Mathew Shanley

Tumor response rates after initial treatment with peptide receptor radionuclide therapy (PRRT) have proven clinical benefit; however, complete response is uncommon. It is more likely than not that residual tumors will develop and progress again, and retreatment with extra cycles of PRRT as salvage therapy can be considered when safer and more efficient alternatives are not available.

At the 10th Annual North American Neuroendocrine Tumor Society (NANETS) Symposium, efficacy, progression-free survival (PFS), overall survival (OS), and toxicity data were presented regarding a cohort of patients with bronchial and gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) who had been treated with salvage PRRT with 177-Lu[Dota⁰,Tyr&sup3;]octreotate.

Study author Wouter van der Zwan, MD, research physician within the PRRT team at the Department of Nuclear Medicine of the Erasmus University Medical Center in the Netherlands explained that somatostatin receptors on the cell membranes are frequently expressed in the slowly-growing bronchial and GEP NETs. These receptors end up being an ideal target for therapy with Lutetium-177-labeled somatostatin analogues. Per the results of the study, outcomes regarding PFS and OS are comparable to that of somatostatin analogs, chemotherapy, or targeted therapies.

While 177-Lu[Dota⁰,Tyr&sup3;]octreotate is most frequently used in a neoadjuvant setting, it may also be used in adjuvant setting after surgery. Data shows that retreatment with additional cycles of 177-Lu[Dota⁰,Tyr&sup3;]octreotate does not lead to serious hematological or nephrotoxic side-effects, however, the reported tumor response rate was lower compared with initial treatment when the drug is used as a salvage therapy.

In a cohort of a study conducted by researchers at the PRRT Treatment Center Rotterdam from the Erasmus University Medical Center, 33 eligible patients with progressive disease after an initial radiologic or clinical response were treated with 2 additional cycles with an intended dose of 14.8 GBq of 177-Lu[Dota⁰,Tyr&sup3;]octreotate.2 Responses were evaluated using Southwest Oncology Group criteria, including minor response (tumor size reduction of &ge;25% and <50%).

After a median follow-up time of 16 months (range, 1-40), the intended cumulative dose was not achieved in 4 patients, 2 of whom had progressive disease. The other 2 suffered from long-lasting thrombocytopenia. Hematologic adverse events (AEs) of grade 3 was observed in 4 patients, and a grade 4 hematologic AE was observed in another. No kidney failure or myelodysplastic syndrome was observed in any patients, and 8 patients experienced renewed tumor regression (2 partial remissions, 6 minor responses). Eight patients were reported to have stable disease. The median time to progression was 17 months.

Patients with pancreatic NETs and GEP NETs experienced similar treatment effects, however, no patients enrolled in the study developed serious delayed adverse events (AEs), and it was concluded that the majority of patients tolerated additional cycles well. Reported effects among some in the study included weight loss and bone metastases, but neither responses were statistically significant.

It was frequently assumed that additional cycles with 177-Lu[Dota⁰,Tyr&sup3;]octreotate could potentially have exhibited antitumor effects; however, effects were less than for the regular cycles. This may be the result of a worse clinical condition, more extensive tumor burden, or changed tumor characteristics. Additionally, antitumor effects could potentially remain less favorable than with initial treatments because the administered activity for the additional therapy is approximately half that of regular treatments, which would lead to lower levels of radiation being delivered to the tumors.

Of 14 patients who were re-re-treated with PRRT,1 Van der Zwan said that the median PFS was 14 months (n = 12; 95% CI, 9.8-18.2) and the median OS was 29 months (n = 14; 95% CI, 4.6-53.4). Across the entire treatment period from initial treatment to salvage therapy, the OS was 77 months (95% CI, 63.1-91).

Following salvage therapy, grade 3/4 bone marrow toxicity was experienced in 7.1% of patients. No grade 3/4 nephrotoxicity was observed that was related to PRRT.

The decision to administer an intended dose of 2 cycles was made to try to avoid long-term side effects in patients, and it was concluded by the study&rsquo;s authors that the drug, when used as a salvage therapy, can be both effective and safe.

1. van der Zwan W, Brabander T, Kam B, et al. PFS and OS after salvage peptide receptor radionuclide therapy (PRRT) with 177-Lu[Dota⁰,Tyr&sup3;]octreotate in patients with gastroenteropancreatic or bronchial neuroendocrine tumours (GEP-NETs)  The Rotterdam Cohort. Presented at: 10th Annual NANETS Symposium; October 19-21, 2017; Philadelphia, PA. Abstract 284.

2. van Essen M, Krenning EP, Kam BLR, et al. Salvage therapy with 177Lu-Octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors.

. 2010;51(3):383-390. doi: 10.2967/jnumed.109.068957.

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Tumor response rates after initial treatment with peptide receptor radionuclide therapy have proven clinical benefit; however, complete response is uncommon.

