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Despite Frontline Benefit in Trial, GI Oncologists Want Better Way to Select Patients for Lutathera


NEW YORK – The gastrointestinal oncology field has been abuzz over data Novartis recently shared on the activity of its radiopharmaceutical therapy Lutathera (lutetium Lu 177 dotatate) in patients newly diagnosed with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

At the American Society of Clinical Oncology (ASCO)'s Gastrointestinal Cancers Symposium on Friday, Simron Singh, a medical oncologist at the University of Toronto, presented promising data from the Phase III NETTER-2 trial comparing Lutathera plus the long-acting somatostatin receptor agonist drug octreotide against high-dose octreotide alone in certain patients with newly diagnosed, grade 2 and 3 GEP-NETs. Since then, GI oncologists have been parsing the data to better understand the implications for treating neuroendocrine cancer patients, especially in the first-line setting, as well as the limits of the biomarkers used to decide which patients should receive the treatment.

Patients who received the radiopharmaceutical plus octreotide lived a median 22.8 months without their cancers progressing, whereas the patients who received high-dose octreotide lived a median 8.5 months without progression. This translates to a 72 percent reduction in the risk of disease progression or death with the first-line Lutathera combination. The overall response rate for patients treated with the radiopharmaceutical-octreotide combination was 65 percent, versus 7 percent among patients on just high-dose octreotide.

"You could drive a truck between these two curves," Jordan Berlin, the director of hematology and oncology at Vanderbilt University Medical Center, commented after seeing a graph of patients' progression-free survival in the two treatment arms during a discussion of the trial results. "That's always nice to see."

In the US, Europe, and other countries, Lutathera is already a commercially approved option for the patient population in NETTER-2. But oncologists haven't been certain about using it as first-line treatment for this specific subgroup of GEP-NETs, said Junaid Arshad, a gastrointestinal medical oncologist, in an interview. Arshad added that he is considering changing his practice after seeing the NETTER-2 results.

In 2018, when the US Food and Drug Administration approved Lutathera — originally a product of Advanced Accelerator Applications, which has since become a Novartis subsidiary ­— regulators kept the indication broad. The radiopharmaceutical treatment, which is designed to deliver the therapeutic isotope lutetium directly to tumor cells while sparing healthy tissue, could be an option for adults with GEP-NETs, the FDA said, so long as their tumors expressed the somatostatin receptor, or SSRT. The FDA-approved label for the radiopharmaceutical did not specify tumor stage, grade, line of treatment, or biomarker status, nor did it specify how to select SSRT-positive GEP-NET patients.

The NETTER-1 trial, which provided data in support of this approval, showed a benefit specifically in previously treated patients. Subsequently, Lutathera became a standard treatment for progressive SSTR-positive, grade 1 or grade 2 midgut GEP-NETs. Beyond this subgroup, however, the jury was still out as to the radiopharmaceutical's benefit.

"NETTER-1 was conducted at a different time when not enough was known about radioligand therapies and neuroendocrine tumor biology and heterogeneity," Arshad said.

At the time of Lutathera's approval in the US, questions still remained as to how best to treat patients in the first-line setting and those with well-differentiated tumors. That earlier trial also focused on patients with midgut tumors and didn't include patients with pancreas tumors, he added. NETTER-1 also didn't include patients with grade 3 tumors.

"NETTER-2 is important since it addresses unanswered questions, including grade 3 tumors and pancreatic primaries," Arshad noted.

In subgroup analysis within NETTER-2, patients with both grade 2 and grade 3 tumors derived greater benefit from the Lutathera combination. This was true of patients across SSTR expression levels with radioligand functional imagining, too. "These data have clinical practice-changing implications and support the use of [Lutathera] earlier within the disease course of high grade 2 and grade 3 GEP-NETs," Singh said.

The Ki67 'myth'?

Although NETTER-2 has shed light on many unknowns, the study is also raising new questions about how to more precisely identify the patients who should receive and are likely to benefit from Lutathera.

Tumor grade in NETTER-2 was defined according to criteria that take into account the Ki-67 index, which measures expression of the Ki67 proliferation marker. As a biomarker, "Ki67 has been a pivotal development in NETs history," Arshad said. But "It is not perfect and cannot be the only marker used to assess prognosis."

Among well-differentiated NETs, grade 1 cancers are considered to be those with Ki67 indexes below 3 percent, and grade 2 NETs are those with Ki67 indexes between 3 percent and 20 percent. Grade 3 tumors with Ki67 indexes above 20 percent are a relatively new classification, Berlin noted in a discussion of the data at the ASCO GI meeting. Due to their exclusion from trials and the shift in classification systems, "up until now, we've had no idea of the effects of any of our approved therapies for this group."

