When it comes to neuroendocrine tumors (NETs), there is no shortage of nomenclature. Broad categories, such as “carcinoid,” belie the true heterogeneous nature of this group of diseases and the complexity of their management.

During the past several years, a wealth of positive clinical trials coupled with an evolution in understanding of the cancer type has altered the treatment landscape. At a recent 

 Peer Exchange session entitled “Neuroendocrine Tumors: An Evidence-Based Discussion,” a panel of experts examined the latest evidence in NETs and provided valuable insight into how these advances are likely to impact clinical practice.

Although carcinoid tumors and pancreatic NETs look identical under the microscope, they respond differently to treatments, said moderator Matthew H. Kulke, MD. This is due to biological differences at the molecular level.

Pancreatic NETs have somatic mutations that have a lot of recurrent chromosomal copy number changes, agreed James C. Yao, MD. Small bowel carcinoid tumors, by contrast, have very few somatic mutations that recur.

“We know now that primary site makes a big difference in terms of prognosis as well as response to some types of treatment,” Yao said. “For example, we have diseases like gastric carcinoid and rectal carcinoid tumor where most of the time they’re localized, have great prognosis, [and] they don’t recur,” he said. “But they are actually malignant, and when they do spread, they tend to have a very aggressive course.”

It is important to note, however, that what was formerly lumped into a single “carcinoid” category is now being recognized as multiple diseases, said Diane Reidy Lagunes, MD. “Now as we’re learning about the genetics, in fact, foregut may be different than the so-called midgut,” she said. The lung, gastric, and pancreatic tumors may have common genetics and seem to have clinical similarities as well, Lagunes said.

In addition to primary site, NETs are classified according to whether they are well differentiated or poorly differentiated, and the treatment options for these tumor types also differ, explained, Jennifer Eads, MD. Within the poorly differentiated tumors, there are further distinctions: large cell and small cell histologies.

Systemic chemotherapy is the standard of care for poorly differentiated tumors, and no targeted agents have been found to be useful in this setting. “It’s very difficult to do clinical trials in this population,” Eads stated. “And historically, because the histology under the microscope has been similar to that seen in small cell lung cancer, we’ve really just extrapolated data from the small cell lung cancer literature to guide our treatments for the poorly differentiated population.”

For patients with well-differentiated NETs, there are more options, noted Eads. These include somatostatin analogues (SSAs), targeted therapies such as VEGF or mTOR inhibitors, and cytotoxic therapies based on primary site.

In order to more fully define the classification, Eads uses supplementary features such as the Ki67 proliferative index. Poorly differentiated tumors typically are defined by a Ki67 of at least 20% up to 100%, said Eads.

However, the panelists agreed that there are gray areas where disease burden trumps this proliferative index. “There’s this borderline in between where sometimes patients can have a well-differentiated histology but may have a Ki67 that technically classifies them as a high-grade or poorly differentiated tumor,” Eads said. “I think that gray area is difficult.”

Clinical features help determine the best course of treatment in these cases, Yao said. For example, patients with 60% liver involvement, a Ki67 less than 20%, and an elevated lactate dehydrogenase, should be treated as though the tumor were poorly differentiated. However, a watch and wait approach is appropriate for patients who have low-volume disease and an indolent course, even if they are found to have a poorly differentiated tumor with a Ki67 of 30%. “The tumor is behaving like a well-differentiated tumor,” Yao said.

Treatments are also driven by the patient’s symptoms. Typically, patients with functional, or hormone-secreting tumors present with stage IV disease, said Lagunes. “My job is to control their disease but also maintain their quality of life,” she said. “Some of these hormone-secreting tumors can be quite debilitating.”

Pancreatic NETs can produce insulin, which can lead to hypoglycemia that is potentially life threatening. Other tumors produce gastrin, and are associated with a high morbidity and the potential for severe ulcers. By contrast, patients with tumors that begin outside of the pancreas, such as in the small bowel or lung, can develop carcinoid syndrome. Those patients typically have flushing and diarrhea as their main symptoms.

Surgery is still considered the only curative approach for NETs. It is important for surgeons to work hand in hand with the medical oncologists, radiologists, and other members of the multidisciplinary team to determine the best options for the patient. “We always say cut is the cure, but, unfortunately, neuroendocrine tumors have a very high metastatic and recurrence rate,” said Eric H. Liu, MD.

Liu explained that a different philosophy is employed with NETs compared with pancreatic adenocarcinoma or metastatic colon cancer. “We are aggressive about adenocarcinomas to try to remove them,” said Liu. “[However], we shy away when there’s metastatic disease, which is actually very different from [our approach in] neuroendocrine [tumors].” In NETs, small tumors can become very bulky disease. Despite this, patients with NETs can live a long time. Thus, quality of life is very important, Liu stated.

Liu said that the questions that arise when deciding whether to perform surgery include: Is there going to be some complication which will hurt this patient down the road? Are they going to have a small bowel obstruction?

Resection may be warranted if the tumors are blocking the intestine or are symptomatic. Debulking surgery is a good option for patients with discrete lesions in the liver. Medication is required to treat any disease that remains. One cautionary note, said Liu, is that hormone-secreting tumors can cause complications during surgery, leading to carcinoid crisis. Having surgical expertise in NETs is important, he added.

SSAs are the standard of care for symptom control in patients with carcinoid and pancreatic and hormone-producing NETs, said Eads. Octreotide and lanreotide are both used in this setting. For patients with breakthrough symptoms, a higher dose of the depot injection or a self-administered, short-acting SSA can help.

