Making Up for Lost Time in GI Cancers

Tanios S. Bekaii-Saab, MD

Until recently, the treatment arsenal for gastrointestinal (GI) cancers has lagged 2 to 3 decades behind other tumor types in the development of targeted and immunotherapy agents, according to Tanios S. Bekaii-Saab, MD. The good news, he says, is that the field has started to gain ground.

“We’re catching up, and we’re catching up quickly,” Bekaii-Saab said in an interview with OncLive^®, adding that investigators are beginning to understand how to better target the biology of GI cancers that they have been studying over the past 30 years. “The great thing is, this is only the tip of the iceberg. We’re learning so much about these hidden targets, and we have so many agents that [will attack these] hidden targets. These agents are going to ultimately transform how we treat GI cancers. We’re catching up, and in the next 3 to 5 years, we’ll probably be ahead of the curve again.”

Bekaii-Saab leads the GI cancer program for the Mayo Clinic Cancer Center through its 3 sites in Arizona, Florida, and Minnesota. He is also the medical director of the cancer clinical research office and vice chair and section chief of medical oncology for Mayo Clinic in Arizona. Additionally, Bekaii-Saab leads the Mayo Clinic–supported cancer research consortium, Academic and Community Cancer Research United (ACCRU), and is one of the leading clinician-scientists in the Alliance for Clinical Trials in Oncology, a National Cancer Institute–supported cooperative research group.

ISGIO: Exploring the Year's Top Research

Bekaii-Saab is a highly regarded clinical and translational investigator who collaborates extensively with various scientists from Mayo Clinic and other academic centers as well as multiple industry partners to design and execute innovative clinical trials, including first-in-human studies. His contributions to the GI oncology field include noteworthy research on emerging agents (Table^1-5).

Table. Select Examples of Bekaii-Saab’s Contributions to Novel Drug Development^1-5

This fall, Bekaii-Saab will serve as program chair for the 2020 International Society of Gastrointestinal Oncology (ISGIO) Conference, marking the first time he has held that role. The meeting, scheduled for October 2 and 3, was planned as an in-person gathering in Nashville, Tennessee, and will now go forward as a virtual interactive meeting. The agenda is not finalized, but Bekaii-Saab said the meeting has been overhauled and is well on its way to becoming a premier conference in GI cancer. The program, which is hosted by Physicians’ Education Resource^®, LLC (PER^®), will feature crossfire-style debate sessions, case presentations, and other elements to make the meeting an interactive experience.

“The ISGIO meeting has essentially been revamped but has kept some of its tradition of being focused on educating young faculty and fellows, in addition to the cancer community at large. At the same time, we’re increasing the level of diversity of speakers, session chairs, and geographical representation, as well, to ensure that we have the largest reach possible for this meeting,” Bekaii-Saab said.

Bekaii-Saab added the timing of the ISGIO conference means that the program can summarize the best and most important data from a full year of relevant meetings held by the American Society of Clinical Oncology, the European Society for Medical Oncology, and the American Association forCancer Research. Over 2 days, ISGIO will cover a year’s worth of research presentations and publications that have not only transformed clinical care, but will also inform future research.

He also said ISGIO will help community oncologists, who see most of the patients with GI cancer and treat a variety of other cancers, cut through the noise and absorb the most important new data in the field.

“If you think about the information overload that we get throughout the year, how do you digest this and bring it in a fashion that’s clinically applicable and easy to follow and easy to understand? Our goal is for the practicing oncologist who sees the next patient with GI cancer to be able to place all this knowledge into immediate practice,” Bekaii-Saab said. “We’ll put all these data into perspective [to show] how to best treat your patient with pancreatic cancer, colon cancer, or gastric cancer in a format that actually makes it very clinically applicable and easily understandable.”

He added that he also wants to continue ISGIO’s tradition of serving fellows and junior faculty. Educating physicians in the early stages of their careers maintains a “continuity of expertise” in GI cancers, Bekaii-Saab said. Doing so benefits the GI field specifically, now and in the future, and also enriches the larger oncology community who cares for these patients.

An Early Passion for Medicine

The role models that shaped Bekaii-Saab’s career journey were readily available in his own family. He fondly recalls 2 of his father’s uncles, Ibrahim and Naeem, who were doctors. Ibrahim traveled on horseback between villages in Lebanon’s Bekaa Valley, whereas Naeem used to make emergency house calls 24 hours a day in Beirut during a ravaging civil war. The brutal war began when Bekaii-Saab was 6 years old and did not end until he was 21.

