New Sequencing Strategies Could Hold Key to Improved Outcomes Across GI Malignancies

Heloisa P. Soares, MD, PhD

With an influx of new therapeutic developments across gastrointestinal (GI) cancers on the horizon, new strategies around the sequencing of available regimens will be key to improving patient outcomes, according to Heloisa P. Soares, MD, PhD.

“There will be a lot of excitement for pancreatic cancer [in the future], although we are not quite there yet,” Soares said. “There are there are many new strategies [in development for other gastrointestinal malignancies] including a whole new role for immunotherapy plus or minus chemotherapy in the up-front treatment of [patients with] metastatic disease, as well as in the adjuvant setting.”

The virtual meeting, chaired by Soares, focused on updates in pancreatic cancer, gastroesophageal (GEJ) junction tumors, and neuroendocrine tumors (NETS).

In an interview with OncLive^® during the webinar, Soares, a medical oncologist and associate professor at Huntsman Cancer Institute, University of Utah, discussed recent developments in NETS, pancreatic cancer, and GEJ tumors, as well as sequencing strategies aimed at improving patient outcomes across GI cancers

OncLive^®: What changes to clinical practice for NETs treatment are taking place?

Soares: It is an exciting time to be a NET provider because there are many things that are coming up in the pipeline. In the last 5 years, there has been the approval of peptide receptor radionuclide therapy [PRRT], which is a game changer for the treatment of these patients, and there are other drugs that [hopefully will be moving through the pipeline, as well]. I am particularly excited about and hope we will be able to use surufatinib as an option for patients. It has shown promising data in the Asian population in studies that have been conducted in China for both pancreatic and extrapancreatic well-differentiated NETs. There was a phase 1 study [NCT0254993] done in the United States [US], so hopefully all of these [data] combined will be enough to support the approval of this medication for the US population.

Recently, [we saw the approval of] belzutifan [Welireg], which is a new medication that can be used for patients who have von Hippel–Lindau [VHL] syndrome. This [agent] has been approved for the treatment of any tumors associated with that [malignancy], particularly renal cell carcinoma, as well as pancreatic NETs. There is a lot of excitement that will come with different variations of PRRT, whether it is PRRT using radiosensitizer, chemotherapy sensitizers, or different radioisotopes. It is not ready for prime time, but I hope it will [be available] in the next few years.

In your presentation, you highlighted upcoming systemic therapies in this patient population. Could you elaborate on the data that have been reported out thus far?

IIn terms of systemic therapies, we heard the updated survival data for the phase 3 NETTER-1 study [NCT01578239] at the 2021 ASCO Annual Meeting. Even though there was not a significant statistical difference between patients who receive PRRT vs the control arm, which was octreotide LAR [Sandostatin] at 60 mg, when looking at the difference in survival between patients, there was a very different median overall survival [OS] of 48 months [vs] 30 months. [These were] encouraging data, which [demonstrated that] PRRT does have an impact on OS.

[Another] systemic treatment in the pipeline is surufatinib, which is a novel mechanism of a TKI that targets VEGFR-1, VEGFR-2, VEGFR-3, FGFR1, and CSF1R. It is an oral medication that is given daily to patients and has been studied in the pancreatic NET population with well-differentiated tumors, as well as the extrapancreatic NET population. The progression-free survival [PFS] in patients who received this [agent] vs the control was positive. This is a medication that will [hopefully be] coming to the market [soon]; the company has already asked the FDA for its approval.

Again, belzutifan is a medication that was approved by the FDA in August 2021 [for patients with VHL disease] and is a hypoxia-inducible factor. We saw encouraging data from a small phase 2 study [NCT03401788] that showed [the agent induced] an overall response rate [ORR] of up to 49%. Twelve of the patients who participated in the study had pancreatic NETS and the ORR of these patients was 83%. We are excited to have the opportunity to use [this agent] in clinic.

Additionally, cabozantinib is a medication that the National Cancer Institute is currently studying for patients with well-differentiated NETS in an ongoing phase 3 study [NCT03375320]. Once this study is completed, hopefully we will have something else on the market for patients with pancreatic NETS.

Regarding the PRESTO study, which evaluated nurse preferences between the lanreotide autogel new syringe vs the octreotide long-acting release syringe, why was lanreotide autogel syringe preferred for patients with NETs?

