Lisa Miller

Adjuvant therapy with tyrosine kinase inhibitors (TKIs) for patients with high-risk renal cell carcinoma (RCC) who have undergone a nephrectomy may be supported by level IIa evidence from the National Comprehensive Cancer Network (NCCN) guidelines, yet this approach is still controversial, with many physicians believing that there are not yet enough data in support of its use.

Several studies have already been completed looking at the use of adjuvant TKIs in this setting, and many more are due to release data and further findings in the near future, so this hot topic is rapidly changing as data become available supporting one side of the debate or the other.

In a debate during the 2017 Debates and Didactics in Hematology and Oncology conference, 2 oncologists argued over the current findings for and against the use of adjuvant TKI treatment in high-risk patients with RCC following surgery. Mehrdad Alemozaffar, MD, spoke in favor of adjuvant TKI therapy and Mehmet Asim Bilen, MD, argued against. Each addressed 3 trials, ASSURE, S-TRAC, and PROTECT, that all studied adjuvant TKI treatments in this setting.

The first trial that both debaters raised was the double-blind, placebo-controlled, randomized phase III ASSURE/ECOG-ACRIN E2805 trial, which looked at 1 year of adjuvant sunitinib (Sutent), sorafenib (Nexavar), or placebo in 1943 patients with resected nonmetastatic RCC at a high risk for recurrence. The trial was looking to disease-free survival (DFS) as its primary endpoint, but no statistically significant DFS advantage was noted in this trial over placebo.

The median DFS for sunitinib at the primary analysis was 5.8 years (hazard ratio [HR] compared with placebo, 1.02; 97.5% CI, 0.85-1.23; P = .8038); with sorafenib the DFS was 6.1 years (HR compared with placebo, 0.97; 97.5% CI, 0.80-1.17; P = .7184); and the DFS was 6.6 years with placebo. Additionally, toxicity was increased with the TKIs, with grade &ge;3 hypertension, hand-foot syndrome, rash, and fatigue all experienced at a higher rate than seen in the patients taking placebo.

However, Alemozaffar, an assistant professor in the Department of Urology at Emory University School of Medicine, believed that this was not the right trial on which to base a decision because of many issues. For example, 79.3% of patients on the trial had clear-cell RCC whereas 20.7% did not. Additionally, although the trial was intended for patients who had a high risk of recurrence, 34.7% were not characterized as high risk; they had either stage I or II disease.

Bilen, an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, pointed out that even in updated findings of the clear-cell RCC subgroup, no DFS advantage was found for either TKI at 5 years compared with placebo.

At 5 years, the DFS rate was 47.7% with sunitinib, 49.9% with sorafenib, and 50% with placebo. A difference in survival was not seen by dose quartile either.

The trial was problematic, with 43.6% patients discontinuing the trial due to toxicity-related issues.

Investigators then had to redesign the trial and reduce the dosage of each treatment and individually bring patients back up to the original full doses if they could tolerate the lower dose. &ldquo;The inadequate dosing may be responsible for the negative findings,&rdquo; Alemozaffar said.

Additionally, the safety monitoring committee determined that blinded follow-up needed to be ended ahead of schedule. And finally, no central review of the primary endpoint by imaging was completed, and statistical issues were found with posthoc analyses of the trial,

including analyses of the discontinuation rates.

Alemozaffar said that the next trial, the S-TRAC trial, was the right trial for this specific setting in that there were far fewer issues associated with the trial design; this trial did show an improvement in DFS for patients treated with a TKI when compared with placebo.

The phase III trial looked at 1 year of adjuvant sunitinib or placebo in patients with locoregional high-risk clear-cell RCC, with DFS again being the primary endpoint. The DFS with sunitinib was 6.8 years (95% CI, 5.8&minus;not reached) compared with 5.6 years (95% CI, 3.8-6.6) in the placebo arm (HR, 0.76; 95% CI, 0.59-0.98; P = .03).

Although there were much higher rates of dose reductions (34.3% vs 2%), dose interruptions (46.4% vs 13.2%), and discontinuations (28.1% vs 5.6%) in the sunitinib arm compared with the control arm, respectively, there was a similar rate of serious adverse events (AEs) in each arm (21.9% vs 17.1%, respectively).