“At the time when there weren’t a lot of roads between mountain villages, I was told by my grandmother that Uncle Ibrahim used to ride on a horse and go from village to village to treat patients,” Bekaii-Saab said. “He never got paid but was offered poultry, vegetables, or whatever else. Most times he didn’t get anything, and it didn’t matter to him. That was his mission, and he loved every bit of it.”

Bekaii-Saab developed a deep admiration and respect for his father’s uncles, who could go from treating a simple cold to performing minor surgeries in a single day. From an early age, he knew he would follow in their footsteps. A few years ago, he was visiting his parents’ house in Lebanon and stumbled upon one of his journals from when he was 10, tucked inside a childhood memory box saved by his mother.

“In between a couple of short childhood poems and drawings of my favorite animals, I found an ‘autobiography’ only with a child’s imagination, where I described becoming a physician when I grow up. I predicted I’d go to medical school at the American University of Beirut, which is interesting because that’s where I ended up studying medicine,” Bekaii- Saab said. “At 10 years of age, I was already thinking about the path I wanted to follow.”

Despite the hardships of the Lebanese Civil War on welfare and education, he was able to pursue his dream. Even after the war ended, electricity remained a luxury, and Bekaii-Saab spent numerous nights studying and preparing for his United States Medical Licensing Examination under candlelight in the sweltering Beirut summers.

He added that the journey of a foreign medical graduate to a position in the United States can be quite challenging, but with an entrepreneurial spirit, perseverance, and hard work, he figured out why indeed America is called the land of opportunity.

Molecular Targets Expand

When it comes to the GI cancer landscape, Bekaii-Saab said oncologists treating patients with metastatic colorectal cancer (CRC) have spent far too long debating the use of the chemotherapy regimens FOLFOX versus FOLFIRI and whether bevacizumab (Avastin) or anti-EGFR inhibitors should come first in the treatment sequence. Oncologists have now moved on to breaking down CRC into therapeutically relevant subgroups based on molecular alterations such as KRAS and BRAF V600E mutations, HER2 amplification, and microsatellite instability (MSI) status. Tumor mutational burden was recently described as another relevant biomarker for choosing candidates for anti–PD-1 inhibitor therapy in certain settings.

Bekaii-Saab said that in GI cancers, he needs data on several factors before he can even begin treating the patient. Collecting all this information using separate tests is possible, but genomic sequencing is faster and more effective.

“I don’t think anymore that genomicsequencing is a privilege—it should be a right,” he said, adding that every patient with an advanced GI malignancy should be sequenced, not just those with CRC. “We have to find every way possible to get their tumors sequenced.

“Sometimes it sounds like we’re looking for needles in a haystack,” he explained further. “Indeed, we are trying to capture rare targets such as NTRK and RET fusions. The less consistently you test, the less likely you’re going to find these rare targets. The more consistently you test, the more likely you’re going to find them, and it is very satisfying when you do. And so 1 snapshot with full genomic sequencing should give you everything you need to best plan for the needs of your patient.”

Developments in molecular testing are driving the field, and the testing itself has gotten better and more clinically relevant. Furthermore, investigators are gaining a deeper understanding of what these molecular defects mean and how to target them therapeutically. Bekaii-Saab added that, in turn, investigators are able to explore drugs that work in novel ways and attack previously unknown but relevant targets.

Moreover, investigators are discovering rare genomic drivers and developing new agents to target those drivers and allow oncologists to further personalize treatment in smaller and smaller subsets of patients. NTRK gene fusions, for example, are present in 0.5% to 1.0% of all GI cancers, but these cancers respond to treatment with the first-generation TRK inhibitors larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) regardless of histology.⁶

RET fusions are present in less than 1.0% of all patients with CRC or pancreatic cancers, with recent study results suggesting that these alterations can be targeted with robust results, Bekaii-Saab said. If they are properly identified, some patients with RET or NTRK fusions will have responses as robust as those induced by PD-1 inhibitors in MSI-high CRC.

Additionally, investigators are unlocking the mysteries of FGFR fusions. On April 20, 2020, the FDA approved pemigatinib (Pemazyre) for patients with cholangiocarcinoma and FGFR2 fusions. Investigators also are exploring this target in other GI cancers, Bekaii-Saab said.

