we get our feet on the ground to demonstrate the benefit of the test and how that saves money downstream in terms of not delivering ineffective therapy: The patient is getting therapy that is more specifically targeted to their actual cancer, which is the essence of precision medicine.

Since many of those therapies are targeted, their (side effect) profile is more tolerable because they are not killing rapidly dividing cells. The patients can tolerate it on an outpatient basis, making their quality of life much higher. In my opinion, cancer (treated this way) is likely to become more of a chronic disease.

Are there unmet needs that should be addressed?

The largest unmet need is for education — not only for the oncologist but even for my pathology colleagues and other health care providers. There are varying levels of implications to the tests, such as testing the tumor to determine whether it has a marker that can be hit. Some of the tests can also imply other things about the patient, such as a hereditary predisposition.

When you start combining those different technologies out there into one result, you have an exponential range of possibilities.

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Genomic testing of gastrointestinal tumors can be essential to proper treatment.

Looking Within: Exploring Genomic Testing for GI Cancers

Molecular testing, targeted therapies and checkpoint inhibitors continue to shape the treatment of patients with gastrointestinal (GI) cancers.

The role of precision medicine has become a significant area of study, specifically with genomics and liquid biopsies. With the introduction of next-generation sequencing and an improvement in the understanding of molecular alterations, treatments for patients have begun to be individualized.

In an effort to overcome resistance to targeted therapies, investigators have started using liquid biopsies. However, expert Luis A. Diaz, M.D., does not predict this will take the place of standard biopsies in the future.

“I do not think [liquid biopsies] are sufficiently sensitive, but I do think that there will be focused applications, like minimal residual disease, early detection, or tracking resistance where they will have profound effects,” said Diaz.

 on Gastrointestinal Cancers, Diaz, head of the division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, discussed the precision medicine approaches available and in development for the treatment of patients with GI malignancies.

Please provide an overview on precision medicine in GI cancers.

I discussed the role of precision medicine, specifically genomics, for the management of GI malignancies. I gave an overview of what genomics is followed by applications in areas such as targeted therapy and immunotherapy. An emerging approach is pan-tumor markers, meaning markers that do not just define one tumor type, but if found in any tumor type could have a dramatic antitumor response. There are many opportunities and pitfalls to that approach. The second part of the talk was about liquid biopsies, circulating tumor DNA, how that leverages precision medicine, and how we can apply that for concepts like minimal residual disease, tracking resistance and even early detection. I discussed how we have evolved from targeted sequencing, meaning one gene at time to more expanded sequencing-like panels and perhaps even exome sequencing. 

At what point do you give a patient genomic testing?

It depends on the scenario. If the patient is metastatic, any genetic testing from the beginning is important. You are dealing with a situation where about 80 percent of patients will be dealing with a lethal scenario. Therefore, it is important to have options. Those options are typically in the form of clinical trials but, more often, we find genomic alterations that could be used earlier and could have profound results for those individual patients. 

What do we know about pan-tumor approaches and what questions remain?

There are two pan-tumor approaches that I would highlight. One is microsatellite instability (MSI) and the second is 

 fusions. Both of those are present at low levels in multiple different tumor types but if you find them, you have dramatic responses. Those dramatic responses tend to appear to be for years. This is only present in 0.1 percent of patients. The question is, “Are we dealing with a curative therapy?” That is the outstanding question right now. Are these going to be long-term survivors or are they going to be survivors who will eventually progress down the road? We do not know the answer to that but hopefully we will know soon.

Anecdotally, have you seen these patients with 

 fusions or MSI having responses to entrectinib?

With MSI and NTRK, we are starting to enter a phase where these are not the old genomic biomarkers, which were mediocre. These are the ones that can have a profound effect. 

Do you expect to see more basket trials where we explore treatments for patients that is not based on tumor type?

I think so and we will have to focus in on applications that have a high potential for working. We have a lot of drugs out there that work and we want to move things to a broader audience and more high-value proposition. 

Expert Discusses Exciting Advancements in Treating GI Cancers

Treating non-small cell lung cancer (NSCLC) can be challenging because of mutations in the KRAS gene, which provides instructions for making a protein called K-Ras that is involved primarily in regulating cell division.  Approximately 25 percent to 30 percent of patients with NSCLC have activating mutations in KRAS

However, studies have shown that by picking apart the KRAS

subtype, there are smaller subsets harboring mutations that could be associated with response to immunotherapy agents. Some of the tumors in one subgroup (the KP subgroup) are more likely to respond to checkpoint inhibition.