Although a benefit with sunitinib in the S-TRAC trial, Bilen said that he would not use it in his practice, due especially to the toxicities seen in the study. Grade 3 AEs were experienced by 48.4% of patients in the sunitinib arm compared with 15.8% of those treated with a placebo, and grade 4 AEs by 12.1% and 3.6%, respectively. The most common grade &ge;3 AEs experienced in the sunitinib arm included palmar-plantar erythrodysesthesia, hypertension, neutropenia, thrombocytopenia, mucosal inflammation, and fatigue. The overall survival (OS) data from the trial have not yet reached maturity, according to Alemozaffar.

In the phase III PROTECT trial, adjuvant pazopanib (Votrient) was compared with placebo in patients with locally advanced RCC following surgery.

Patients in the pazopanib arm first received 800 mg of pazopanib, which was later lowered to 600 mg for tolerability. In the pazopanib 600 mg intent-to-treat (ITT) group, the DFS difference was not significant (HR, 0.862; 95% CI, 0.699-1.063; P = .165). The primary endpoint of DFS for 600 mg of pazopanib was not reached in this group and OS was not increased either. Bilen found the benefits from this trial to also be negligible.

A 31% decrease in the risk of recurrence was observed, however in the 800-mg ITT group (HR, .663; 95% CI, 0.491-0.895). In the overall ITT population, the risk of recurrence was reduced by 20%. Alemozaffar found the secondary endpoint results promising in the 800-mg pazopanib arm.

Additional trials are looking at the use of adjuvant TKIs in this setting, including the SORCE trial (NCT00492258). The EVEREST trial is exploring 1 year of everolimus (Afinitor) treatment compared with placebo in this setting (NCT01120249). And ATLAS, which is looking at 1 year of adjuvant axitinib (Inlyta) therapy compared with 1 year of placebo in high-risk patients with RCC (NCT01599754).

Alemozaffar believed that use of the 16-gene recurrence score, which was validated in high-risk stage III patients from the S-TRAC trial,

could help to identify which patients are most likely to benefit from adjuvant therapy with TKIs, which should be a goal of future study.

Although he believed in the potential benefit of adjuvant therapy in this setting, Bilen noted that the research community has not yet landed on the correct treatment approach for this patient population. Bilen also considered that immunotherapy could play a role in the adjuvant setting for patients with high-risk RCC, but that this would need to be confirmed in clinical trials. The IMmotion 010 trial and the new PROSPER RCC trial are investigating immunotherapy in the adjuvant setting, with the IMmotion 010 study looking at atezolizumab (Tecentriq) and PROSPER RCC studying nivolumab (Opdivo) in high-risk patients with RCC following nephrectomy.

Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal- cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008-2016. doi: 10.1016/S0140-6736(16)00559-6.

Haas NB, Manola J, Dutcher JP, et al. Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the ASSURE randomized trial [published online March 9, 2017]. JAMA Oncol. 2017. doi: 10.1001/jamaoncol.2017.0076.

Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246-2254. doi: 10.1056/NEJMoa1611406.

Motzer RJ, Haas NB, Donskov F, et al; PROTECT investigators. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol. 2017;35(suppl; abstr 4507).

Escudier BJ, Rini BI, Martini J-F, et al. Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma (RCC): validation of the 16-gene Recurrence Score in stage III patients. J Clin Oncol. 2017;35(suppl 15; abstr 4508).

Articles

Adjuvant therapy with TKIs for patients with high-risk renal cell carcinoma who have undergone a nephrectomy may be supported by level IIa evidence from the National Comprehensive Cancer Network guidelines, yet this approach is still controversial, with many physicians believing that there are not yet enough data in support of its use.&nbsp;

Debating the True Benefit of Adjuvant TKIs in High-Risk RCC

There may be systemic targeted therapies available for patients with advanced thyroid cancer, yet they do not last forever and the side effects of these current therapies are limiting, according to Lori J. Wirth, MD.

However, during her keynote address at the 3rd World Congress on Thyroid Cancer in Boston, Massachusetts, she stated that the era of precision genotype targeted therapy is upon us in advanced thyroid cancer, focusing on individual targets in subtypes of thyroid cancer.

Sorafenib (Nexavar) and lenvatinib (Lenvima) are both FDA approved for patients with radioactive iodine (RAI)refractory differentiated thyroid cancer (DTC). Lenvatinib, for example, showed a 65% objective response rate (ORR) in the SELECT trial that led to its approval and a median progression-free survival (PFS) of 18.3 months compared with 3.6 months with placebo.

For medullary thyroid cancer (MTC), both vandetanib (Caprelsa) and cabozantinib (Cometriq) are FDA approved in the setting of progressive disease, each showing a significant improvement over placebo in these patients.