Other interesting targets include NRG1 gene fusions, present in a variety of cancers but of special interest in approximately 20% of patients with RAS wild-type pancreatic cancer. “Agents like the bispecific antibody MCLA-128, afatinib [Gilotrif], or other agents in development could, for 0.5% of patients with pancreatic cancer, transform how we treat that small subgroup,” Bekaii-Saab added.

He noted that investigators are actively exploring the role of cellular therapy and chimeric antigen receptor (CAR) T-cell therapy in colon, pancreatic, and gastroesophageal cancers based on target validation. “Across the board in oncology, we’re seeing an explosion of targets and immunotherapeutic strategies from enhancing the activity of PD-1/PD-L1 inhibitors to CAR T-cell therapy,” he said. “We’re really moving that field at an astronomical speed. It gets dizzying sometimes to keep up with the evolving landscape.”

Four Practice-Changing Studies

In shaping the conversation about recent studies with the potential to change practice in GI malignancies, Bekaii-Saab cited recent findings from 4 clinical trials: KEYNOTE-177 and BEACON CRC in colorectal cancer, IMbrave150 in hepatocellular carcinoma (HCC), and POLO in pancreatic cancer.

KEYNOTE-177 Study in CRC

In KEYNOTE-177 (NCT02563002), pembrolizumab (Keytruda) therapy significantly reduced the risk of disease progression or death by 40% (HR, 0.60; 95% CI, 0.45-0.80; P = .0004) versus standard-of-care chemotherapy in the first-line treatment of patients with MSI-high or mismatch repair–deficient (dMMR) unresectable or metastatic CRC. Additionally, the PD-1 inhibitor was found to more than double progression-free survival (PFS) versus chemotherapy, at 16.5 versus 8.2 months.⁷

Additional results showed that the 12-month PFS rate was 55% in the pembrolizumab arm and 37% in the chemotherapy arm; the 24-month PFS rates were 48.3% and 18.6%, respectively. The overall response rate (ORR) was 43.8% with pembrolizumab, which included a 11.1% complete response (CR) rate and 32.7% partial response (PR) rate. TheORR was 33.1% with chemotherapy, which comprised a 3.9% CR rate and a 29.2% PR rate.

The median duration of response was not reached in the immunotherapy arm compared with 10.6 months with chemotherapy. Responses lasted more than 2 years for 83% of responders in the pembrolizumab arm and for 35% of responders in the chemotherapy arm.

In the phase 3 trial (N = 308), patients were randomized to investigator’s choice of 1 of 6 standard-of-care chemotherapy regimens or a fixed dose of pembrolizumab 200 mg every 3 weeks for up to 35 cycles or approximately 2 years. Overall survival (OS) data are not yet mature.

On June 29, 2020, the FDA approved pembrolizumab in this patient population based on findings from KEYNOTE-177. Approximately 10% to 15% of patients with CRC are likely to have MSI-high or dMMR tumors.

Bekaii-Saab called the results “one of the biggest stories over the past few years, at least in colon cancer.” Not only is the breadth of response impressive, he said, but responses are deep and durable.

“The response is, for most of these patients, quite meaningful. It’s not just the level of response, which in many patients is actually a complete response,” Bekaii-Saab explained. “It’s the durability of the response whereby about 20% to 30% of the patients continue to respond to treatment, even after you stop the treatment at 2 years, which was the intent of the original study with pembrolizumab, and then continue to be in remission, which is the equivalent of a cure after 5 years.”

These data mean that patients no longer have to fail on chemotherapy before moving on to immunotherapy. In his practice, Bekaii-Saab was already using pembrolizumab in the first-line setting for patients with MSI-high tumors, reasoning that up to one-third may never need chemotherapy.

“I would say this has transformed the way we treat MSI-high tumors period, beyond just metastatic CRC,” he said. “Meaning that if I have a gastric cancer or a pancreatic cancer, or a patient with cholangiocarcinoma who has MSI-high [disease], I’m going to treat them with pembrolizumab at first, before even trying to consider chemotherapy, because I do believe that the results—and we’ve seen that in the later lines—are consistent regardless of anatomic site. It doesn’t matter where the cancer [originates]; it’s the presence of the MSI-high phenotype that’s essentially determining the level of response.”