Additionally, according to data from the CheckMate-057 trial, immunotherapy might offer a valid treatment option for people with these mutations. This study randomized 582 patients after failure with platinum-based doublet chemotherapy to Opdivo (Nivolumab) or docetaxel. In a subgroup analysis of CheckMate-057, people with KRAS

mutation were more like to benefit from Opdivo in terms of an improvement in overall survival (OS).

“Immunotherapy has emerged as a major treatment option in both metastatic and even earlier stage squamous carcinoma and adenocarcinoma,” said Ferdinandos Skoulidis, M.D, Ph.D.

 on Advanced NSCLC, Skoulidis, an assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed potential treatment options for 

-mutated lung cancer and highlighted developments in biomarker research in other areas in the field.

Please provide an overview of your presentation.

I discussed the role of biomarkers in the management of NSCLC. This is a very topical theme because lung adenocarcinoma is emerging as the pinnacle of precision cancer medicine among the solid tumors, with the recognition that NSCLC does not constitute a single disease. NSCLC consists of many different molecularly definitive entities, each of which needs to be treated in a unique way.

I discussed the five biomarkers that are currently linked to FDA-approved therapies in NSCLC. Those mutations include EGFR, ALK, and ROS1 rearrangements, BRAF

What are the best treatment options for patients with KRAS-mutant lung cancer?

KRAS represents the “elephant in the room” in the field of targeted cancer therapy. Approximately 25 percent to 30 percent of patients with lung adenocarcinoma will be found to have an activating mutation in KRAS. We have known about KRAS

for a long time. There are no FDA-approved targeted therapies for patients with KRAS-mutant lung adenocarcinoma, so this represents a major unmet clinical need.

Over the last couple of years, immunotherapy has emerged as a major treatment option in both patients with metastatic and even earlier-stage squamous carcinomas and adenocarcinomas. There is some evidence from the CheckMate-057 trial that immunotherapy might represent a very valid treatment option for patients with KRAS-mutant lung cancer. 

However, what has become clear to us is that KRAS-mutant lung adenocarcinoma is clinically heterogeneous, meaning one patient does not respond in the same way as another due to molecular diversity. We have previously shown that one of the major determinants of the heterogeneity of KRAS-mutant lung adenocarcinoma is common mutations or mutations in genes that happen together with KRAS.

We have identified mutations in three key tumor suppressor genes that we believe define three major subgroups of KRAS

mutant lung adenocarcinoma. Those are mutations in TP53

in the KP subgroup, STK11 in the KL subgroup, and the p16

We have previously shown that there are many differences between these subgroups. Potentially, the most clinically relevant difference is in the response of the subgroups to immunotherapy. Through a large collaboration between The University of Texas MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, and Massachusetts General Hospital, we collected 174 patients with RAS-mutant lung adenocarcinoma and assessed their response to immunotherapy based on common mutations. 

What became immediately apparent was that there were very big differences in how these tumors responded to immunotherapy depending on their common mutations. Tumors that had common mutations in the KL subgroup exhibited primary resistance to immunotherapy. The likelihood of responding was only 7.4 percent. On the other hand, tumors in the KP subgroup had a 35.7 percent likelihood of responding to immunotherapy. This is more than five-fold compared with the KL subgroup. This suggests that we should be looking at what happens with mutations together with KRAS

In addition to differences of objective response rates (ORR) there were statistically significant differences in progression-free survival and OS. The median OS of the KP subgroup that responded to immunotherapy was more than double that of the median OS of the KL subgroup. This suggests that it adds an extra parameter to what we believe should be a composite predictive biomarker panel to determine benefit from immunotherapy. PD-L1 expression plays a role and will continue to have one. 

There are emerging data about tumor mutational burden as a predictive biomarker for response to immunotherapy. We believe that those two parameters should be coupled with mutations or genetic alterations. There are three individual genes that we are particularly interested in, which are KRAS, p53

 and STK11. By adopting an integrative approach to biomarker development, we can achieve greater predictive power.

What is the promise of combinations with immunotherapy in the field of lung cancer overall?

Data from KEYNOTE-021 trial suggested that the combination of Keytruda (pembrolizumab) with platinum-doublet chemotherapy of carboplatin/pemetrexed was associated with a 55 percent ORR. This is almost double that of chemotherapy alone, which is in the region of 25 percent to 30 percent.