These agents are multikinase inhibitors and are involved in the downstream inhibition of the RAS/RAF/ERK and PI3K/AKT/ mTOR pathways. However, Wirth, associate professor of medicine, Harvard Medical School, and medical director, Center for Head and Neck Cancers, Massachusetts General Hospital Cancer Center, noted that adverse events (AEs) seen with these multikinase inhibitors could often impact patients&rsquo; quality of life. AEs, including hypertension, diarrhea, fatigue, weight loss, nausea, stomatitis, and hand-foot syndrome, could usually be managed by dose holds or reductions and supportive care. She noted, though, that &ldquo;patients will eventually progress or discontinue treatment due to toxicity.&rdquo;

Fortunately, new targeted treatments are emerging to directly target driver mutations of the disease, potentially causing fewer or more manageable AEs. Somatic RET mutations occur in 40% to 65% of sporadic MTCs and germline mutations of RET are found in all familial cases of MTC.

RET fusions have been found in 6% of papillary thyroid cancers (PTCs).

As such, a new focus has been placed on targeting RET for patients with MTC or PTC. &ldquo;Efficacy of other multikinase inhibitors may in fact be limited by insufficient RET inhibition,&rdquo; Wirth said.

She mentioned that there are 2 new highly potent and specific RET inhibitors that are now involved in first-in-human trials: BLU-667 and LOXO-292, which are both design to inhibit oncogenic RET mutations for MTC and RET fusions for PTC with little activity against KDR/VEGFR-2. &ldquo;And, the V804L/M gatekepper mutation should prevent the emergence of acquired resistance,&rdquo; she added.

A 2-part phase I study is open and enrolling to study BLU-667 in patients with thyroid cancer and other solid tumors with RET alterations (NCT03037385). A phase I study is also ongoing for LOXO-292 in patients with RET fusion-positive lung cancer, MTC, and other solid tumors (NCT03157128).

BRAF mutations are among the most frequently identified mutations in patients with PTC, found in 60% of 496 samples of PTC tumors.

In a nonrandomized, open-label phase II study, of vemurafenib (Zelboraf), a BRAF kinase inhibitor that has been approved for the treatment of patients with BRAF-positive melanoma, showed antitumor activity in patients with progressive BRAF V600E-positive PTC who were RAI-refractory and had no prior multikinase inhibitor treatments (n = 26).

Ten patients achieved a partial response (38.5%), and 15 patients achieved stable disease (57.5%). Sixty-five percent of patients in the cohort had a grade 3/4 AE, most commonly including squamous cell carcinoma of the skin, lymphopenia, and increased gamma-glutamyltransferase.

In a randomized phase II study looking at the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) in patients with BRAF-mutant PTC, 9 patients achieved a partial response to the combination and 4 patients achieved a minor response for an ORR of 54% compared with an ORR of 50% for those treated with dabrafenib alone (P = .78).5 The median PFS with the combination was 15.1 months versus 11.4 with dabrafenib monotherapy (P = .27). Wirth noted that the treatments were well tolerated in both arms and that responses were durable.

In another study of the combination in patients with BRAF V600E-mutant anaplastic thyroid cancer (ATC), dabrafenib and trametinib demonstrated robust and durable responses with a favorable safety profile.6 The ORR was 69% with 7 of 11 responses ongoing at the time of data cutoff. Kaplan-Meier estimates of PFS and overall survival at 1 year were 79% and 80%, respectively. Common grade 3/4 AEs included hyponatremia (19%), pneumonia (13%), and anemia (13%).

NTRK1 and NTRK3 fusions are present in about 2% of PTCs, and patients with NTRK1/3-mutant PTC are being included in basket trials with TRK inhibitors, including larotrectinib (LOXO- 101; NCT02576431) and entrectinib (NCT02568267), both of which have shown promising responses across tumor types.

&ldquo;One great challenge [in precision medicine in thyroid cancer] is to identify each patient&rsquo;s genotype and match them up with the best clinical trial to demonstrate efficacy toward health-authority approvals in rare patient populations,&rdquo; Wirth noted. She urged that all patients undergo full genomic sequencing to determine targets for their disease.

Another step toward precision medicine in thyroid cancer, according to Wirth, is the examination of immunotherapy, including combinations with targeted therapies.

Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. doi: 10.1056/NEJMoa1406470. 2. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173- 186. doi: 10.1038/nrc3680.

Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173- 186. doi: 10.1038/nrc3680.

Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676-690. doi: 10.1016/j.cell.2014.09.050.