BEACON CRC Trial in CRC

Updated findings from the BEACON CRC study (NCT02928224) demonstrated a continuing OS benefit for patients with BRAF V600E–mutated metastatic CRC treated with encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) compared with cetuximab plus irinotecan-containing regimens.⁸

Data presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed that the median OS was 9.3 months with the triplet compared with 5.9 months in the control arm (HR, 0.60; 95% CI, 0.47-0.75). The doublet also demonstrated superior OS compared with the control (9.3 vs 5.9 months; HR, 0.61; 95% CI, 0.48-0.77). Median OS for the entire cohort was 12.8 months.

PFS was 4.5 months with the triplet compared with 1.5 months for the control arm (HR, 0.42; 95% CI, 0.33-0.53). The median PFS with the doublet was 4.3 months (HR, 0.44; 95% CI, 0.35-0.55).

ORR was 27% with the triplet, 20% with the doublet, and 2% in the control arm. The ORR with the triplet comprised a CR rate of 4% and a PR rate of 23%. An additional 48% of patients had stable disease, whereas 11% of patients had progressive disease and 14% were not evaluable for response. Among patients who received the doublet of encorafenib and cetuximab, the ORR comprised a CR rate of 3% and a PR rate of 16%.

Updated safety data showed that grade 3 or greater adverse events (AEs) and laboratory abnormalities were consistent with the previously reported safety profile for the treatments.

“With the biologic combo versus chemotherapy plus cetuximab, what we’ve seen essentially is a significant improvement of survival and overall survival,” Bekaii-Saab said. “Enhancing response rate in up to a quarter of the patients will have a meaningful response. The patient’s quality of life was also significantly better, and patients experienced less toxicity. So you win on all these important points reflecting qualityand quantity-related outcome measures. The doublet of encorafenib with cetuximab is now a standard for our patients with colon cancer and BRAF V600E mutations who failed prior chemotherapy.”

Based on previously published data from BEACON CRC, the FDA approved the doublet regimen of encorafenib plus cetuximab on April 8, 2020, for the treatment of adult patients with metastatic CRC with a BRAF V600E mutation following failure of prior chemotherapy. Given the transformative results of the refractory trial, plans call for this combination regimen to be tested in the frontline setting versus standard chemotherapy in the BREAKWATER study.

Based on the promise of circulating cellfree DNA next-generation sequencing in the detection of relevant genomic targets in CRC, the ACCRU consortium has launched COLOMATE (NCT03765736) to assess the impact of molecularly assigned therapy accordingly under its growing list of individual companion studies. Investigators aim to screen 5000 patients, making it the largest international umbrella screening protocol to identify actionable genomic alterations in patients with metastatic CRC.

IMbrave150 Trial in HCC

Bekaii-Saab said expectations were low for immunotherapy in HCC following disappointing results from studies assessing PD-1/PD-L1–immune checkpoint inhibitors. Data from the IMbrave150 trial (NCT03434379) “reenergized the field of immunotherapy in targeting HCC,” he said.

In the global, randomized, phase 3 trial, patients with treatment-naïve advanced HCC were randomly assigned to bevacizumab plus the PD-L1 inhibitor atezolizumab (Tecentriq; n = 336) or sorafenib (Nexavar; n = 165).

At the time of the primary analysis in August 2019, the HR for death with the atezolizumab/bevacizumab regimen was 0.58 (95% CI, 0.42-0.79; P < .001). Twelvemonth OS was 67.2% (95% CI, 61.3%-73.1%) with atezolizumab/bevacizumab compared with 54.6% (95% CI, 45.2-64.0) with sorafenib.9 The median PFS was 6.8 versus 4.3 months favoring the combination (HR, 0.59; 95% CI, 0.47-0.76; P < .001).

Among patients who received at least 1 dose of atezolizumab/bevacizumab (n = 329), 56.5% experienced grade 3/4 AEs compared with 55.1% of patients who received at least 1 dose of sorafenib (n = 156). In the combination arm, 15.2% of patients experienced grade 3/4 hypertension.

An analysis of patient-reported outcomes presented at the 2020 Gastrointestinal Cancers Symposium showed that patients treated with atezolizumab/bevacizumab experienced more prolonged quality of life. The median time to quality-of-life deterioration was 3.6 months with sorafenib versus 11.2 months with atezolizumab/ bevacizumab (HR, 0.63; 95% CI, 0.46-0.85). These findings further support the positive benefit-risk profile of atezolizumab plus bevacizumab and complement the efficacy data in these patients with HCC.¹⁰

“This is now the undisputed standard of care for most patients with advanced HCC,” Bekaii-Saab said. “Our focus is to define the best strategy following failure of this combo in further lines of therapy.”