Nurses are very important in the care of patients with NETs. These patients are seen in clinic frequently as they have a chronic disease, and we establish long-lasting relationships with them. The nurses are the ones administering the drugs [to patients], and their feedback is crucial in terms of impacting the quality of life for patients in a positive way.

Knowing and understanding their experiences when they administer the drug is important. This study was done to assess nurse’s preference in terms of giving the injection, and comparing lanreotide autogel vs octreotide long-acting release, and favored lanreotide autogel in the sense that nurses felt the experience of giving the drug was much better. [With lanreotide autogel] there were less issues with clotting in the syringe, which is something important [day-to-day in clinic], as this causes patients to have to get the injection again, and [more doses need to be used]. There is a whole logistical operation [that is disrupted] if the syringe clots. [This study] validated some of the feedback we receive from patients and nurses in terms of the different syringes and drugs.

During the program, your colleague Ignacio Garrido-Laguna, MD, discussed optimizing therapy in patients with advanced pancreatic cancer. Could you speak to some strategies for first- and second-line treatment in terms of sequencing?

For locally advanced metastatic pancreatic cancer, there are [currently] 2 chemotherapy regimens that are used, FOLFIRINOX or gemcitabine and nab-paclitaxel (Abraxane). No study has done a head-to-head comparison, therefore, deciding which patients should get which treatment is challenging. Typically, FOLFIRINOX is reserved for patients with a very good [ECOG] performances status, [and those with a performance status of] 2 tend [to get] gemcitabine and nab-paclitaxel because FOLFIRINOX can be harder on them.

There are some retrospective studies investigating sequencing and whether there is a true difference between choosing 1 regimen to give first over the other, assuming that [both regimens can be utilized. There are maintenance strategies [that can be used] after completing initial treatment, [such as that seen in the] PRODIGE 35-PANOPTIMOX trial, which [examined] maintenance after patients received an initial induction with FOLFIRINOX. There is also the phase 2 APOLLO trial [NCT04858334], investigating the use of a maintenance strategy with olaparib [Lynparza] once the initial induction with FOLFIRINOX is completed. This study did show improvement in PFS, but so far has not shown improvement in OS.

Additionally, it is important to be aware that patients with BRCA mutations could benefit from a treatment strategy using gemcitabine and cisplatin as an up-front regimen compared with FOLFIRINOX.

Another lecture given by G. Weldon Gilcrease, MD, discussed updates in upper GI malignancies, and hit on trials such as the phase 3 Neo-AEGIS (NCT01726452), CheckMate 648 (NCT03143153), and CheckMate 577 (NCT02743494). What is the impact of these trials on clinical practice?

First, Neo-AEGIS was a study examining whether there is a better option for patients who have GEJ tumors, and whether they should receive perioperative chemotherapy or radiation. In brief, there was no difference in OS between both strategies, so the take-home message was that [both are feasible options].

The CheckMate 577 study looked at the role of adjuvant immunotherapy with nivolumab [Opdivo] in patients with GEJ tumors who have received chemoradiation and have residual disease. These patients were randomized to receive either nivolumab or observation, as there are no other adjuvant strategies in place for this population. The study was positive [in terms of] disease-free survival [DFS]. The DFS of the patients who received nivolumab was approximately 22 months vs 11 months in those randomized to observation only. This is practice changing based on the data that we have thus far. We do not have OS data for these patients yet, but the DFS is something that is clinically meaningful.

The CheckMate-648 study examined chemotherapy plus immunotherapy or immunotherapy alone for the treatment of patients with metastatic GEJ squamous cell carcinoma. This study showed that chemotherapy plus immunotherapy is positive compared with chemotherapy alone, and that there may be a subgroup of patients that benefit from dual immunotherapy strategies and can completely avoid chemotherapy. In the United States, a minority of patients have GEJ squamous cell carcinoma, so although it important to be implementing these strategies, they are not the backbone of the clinical.

Finally, Dr. Vaia Florou’s presentation discussed updates in gastrointestinal stromal tumors (GIST). What is the importance of mutational testing in this population, and how might it help to guide treatment?

GIST is an evolving field, and it is important to decide on strategies either up front, or through refractory disease. It is important to get sequencing on the tumors and to assess tumor mutational burden, new mutations, and gatekeeper mutations at the time of progression. [Additionally, it is important to note] that either tissue biopsy or liquid biopsy can be used, so tissue biopsy is not necessary the only way to evaluate mutations at the time of progression.