Brose MS, Cabanillas ME, Cohen EE, et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(9):1272-1282. doi: 10.1016/S1470-2045(16)30166-8.

Shah MH, Wirth LJ, Daniels GA, et al. Results of randomized phase II trial of dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma. J Clin Oncol. 2017;35(suppl; abstr 6022).

Subbiah V, Kreitman RJ, Wainberg ZA, et al. Efficacy of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600Emutated anaplastic thyroid cancer (ATC). J Clin Oncol. 2017;35(suppl; abstr 6023).

Lori J. Wirth, MD, discusses the era of precision genotype targeted therapy in advanced thyroid cancer, with a focus on individual targets in subtypes of thyroid cancer.&nbsp;

Emerging Single-Target Approaches to Treating Thyroid Cancer Subtypes

Advancements made in the field of molecular genetics for patients with myeloproliferative neoplasms (MPNs) may be increasingly incorporated into treatment decisions, according to Ann Mullally, MD.

In her presentation during the 2017 SOHO Annual Meeting on our current understanding of the molecular genetics of MPNs, she indicated that the strides that have been made in identifying the driver mutations of these diseases has had the greatest impact upon diagnosing a patient with one of the myeloproliferative diseases. However, Mullally, assistant professor of medicine at Harvard Medical School, attending physician of the Leukemia Program at Dana-Farber Cancer Institute, and associate physician of hematology at Brigham and Women&rsquo;s Hospital, believes that next the field of molecular genetics will impact treatment decision making, such as in patients with a more or less aggressive clinical progression.

Mullally discussed how molecular genetics has led to further advancements for patients with MPNs and is contributing to the search for better treatments and combination approaches.

Could you give a summary of the recent updates of molecular genetics in MPNs?

We have a good understanding in that we&rsquo;ve really defined the major genes that drive the development of this disease. We&rsquo;ve defined the concomitant or coexisting mutations that occur in cooperation with these phenotypic driver mutationsthe 3 being

The most recent advances have been in the understanding of the mechanism by which

causes MPN, and this is work that my laboratory and other laboratories have worked on over the last few years. When these mutations were identified in 2013, it wasn&rsquo;t apparent how a gene like

could cause an MPN because it&rsquo;s not a signaling gene, there was nothing that associated it with the JAK-STAT pathway and now we know that it causes MPN by physically interacting with

, the thrombopoietin receptor, and activating the JAK-STAT signaling. That&rsquo;s probably been the most significant advance in terms of the understanding of the molecular genetics of MPNs recently.

Are there any other molecular abnormalities other than

that are being targeted, and if so, have you seen any potential therapies effectively targeting these abnormalities?

The JAK-STAT pathway is central to the pathogenesis of MPN, regardless if you have a

mutation. They all converge on activated JAK-STAT signaling, so I think most of the work [revolves around] trying to actually target

better, and that either means developing better JAK2 inhibitors or mutant-specific inhibitors, and there is a lot of [ongoing work in these areas]. I think there are a lot of clinical trials on using combinations with JAK2 inhibitors to try to look for synergy with inhibiting JAK2 and something else downstream of JAK2.

In terms of entirely novel targets, I think mutant

itself may be an interesting target, and particularly from an immunological perspective, so there is some preclinical data to indicate that mutant

is immunogenic and I think there are many potential ways that this could be targeted using immunotherapy approaches. There are some clinical trials that are open using PD-1 inhibitors in MPNs, and it will be interesting to see whether the patients who have

mutations who are enrolled in those trials have higher or different types of responses.

Do you see any advancements or improvements in the diagnostic tools in the next few years that will aid in better diagnosing MPNs?

I think that molecular genetics have really helped us a lot here in that they are pretty definitiveyou either have the mutation or you don&rsquo;t. And, as I said, we have a comprehensive understanding of the key genes that drive the mutation, so I think that has helped us a lot, the molecular genetics. Obviously, we use all the traditional things, like the clinical picture of the patient, the bone marrow biopsy, but I think increasingly, we rely on molecular genetics to help us understand where in the spectrum of myeloid diseases the patient lies.

What I see happening is using molecular genetics more in treatment decisions, so I think we&rsquo;ll probably be doing a lot more sequential molecular monitoring, where a patient has clinical progression or a change in their clinical status or a change in their blood counts, I think we&rsquo;ll try to understand what&rsquo;s happening to the biology of their disease by looking at molecular diagnostic panels and comparing them with prior ones, and using that information to help us make better treatment decisions. For example, if someone has evidence that they&rsquo;ve had aggressive progression, then you might be more likely to recommend a transplantation for a patient with myelofibrosis rather than changing therapies. So, I think molecular diagnostics has helped us the most in diagnosis and I think that we&rsquo;ll start to increasingly integrate that into clinical decision making going forward.

