Strosberg Shares Key Strategies Propelling Progress in Gastrointestinal Cancers

Jonathan Strosberg, MD

Several research efforts examining novel approaches are showing improved survival benefit in patients with gastrointestinal cancers, according to Jonathan Strosberg, MD, who added that progress has even been observed in harder-to-treat diseases for which there had been years of stagnation between advancements.

“The progress in GI cancers has been mixed, but overall, if we look at all of the different types of cancers, some definite [advances] have been made over the past couple of years,” said Strosberg.

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Strosberg, a professor specializing in the management of gastrointestinal and neuroendocrine malignancies at Moffitt Cancer Center, highlighted key trials spanning gastrointestinal cancers, challenges faced in certain diseases, and the focus of future research efforts.

OncLive^®: Starting with pancreatic cancer, could you discuss the NAPOLI-1 trial? How did this trial lead to the NAPOLI-3 trial?

Strosberg: In the NAPOLI-1 trial, investigators evaluated second-line liposomal irinotecan (Onivyde) combined with 5-florouracil (5-FU)/leucovorinin patients who progressed on gemcitabine-based therapy. When compared with 5-FU/leucovorin, [the investigational regimen] resulted in an improvement in overall survival (OS).

The NAPOLI-3 trial is examining liposomal irinotecan in combination with 5-FU/leucovorin and oxaliplatin (NALIRIFOX) in the first-line setting. That study is comparing NALIRIFOX with gemcitabine and nab-paclitaxel (Abraxane). It will be interesting to establish whether NALIRIFOX is superior to gemcitabine and nab-paclitaxel and to see how liposomal irinotecan acts in combination with 5-FU/LV and oxaliplatin.

Could you highlight the anticipated results of the NAPOLI-3 trial?

Preliminary, single-arm data [from the trial] suggested reasonably high response rates and acceptable tolerability [with NALIRIFOX]. As far as the final trial outcomes, it will be interesting to see how the OS compares with [what has been seen with] FOLFIRINOX. We not only want to see how this regimen compares with that of gemcitabine/nab-paclitaxel; we would like to do a bit of a cross-trial comparison.

Shifting to hepatocellular carcinoma (HCC), 1 of the key trials that has generated excitement is the phase 3 IMbrave150 study. Could you shed light on this research and the clinical significance of its findings?

In this study, investigators evaluated the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) compared with sorafenib (Nexavar)in the first-line setting for patients with metastatic or locally advanced HCC.

This study was remarkable in terms of meeting the primary end point of significant improvement in both progression-free survival (PFS) and OS. In fact, OS was not reached in the investigational arm at the time of the primary analysis. This [trial] was a major step forward for patients with Child-Pugh class A HCC.

This was also the first significant advancement made in this disease since sorafenib was introduced, which was about 10 years ago. Other studies have demonstrated noninferiority [between experimental agents] and sorafenib, but I don't believe any agent has shown this degree of improvement.

Where should future research efforts be focused?

Now that we've developed a new first-line regimen with atezolizumab and bevacizumab in HCC, there's an opportunity to determine the optimal second-line treatment. Moreover, with the increasing use of tumor sequencing, there’s an opportunity to find out more about rare subpopulations and to develop targeted drugs that focus on particular mutations, rather than just treating tumors and conducting trials based on site of origin. Hopefully, sequencing and gene expression data will allow for a more targeted clinical trial platform.

Another trial that is generating excitement in the gastric cancer space is the phase 2 DESTINY-Gastric01 trial with fam-trastuzumab deruxtecan-nxki (Enhertu)? What data have read out and how has this agent performed in this space versus what has been observed with its use in other diseases?

This study evaluated trastuzumab deruxtecan versus investigator’s choice of chemotherapy in the third-line setting in patients with gastric or gastroesophageal junction adenocarcinoma. The response rate was 51% in the group of patients who received the antibody-drug conjugate versus 14% in the patients that received investigators choice chemotherapy. Promising preliminary activity was observed with this drug, which has also been used in breast cancer.

One of the last tumor types discussed during the IPC webinar was colorectal cancer (CRC). Could you speak to the importance of the phase 3 BEACON CRC trial? What should be taken away from this work?

This study evaluated the efficacy of targeted therapy for [patients with] BRAF V600E–mutated metastatic CRC. Results showed a remarkable improvement with encorafenib (Braftovi) plus cetuximab (Erbitux) versus investigator's choice of either cetuximab and irinotecan or cetuximab and FOLFIRI. This was 1 of the first studies to show that targeting 2 different pathways with a doublet regimen could significantly improve prognosis in these patients.

What challenges have been faced in this disease?

In CRC, which is the most common of these cancers in terms of incidence, the advancements have been relatively slow for microsatellite-stable tumors. We're starting to see new data in patients with BRAF mutations and even earlier data in patients with HER2 mutations, which represent about 4% of patients with metastatic disease. Beyond that, however, we’ve been using the same drugs that we have used for the past decade. As such, there is a lot of room for improvement.

You specialize in the treatment of patients with neuroendocrine tumors. What are some of the key developments to read out recently?

We have seen several updates in this space. A study in China evaluated the TKI surufatinib, which inhibits VEGF as well as other tyrosine kinase receptors. Results [with this agent] showed a significant improvement in PFS in patients with non-pancreatic gastrointestinal and thoracic neuroendocrine tumors (NETs),as well as in those with pancreatic NETs.

The company is applying to the FDA for [an] indication [with this agent] in the United States. We'll see if the regulatory agency will accept the data from China [and approve] this drug. To provide context, in non-pancreatic NETs, no VEGF-targeting TKIs are approved despite the fact that these tumors are highly vascular.

For pancreatic NETs, we already have sunitinib and it will be interesting to see whether physicians choose to go with surufatinib instead, or after sunitinib, based on a slightly different safety profile and potentially higher efficacy.

Multiple other TKIs are also under investigation, such as axitinib (Inlyta), which is being evaluated versus placebo in patients with non-pancreatic NETs; this is a large phase 3 study that is being conducted in Spain and results [are expected to] read out during the 2020 ESMO Virtual Congress. In the United States, another ongoing study is assessing cabozantinib (Cabometyx) versus placebo, based on promising phase 2 data.

All these studies have the potential to be positive; however, like other targeted agents [in this space], the objective response rates [observed with these agents] are relatively low, [ranging from] 10% to 20%. The main effect [of this treatment] is disease stabilization.

What are your thoughts on peptide receptor radionuclide therapy?

Some exciting data on peptide receptor radionuclide therapy have been released with regard to the alpha particle–emitting isotope ²¹²Pb–DOTAMTATE; this [treatment] was associated with exceptionally high response rates with the maximum-tolerated dose, which was discovered in the phase 1 study. Alpha emission is completely different from beta-emitting [radionuclide therapy], such as lutetium-177 (Lutathera)or yttrium-90; it delivers a much higher energy over a much shorter particle length. Although development may take more than a few years, I believe this [approach] has the potential to improve the therapeutic index that we are currently seeing with lutetium-177.

Novel immunotherapy combinations are also under exploration. Could you highlight a few approaches for which data are anticipated?

We have seen some interesting data looking at ipilimumab (Yervoy)and nivolumab (Opdivo) in poorly-differentiated neuroendocrine carcinomas. The prospective studies come from a basket study and the numbers are quite small, so it’s a bit hard to nail down the specific ORR.

Another study is evaluating durvalumab (Imfinzi) in combination with tremelimumab. For poorly-differentiated neuroendocrine carcinomas, where there are very few options beyond first-line treatment, I believe dual inhibitor immunotherapy may show some response.