What was particularly interesting was that the benefit of combining chemotherapy to immunotherapy seemed to extend to PD-L1—negative tumors. These are tumors where we would not use immunotherapy as first-line treatment. Those are the more challenging tumors. By combining chemotherapy with immunotherapy, we are achieving an additive effect. We do not know whether it is synergistic, but at least there is an additive effect. This is a treatment option for patients whom monotherapy with a PD-1 inhibitor is not currently indicated. 

What else is important to note about genomic testing?

We would advocate for broad genomic profiling in every patient with lung adenocarcinoma that walks through the clinic. Some of these genetic alterations are already linked to FDA-approved therapies, and those should continue to be tested.

However, there is a broad panel of emerging biomarkers. For example, with MET

exon 14 skipping mutation, the HER2 mutation, or RET rearrangements, there are no FDA-approved drugs in lung cancer. Yet, there are drugs [that target these mutations] that have been approved in other disease settings. Even if we cannot offer something as standard of care, we can at least direct patients into appropriate clinical trials.

Overall, broad genomic profiling in addition to determining PD-L1 expression status should be the standard of care for patients with stage 4 disease that walk through the clinic. 

KRAS mutations in non-small cell lung cancer (NSCLC) present significant treatment challenges, with 25-30% of patients affected. Immunotherapy, particularly checkpoint inhibitors, shows promise for certain KRAS subgroups, notably the KP subgroup, which demonstrates a higher response rate. The CheckMate-057 trial supports immunotherapy's potential, especially with Opdivo, for KRAS-mutant patients. Biomarker research is crucial, with KRAS, p53, and STK11 mutations influencing treatment responses. Combining immunotherapy with chemotherapy, as seen in the KEYNOTE-021 trial, enhances outcomes, even in PD-L1-negative tumors. Broad genomic profiling is essential for personalized treatment strategies.

Ferdinandos Skoulidis, M.D., Ph.D. highlights potential treatment options for KRAS-mutated lung cancer and explores developments in biomarker research in other areas in the field.

Examining the Role of Biomarkers in the Management of Non-Small Cell Lung Cancer

When combined with other regimens in the treatment of patients with bladder cancer, immunotherapy has been shown to be beneficial, according to Arjun Balar, M.D., assistant professor in the Department of Medicine, and director, Genitourinary Medical Oncology Program, NYU Langone’s Perlmutter Cancer Center.

A phase 3 study is testing the combination of immunotherapy treatment Keytruda (pembrolizumab) and the IDO-inhibitor epacadostat. If it is shown to work well, it could become a preferred frontline regimen for patients with bladder cancer.

Keytruda is currently FDA-approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The PD-1 inhibitor is also approved in the frontline setting for patients with locally advanced or metastatic disease who are not eligible for cisplatin-containing chemotherapy.

In an interview with CURE, Balar, discussed novel immunotherapy combinations for the treatment of patients with bladder cancer.

 What is the status of immunotherapies and what are we looking forward to in the future?

Balar: There are several different ways of addressing the immune system in bladder cancer that are being tested in multiple clinical trials. One of the important pathways is the CTLA-4 pathway. There are early phase studies suggesting that the combination may lead to higher response rates and perhaps these responses might be durable. 

There are large experiences that are soon to be published. There is the phase I dose-expansion cohort of patients treated with Imfinzi (durvalumab) and tremelimumab. That data will hopefully be presented soon for patients with metastatic bladder cancer in the second-line setting. In the first-line setting, there are 2 large randomized phase 3 trials of PD-1 plus CTLA-4 that are currently ongoing but data for those 2 studies will not be available for a couple of years.

The IDO pathway is also interesting. IDO1 seems to be a key enzyme that regulates T-cell function, especially in PD-1 blockade tumors. The combination seems to be very well tolerated in terms of IDO plus PD-1. There are now phase I studies showing that the response rate of epacadostat, which is an IDO1 inhibitor, plus Keytruda seems to achieve a higher response rate. That has led Merck [the developer of Keytruda] to partner in 2 randomized phase 3 trials. One is in the first-line setting, whereas the other is in the second-line setting testing Keytruda with or without epacadostat.

What do you predict the treatment field of bladder cancer will look like in 5 or 10 years?

In 5 or 10 years, I believe that patients with metastatic bladder cancer will be receiving some form of combination immunotherapy. What is unknown at this point is what that combination might be. It is possible that a subset of patients will be treated with CTLA-4—based combinations. The other could be IDO plus PD-1 combinations but that certainly would be a significant contribution in terms of a new standard of care. 