What is the clinical utility for ruxolitinib (Jakafi) as of now? Are there any ongoing studies or new findings that are clinically significant?

Ruxolitinib is approved by the FDA for the treatment of patients who have intermediate or advanced-phase myelofibrosis and it&rsquo;s also approved for patients with polycythemia vera who are resistant to or refractory to hydroxyurea. We know that ruxolitinib is a good drug at reducing blood counts, reducing spleen size, and improving symptoms. As we get more experience with ruxolitinib, what I think we&rsquo;ve found is that we have a better sense of which patients, particularly with myelofibrosis, who respond better or worse to ruxolitinib, and this again comes back to molecular genetics. A lot of molecular analysis of the ruxolitinib clinical trials has now been done, and we understand which patients respond better and which don&rsquo;t. For example, if you have a lot of concomitant mutations, you are more likely to have a short duration of response and progress than if you have a small number of concomitant mutations. So, I think we&rsquo;re starting to understand better the limitations of ruxolitinib.

I mentioned already there&rsquo;s a lot of clinical trials, combinatorial trials, combining ruxolitinib with various other agents, and I think this is primarily driven by the fact that although ruxolitinib has clinic efficacy, it is not able in any significant way to eliminate the cells that harbor the mutationsthe

mutationsthe cells that harbor those mutations are not preferentially targeted by the drug, and so that raises concerns about its ability to alter the natural history of the disease. I think that is something that needs additional work, and we need better therapies to address that specific point.

Are there any significant challenges that you&rsquo;d like to see addressed in the next 5 to 10 years?

I think it gets back to this idea of preferentially or selectively targeting the malignant clone, the cells that harbor the mutations. Currently, we know that interferon can eradicate, or at least render patients undetectable, for the

mutation in a minority of patients who have polycythemia vera or essential thrombocythemia, so probably 15% to 20% of patients can become undetectable for that mutation with interferon. As I already mentioned, ruxolitinib is not strongly selective for the mutant cells, so if we look at sequential allelic burdens for

Advancements made in the field of molecular genetics for patients with myeloproliferative neoplasms may be increasingly incorporated into treatment decisions, according to a presentation by Ann Mullally, MD, during the 2017 SOHO Annual Meeting.

Expert Sees Molecular Genetics Increasingly Integrated into Clinical Decision Making in MPNs

There is a great deal of excitement in the oncology field over the use of peptide receptor radionuclide therapy (PRRT) with lutetium-177 (

Lu-Dotatate, Lutathera) for the treatment of patients  with neuroendocrine tumors (NETs) following the positive results of the phase III NETTER-1 trial.

As such, the treatment is being explored in potential combinations with other modalities, including with systemic treatment with PARP inhibitors, in this patient population.

During the 2017 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting that took place June 10 to 14 in Denver, Colorado, presenters explored the results of the NETTER-1 trial, as well as ways upon which this treatment could be further improved.

&ldquo;There are many ways this is going to go in the future,&rdquo; said Erik Mittra, MD, PhD, during a presentation at the meeting.

Radiolabeled somatostatin analogue therapy, or PRRT, is a targeted form of systemic radiotherapy that helps to deliver radionuclides directly to tumors that express somatostatin receptors. PRRT has demonstrated its efficacy among patients with inoperable or metastatic NETs. The radionuclide

Lu-Dotatate binds to somatostatin receptor type 2s that are over expressed in NETs and delivers radiation within the cancer cell that induces the DNA strand to break, thereby causing apoptosis, according to Mittra, clinical associate professor of radiology/nuclear medicine, Stanford University Medical Center.

In the international, randomized, multicenter NETTER-1 trial, 177Lu-Dotatate was investigated in 229 patients with midgut NETs who had progressed on prior octreotide therapy. Patients were randomized to either 4 administrations of 7.4 GBq of 177Lu-Dotatate every 8 weeks plus 30 mg of octreotide or a higher dose of long-acting release (LAR) 60-mg octreotide every 4 weeks.

Lu-Dotatate was not being compared with a placebo but with high-dose therapy. &ldquo;In a way, the control is actually also experimental,&rdquo; he said, because the higher dose of the octreotide could be effective as well.