Patients enrolled in NETTER-2 had to have a Ki67 index of at least 10 percent and no more than 55 percent. In contrast, the NETTER-1 study only included patients with Ki67 indexes up to 20 percent. "In NETTER-1, we did not look at the high-grade differentiated tumors based on Ki67," Berlin said.

Exploring further the role of the Ki67 biomarker in GEP-NETs in the context of the Lutathera results across both studies, Berlin said he now considers the biomarker a "myth."

"Ki67 was supposed to identify a very aggressive subset of well-differentiated neuroendocrine tumors," he said. "I would argue it didn't do a darn thing. It just confused neuroendocrine tumors."

The NETTER-2 results question the idea that tumors with high Ki67 indexes aren't sensitive to somatostatin analogues, too, according to Berlin.

"A gemish of retrospective data for a biomarker should not change the standard of care," he said. "Honestly, we really have not performed a thorough, prospective analysis of Ki67. I think we need to understand it a little bit better. We employed it before its time."

Echoing Berlin's concern about the utility of Ki67 as a GEP-NET biomarker, Arshad pointed out that the range for grade 2 NETs — 3 percent to 20 percent Ki67 indexes — is perhaps too wide to draw definitive conclusions about the biomarker's prognostic or predictive performance.

"Do patients with 4 percent Ki67 behave the same as 18 percent?" he asked hypothetically, noting that both biomarker values would classify a tumor as intermediate grade. Furthermore, Arshad pointed out that Ki67 testing from patients' biopsies may not consider intratumor heterogeneity.

As of now, "we do not have enough evidence to answer these questions," he said. Looking ahead, "one way of exploring this is a study of molecular alterations with Ki67 [to] understand the tumor biology and prognosis."

Radiopharmaceuticals enter the first line

Despite the remaining biomarker questions surrounding Ki67, the implications of NETTER-2 — particularly the fact that it was the first randomized trial to show radiopharmaceutical benefit in the first-line treatment setting — could be quite broad. And the Swiss drugmaker leading the way in radioligands is indeed championing the results.

Novartis has been actively working to develop this relatively new class of therapies for just-diagnosed cancer patients across tumor types, including in prostate cancer, where Novartis' prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical Pluvicto (lutetium vipivotide tetraxetan) was the first radiopharmaceutical to be FDA-approved, albeit in heavily pretreated patients. Novartis has been trying to establish Pluvicto's — and radiopharmaceuticals' overall — benefit in earlier treatment settings ever since its later-line Pluvicto approval in early 2022.

Establishing a benefit for first-line radiopharmaceutical treatment in SSRT-positive GEP-NETs, an indication where the radiopharmaceutical is, on paper, already FDA-approved, gives the company an immediately useful example to point to.

"This is the first positive Phase III trial of a radioligand therapy in the first-line setting, and the overall efficacy and safety results are amongst the most clinically relevant observed to date in this kind of advanced cancer," Novartis Global Head of Oncology Development Jeff Legos said in a statement released in tandem with the NETTER-2 data. "The positive results are a significant advancement and further reaffirm our strategy to research and develop radioligand therapies in earlier lines of treatment or stages of disease to improve outcomes for patients."

Still too early for universal uptake?

Even though Arshad, Berlin, and Singh all agreed that NETTER-2 establishes Lutathera as an option in the first-line setting, some GI oncologists still believe that perhaps not all patients need to receive the radiopharmaceutical as soon as they're diagnosed. Somatostatin analogues like octreotide are well established in the frontline setting, and Arshad stressed that he and his colleagues still want to see long-term efficacy and safety data. In NETTER-2, the safety profile for Lutathera was encouraging, but there was one concerning case of a patient developing a secondary hematologic malignancy related to the therapy.

"Further follow-up from NETTER-2 is still needed to answer questions in the tumors of different grades and primaries," he said, alluding to another question he still has: Are the overall response rates to the Lutathera regimen the same for patients with small intestine and pancreatic primary cancers?

"This study was well done and was clearly positive, but it's not the only option," Berlin said, expressing an interest in seeing overall survival analyses when the data mature. In the meantime, Berlin said he will likely use patients' tumor size as a way to stratify them for first-line Lutathera, instead of Ki67.

In his clinic, Berlin said that even though this isn't rooted in clinical data, he'll likely prescribe first-line Lutathera plus a somatostatin analogue like octreotide if patients have larger tumors. For patients with smaller tumors and small liver metastases, on the other hand, Berlin said he might begin with just a somatostatin receptor analogue.

Arshad said he might be inclined to do the same in the absence of further subgroup analyses. "It's too early to recommend Lutathera for all GEP-NETs in the first-line setting," he said. "The decision must be individualized based on tumor grade, disease burden, patient characteristics, safety, and access to therapy."