In the muscle-invasive setting, patients with localized bladder cancer who may not be candidates for cystectomy or are refusing cystectomy may be treated with chemoradiation in addition to PD-1 blockade. We are seeing that there may be synergy between the combination of those treatment options. Now there are trials testing those combinations which may be a new standard of care in muscle-invasive disease, as well. 

Currently, how do you determine the sequencing of treatments for patients?

That is a tough question. I do not know if we have an answer of exactly how we should sequence therapies for patients with metastatic bladder cancer. We have 2 approvals in terms of disease settings. First, we have second-line metastatic bladder cancer after failure with platinum-based chemotherapy. It is clear that, for any patient who had previously received platinum-based chemotherapy and has now progressed, immunotherapy should be an option for them. 

The bigger question is for patients in the first-line setting who may be cisplatin ineligible; is immunotherapy the best treatment for the patient or is chemotherapy still an option? The majority of patients who are not eligible for chemotherapy should be treated with immunotherapy, and then perhaps with chemotherapy after. However, there is clearly a subset of patients who have a very extensive disease burden who are symptomatic and may benefit from chemotherapy first and followed by immunotherapy. That represents about 10 percent of all patients with bladder cancer.

Will chemotherapy be a mainstay in the treatment of patients with bladder cancer?

Absolutely; I do not think we are ready to give up on chemotherapy. Chemotherapy is still here to stay. It may represent the best option for a proportion of patients. It is still effective and can lead to durable responses in a minority of patients. Certainly, there may be ways of leveraging the effects of chemotherapy along with immunotherapy, perhaps in combination, as well. Certainly, chemotherapy will still be a part of the standard of care for some patients with metastatic bladder cancer.

As we continue to see advances in the field of metastatic bladder cancer, what advice do you have for community oncologists to decipher the new information?

It is tough when there are data coming out almost every other week at another medical meeting. [It is often challenging] to keep up with this information. Participating and continuing medical education activities, trying to attend meetings, and keeping up to date is one of the best ways of doing it. Are we looking at Bacillus Calmette-Guerin (BCG) in combination with systemic therapies? In non-muscle invasive bladder cancer that is intermediate or high risk, patients are often treated with intravesical immunotherapy with BCG. We know that a substantial proportion of these patients, even though they respond to intravesical BCG, will ultimately progress and have refractory/recurrent disease. For those patients, we often treat them with cystectomy, meaning that their bladder must come out. This is after multiple courses of BCG. 

Obviously, the challenge is that many of these patients do not want their bladder out. It is a morbid surgery where 60 percent of patients will have some form of a perioperative complication. This is a pressing need in terms of a novel therapy. There are now trials of systemic immunotherapy agents, such as PD-1 blockade, that is being tested in patients with non-muscle invasive bladder cancer focusing on several subgroups. One of them are patients who had prior BCG and have no other options. They are being treated with PD-1 blockade. 

There are also other trials looking at BCG plus PD-1 as primary therapy in patients who have high-risk muscle-invasive disease. We do not have any data yet from any of these trials to know how much PD-1 adds to this disease population. Ultimately, if we see that there are some durable benefits to these patients, then we may envision a future where systemic immunotherapy, such as PD-1 agents, may become standard of care for high-risk non-muscle invasive bladder cancer. 

Smith DC, Gajewski T, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: preliminary phase I/II results of ECHO-202/KEYNOTE-037. 

Immunotherapy, particularly when combined with other treatments, shows promise in bladder cancer management. Keytruda, an FDA-approved PD-1 inhibitor, is being tested with the IDO-inhibitor epacadostat in phase 3 trials, potentially becoming a frontline regimen. Novel combinations, such as PD-1 with CTLA-4 or IDO inhibitors, are under investigation. Future treatment may involve combination immunotherapies, with chemotherapy remaining a key component. Sequencing treatments remains complex, especially for cisplatin-ineligible patients. Ongoing trials explore systemic immunotherapy for non-muscle invasive bladder cancer, potentially establishing new standards of care.

When combined with other regimens in the treatment of patients with bladder cancer, immunotherapy has been shown to be beneficial, according to Arjun Balar, M.D.

Danielle Bucco

Looking Within: Exploring Genomic Testing for GI Cancers

Expert Discusses Exciting Advancements in Treating GI Cancers

Examining the Role of Biomarkers in the Management of Non-Small Cell Lung Cancer

Combination Immunotherapy Shows Promise for Bladder Cancer

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