Based on these data, on May 29, 2020, the FDA approved atezolizumab in combination with bevacizumab for patients with unresectable or metastatic HCC who have not received prior systemic therapy.

POLO Study in Pancreatic Cancer

Findings from the phase 3 POLO trial (NCT02184195) demonstrated that the PARP inhibitor olaparib (Lynparza) induced a 47% reduction in the risk for disease progression or death (HR 0.53; 95% CI 0.35-0.81; P = .0035) among patients with germline BRCA1/2-mutated metastatic pancreatic cancer.^11,12 Moreover, in confirming that BRCA is a driver mutation in this malignancy, the results provide the first actionable molecular target in pancreatic cancer.

“That is transformative,” Bekaii-Saab said. “That tells us that when you identify the driver, you can actually off-load the switch in a way that for some patients, durable remissions could be achieved.”

In the randomized, double-blind, placebocontrolled trial, investigators evaluated the efficacy of olaparib as maintenance therapy in 154 patients with a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy.

Patients were randomly assigned to 300-mg twice-daily oral olaparib tablets (n = 92) or placebo (n = 62). The median duration of therapy was 6 months in the olaparib arm and 3.7 months in the placebo arm. Treatment continued until objective radiological disease progression. Following progression, patients were followed for second progression every 8 weeks and then for survival until final analysis.

Median PFS was consistent irrespective of response to prior platinum-based chemotherapy (complete/partial HR, 0.62; stable disease HR, 0.50). At 6, 12, 18, and 24 months, the percentage of patients who were progression free in the olaparib arm was more than twice that in the placebo arm (6-month PFS, 53% vs 23%, respectively).

Additional results showed that the ORR was 23.1% with olaparib compared with 11.5% in the placebo arm (odds ratio, 2.30). Two patients (11.1%) assigned to olaparib achieved CR compared with 0 on placebo. The median duration of response was 24.9 versus 3.7 months in favor of olaparib.

Unfortunately, an early switch to olaparib did not improve OS. “The absence of a survival benefit limits the clinical applicability of the study,” Bekaii-Saab said. “The main transformational aspect of POLO is the validation of BRCA as a target of interest in pancreatic cancer, with more research warranted to help enhance the modest activity observed with single-agent PARP inhibition in this disease.”

A Good Kind of Pride

As he works to move the field of GI cancers forward, Bekaii-Saab embraces the task of training and mentoring fellows and junior faculty. Early in his career, he benefited from the guidance of advisers including Miguel Villalona-Calero, MD; Michael A. Caligiuri, MD; and the late cancer genetics pioneer Clara D. Bloomfield, MD, a Giants of Cancer Care^® award winner. But he never had a more experienced GI specialist as a mentor. He sometimes struggled to find his way, which may be why he spends so much of his time working with younger physicians today.

“My development was a little bit unorthodox in that sense. But I would say that I learned quite a bit from the limitations of how I initially developed my career,” Bekaii-Saab said. “I sometimes overcompensate, I think, when I mentor younger folks and try to make sure that they get as many opportunities as possible early on, so they don’t have to go through some of the struggles I had to go through.”

Young physicians need strong mentorship for the first few years of their careers, Bekaii- Saab said. A good mentor, he said, must provide their protégés with opportunities to grow while also knowing when to get out of the way and let them take the spotlight.

“Oftentimes, mentors forget that ultimately we will be, hopefully, replaced by this younger generation of GI oncologists,” Bekaii-Saab said. “But to get them there, we have to start initiating their growth early and hope that they’ll become better than their mentors when they reach their peak. If you go with that frame of mind, you will enjoy mentorship.”

Which is not to say his motivations as a mentor are entirely altruistic. Bekaii-Saab admits to personal satisfaction in seeing the physicians he has trained go on to develop novel cancer therapies, stand as a discussant in large meetings, or become leaders in the field.

“It’s almost like a parent who sees a child grow up, go to college, and develop a successful destiny in life,” Bekaii-Saab concluded. “It’s the same thing when someone you mentored becomes incredibly successful—you want to aim for someone you mentored to become your boss one day, and you’re going to be the proudest ever.”

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