Patients had to have inoperable, somatostatin receptor-positive and metastatic or locally advanced disease; they were either grade 1 or 2, with a Ki-67 index of &le;20%. All patients had a Karnofsky performance status score of &ge;60.

As of data cutoff, the median progression-free survival had not yet been reached with

Lu-Dotatate compared with 8.4 months (95% CI, 5.8-9.1) in the 60-mg octreotide LAR arm (HR, 0.21; 95% CI, 0.13-0.33; P <.001). As of the interim overall survival (OS) analysis, there was a signi ficant difference in the OS between the 2 arms favoring

Lu-Dotatate (hazard ratio [HR], 0.40; P <.004). The objective response rate was 18% (95% CI, 10%-25%) with

Lu-Dotatate versus 3% (95% CI, 0%-6%) with high-dose octreotide (P <.001).

Similar toxicities were noted between the 2 arms, although a higher degree of adverse events was noted in the

Lu-Dotatate arm than in the control (95% vs 84%, respectively; P = .01). Rates of grade 3 or 4 lymphopenia (9%), thrombocytopenia (2%), and neutropenia (1%) were noted in the experimental arm that were not seen in the control arm.

&ldquo;At least based on the data we have now, [

Lu-Dotatate] actually appears to be very safe, and the 2 main things that are of concern are hematologic toxicity and renal toxicity,&rdquo; said Mittra.

He concluded that this therapy would be beneficial for patients with well-differentiated NETs who have a lower Ki-67 index, but that it could also be used in anyone who expressed suf cient somatostatin receptors.

A new drug application for the radionuclide was accepted by the FDA in June of 2016 for the treatment of gastroenteropancreatic NETs. Advanced Accelerator Applications, the developer of 177Lu-Dotatate, received a complete response letter from the FDA in December asking for new subgroup and safety data to be resubmitted.

While 177Lu-Dotatate has not yet been FDA approved, Mittra noted that approval is expected sometime this year, and in the meantime, it is available in the United States under an expanded access program. The European Medicines Agency&rsquo;s Committee for Medicinal Products for Human Use has recommended the approval of the agent in the European Union. He suggested that the PRRT could be used in other indications and in combination with other treatment modalities in NETs, including with selective internal radiation therapy, chemotherapy,

In another presentation during the SNMMI meeting, Canadian investigators addressed the possibility of adding PARP inhibitors to PRRT with

Lu-Dotatate, as PARP could make the tumor cells more sensitive to radiation therapy.

&ldquo;The use of PARP inhibitors is a promising approach to enhance targeted radionuclide therapy for neuroendocrine cancer,&rdquo; Samuel Adant, a member of the research team from the CHU de QuébecUniversité Laval Research Center in Quebec City, Canada, said in a statement. &ldquo;Furthermore, PARP inhibitors could enhance many other current and emerging radionuclide therapies.&rdquo;

In preclinical in vitro 3-D models of 2 human-derived NET cell lines, the combination of the 2 modalities was found to be more cytotoxic than either alone. The models were dosed for 5 days and monitored for 15 subsequent days. The cancer cells in the untreated models increased 16.7-fold from their original volume during the 15 days. Comparatively, the models treated with the combination regimen grew by only 1.9-fold compared with 5.1 and 11.0 times with PRRT or PARP inhibition alone, respectively.

The investigators believed that this was one potential promising combination approach to improve upon the benefit already seen with

Strosberg J, El-Haddad G, Wolin E, et al; NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi: 10.1056/NEJMoa1607427.

Adant S, Purohit NK, Shah RG, Shah G, Beauregard JM. Potentiation of 177Lu-octreotate PRRT by PARP inhibitors in a 3D spheroid model of human-derived neuroendocrine tumor cell lines. J Nucl Med. 2017;58(suppl 1, abstr 243).

There is a great deal of excitement in the oncology field over the use of peptide receptor radionuclide therapy with lutetium-177 (<sup>177</sup>Lu)-octreotate (<sup>177</sup> Lu-Dotatate, Lutathera) for the treatment of patients &nbsp;with neuroendocrine tumors. The treatment is being explored in potential combinations with other modalities, including with systemic treatment with PARP inhibitors, in this patient population.

Lisa Miller | Authors

Articles

Debating the True Benefit of Adjuvant TKIs in High-Risk RCC

Emerging Single-Target Approaches to Treating Thyroid Cancer Subtypes

Expert Sees Molecular Genetics Increasingly Integrated into Clinical Decision Making in MPNs

Improving Upon Exciting Radionuclide Therapy in Neuroendocrine Tumors