PRRT Effective and Safe as Salvage Therapy for GEP and Bronchial NETs

Encouraging results are being seen following the administration of cabozantinib (Cabometyx) in patients with carcinoid and pancreatic neuroendocrine tumors (NETs). Clinical benefit of the drug has been exhibited in patients enrolled in a prospective phase II trial, which was initiated in July 2012; however, a randomized phase III trial will be necessary for confirmation.

During the 10th Annual North American Neuroendocrine Tumor Society (NANETS) Symposium in Philadelphia, Pennsylvania, the study&rsquo;s lead investigator, Jennifer A. Chan, MD, MPH, of the Dana-Farber Cancer Institute reported the recent successes of the multikinase inhibitor.

Cabozantinib targets vascular endothelial growth factor (VEGFR), among other tyrosine kinase receptors, including MET, and was approved in April 2016 for the treatment of advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy.

The expression of MET has been associated with decreased overall survival, and based on data from preclinical models that suggest the drug&rsquo;s ability to decrease the viability of cell lines, as well as metastasis and invasion in mass models, the phase II trial was conducted at the Dana-Farber Cancer Institute and Massachusetts General Hospital. Enrollment concluded in November 2015.

The primary endpoint of the study was objective response rate (ORR) based on RECIST v1.1 criteria and patients were stratified based on whether they had a NET of the pancreas or a carcinoid. It was hypothesized that cabozantinib would have a ORR of 12% or more. Secondary endpoints included progression-free survival (PFS), overall survival (OS), tolerability, and safety.

Sixty-one patients were dosed orally with cabozantinib at 60 mg daily by the commencement of the study, and continued treatment until disease progression, unacceptable toxicity, or withdrawal with consent. Twenty enrolled patients had previously been diagnosed with pancreatic NETs, and had received a median of 3 prior therapies (range, 0-8). The median age of these patients was 55 years, 60% were male, 40% had an ECOG performance status of 0, and 60% had a performance status of 1.

The remaining 41 patients had been diagnosed with carcinoid tumors, and the median number of previously administered therapies they had received was 1 (range, 0-6). Among the patients with carcinoids, the median age was 63 years, 44% were male, 51% had an ECOG performance status of 0, and 49% had a performance status of 1. No minimum pretreatment was necessary for inclusion.

Dose reduction was common (81%) throughout the evaluation of both groups, despite the carcinoid group being less heavily medicated prior to the start of the study.

Cabozantinib was administration over a 28-day cycle, and patients were re-staged after every 2 cycles for the first 6 cycles, followed by every 3 cycles. Patients with pancreatic NETs completed a median of 10 cycles of treatment (range, 0-35), while patients with carcinoid NETs completed a median of 8 cycles (range, 0-44).

Among the enrolled patients in the study, both those with pancreatic NETs and carcinoid tumors, the agent produced an ORR of 15% (95% CI, 5%-36%) in each group, all of which were partial responses. Data were analyzed in July of 2016 with a median follow-up time of 23.3 months, that demonstrated that median PFS was 21.8 months (95% CI, 8.5-32.0) in patients with pancreatic NETs and 31.4 months (95% CI, 8.5-not reached) in patients with carcinoid tumors.

When evaluating patients at follow-up, 15 of 20 patients with pancreatic NETs had stable disease with several experiencing a reduction in tumor size. In patients with carcinoid NETs, 26 had stable disease and 2 had progressive disease. Among grade 3/4 adverse events (AEs) experienced by the study&rsquo;s subjects, hypertension (13%), hypophosphatemia (11%), and diarrhea (10%) were the most common. Patients discontinued from treatment due to cabozantinib due to progression/death in 54%, withdrawal of consent or investigator decision in 28%, and AEs in 21%.

While these results are promising, Chan stressed the need to confirm the activity of cabozantinib in a phase III setting.

&ldquo;There are certainly limitations in interpreting progression-free survival durations in a relatively small single-arm phase II study,&rdquo; said Chan, &ldquo;but the results do look encouraging within the context of what&rsquo;s been reported in prior studies of targeted therapy for neuroendocrine tumors. It will be important to confirm the activity of cabozantinib in a randomized phase III trial setting.&rdquo;

The Dana-Farber Cancer Institute is currently in the final stages of planning a phase III randomized trial for the Alliance Cooperative Group of cabozantinib versus placebo in patients with advanced NETs after progression on everolimus (Afinitor).

Chan F, Fairs J, Murphy J, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors. Presented at: 10th Annual NANETS Symposium; October 19-21, 2017; Philadelphia, PA. Abstract 290.

Encouraging results are being seen following the administration of cabozantinib (Cabometyx) in patients with carcinoid and pancreatic neuroendocrine tumors. Clinical benefit of the drug has been exhibited in patients enrolled in a prospective phase II trial, which was initiated in July 2012; however, a randomized phase III trial will be necessary for confirmation.

Mathew Shanley | Authors

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PRRT Effective and Safe as Salvage Therapy for GEP and Bronchial NETs

Phase III Trial Needed to Confirm Clinical Benefit of Cabozantinib in Carcinoid and Pancreatic NETs