Telotristat etiprate, a tryptophan hydroxylase inhibitor, is a new option for patients with poorly controlled diarrhea, said Yao. In the phase III TELESTAR trial, patients with well-differentiated metastatic NETs and carcinoid syndrome as well as diarrhea that was refractory to SSAs were randomized to telotristat etiprate 3 times daily plus an SSA or placebo plus an SSA.

Topline results from the trial, led by Kulke, were presented at the 2015 European Cancer Congress (ECC). At week 12, treatment with telotristat etiprate at 250 mg demonstrated a 29% reduction in daily bowel movement frequency compared with baseline. Patients receiving 500 mg had a 35% reduction compared with baseline. Those in the placebo arm experienced a 17% reduction in average daily bowel movements.

Although the goal of therapy with SSAs is symptom control, the PROMID and CLARINET trials demonstrated that SSAs also have an antiproliferative effect. The PROMID study showed that octreotide LAR increased progression-free survival (PFS) among patients with locally inoperable or metastatic midgut NETs compared with placebo (14.3 months vs 6 months; 

The CLARINET study looked at a broader population, including patients with pancreatic, midgut, or hindgut NETs. In this study, lanreotide decreased the risk of progression by 53% compared with placebo.

The median PFS for patients who received lanreotide was not reached compared with 18.0 months with placebo (HR, 0.47; stratified log-rank 

 <.001). The increase in PFS was seen in patients with midgut (HR, 0.35) and pancreatic tumors (HR, 0.58), but was not observed in patients with hindgut tumors (HR, 1.47).

“Essentially, for patients with pancreatic neuroendocrine tumors and bowel carcinoids, we’re able to use somatostatin analogues in an effort to try and control tumor growth as well,” Eads said.

Targeted therapies, such as the mTOR inhibitor everolimus, have primarily been used for pancreatic NETS. The FDA’s 2011 approval of everolimus in this setting was based on the RADIANT-3 study.

Data from the RADIANT-4 trial, presented at the 2015 ECC, showed more than a 7-month increase in PFS with everolimus versus placebo in 302 patients with advanced, progressive, nonfunctional NETs in the GI tract, lung, or of unknown origin.

 The median PFS was 11.0 months among patients who received everolimus compared with 3.9 months for those on placebo (HR, 0.48; 

“There was a 2.8-fold improvement in median progression-free survival, so more than 50% reduction in risk of disease progression,” said Yao, who served as principal investigator for the study.

In February, the FDA approved a new indication for everolimus for unresectable, locally advanced, or metastatic nonfunctional NETs of lung or GI origin based on the RADIANT-4 trial results.

“Now with the RADIANT-4 data, we have other therapies to consider,” Lagunes said. “So, everolimus is absolutely a very appropriate treatment which I may use more frequently now.”

Another targeted strategy under consideration employs antiangiogenesis drugs such as sunitinib and pazopanib. The data for sunitinib show a benefit in pancreatic NETs, said Yao, adding, “but the role of sunitinib in nonpancreatic primary [tumor] is undefined at this time point.”

Peptide receptor radionuclide therapy (PRRT), which is not currently an option in the United States outside of clinical trials, is available in Europe for patients with somatostatin receptor— positive, inoperable NETs. The therapy targets tumors with radiolabelled SSA peptides. “It absorbs the radiation within the tumor itself, and then it continually radiates the tumors from the inside out,” explains Liu.

The phase III NETTER-1 trial compared PRRT using 177Lu-DOTATATE with the current standard of care (octreotide LAR) in patients with inoperable, progressive, somatostatin receptor—positive midgut NETs. After a median follow up of 30 months in the intent-to-treat population, the median PFS in the experimental arm was not reached compared with 8.4 months with the control (HR, 0.209), providing a risk reduction of 79.1% (

Now that the results from the NETTER-1 study have been presented at the 2015 ECC, the panelists expect PRRT to become part of the armamentarium in the near future.

“I think that the opportunity to be able to integrate things that are not yet available to us, such as PRRT, is very exciting,” Eads said. “It obviously leads to a lot of unanswered questions, but I feel very grateful that we now have the options that we do available for both pancreatic neuroendocrine patients and carcinoid patients.”

Kulke MH, Hörsch D, Caplin M, et al. Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase III TELESTAR clinical trial). Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract 37LBA.

Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. 

Caplin ME, Pavel M, Ä†wikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. 

Yao JC, Fazio N, Singh S, et al. Everolimus in advanced nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) origin: efficacy and safety results from the placebo-controlled, double-blind, multicenter, phase 3 RADIANT-4 study. Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract LBA5.

Strosberg J, Wolin E, Chasen B, et al. 177-Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours: results of the phase III NETTER-1 trial. Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract LBA6.

Articles

During the past several years, a wealth of positive clinical trials coupled with an evolution in understanding of neuroendocrine tumors has altered the treatment landscape.

Neuroendocrine Tumor Treatment Options Are Growing

Compared with estrogen receptor (ER)—positive and HER2-positive breast cancer, triple-negative breast cancer (TNBC) is typically more aggressive and carries a higher mortality rate. Several ongoing clinical trials are attempting to gain ground. In February, the antibody–drug conjugate sacituzumab govitecan (IMMU-132) received a breakthrough therapy designation based on phase II trial data showing a response rate of 31% in heavily pretreated patients with metastatic TNBC. However, treatment advances are lagging behind those seen in other breast cancer phenotypes.

 Peer Exchange® program provided context to the emerging evidence in TNBC, highlighting some of the key clinical trial data presented at the 2015 San Antonio Breast Cancer Symposium (SABCS). Moderated by Adam M. Brufsky, MD, PhD, the panel shed light on the impact this recent evidence may have on clinical practice.

One area open for debate is whether platinum agents should be added on to standard chemotherapy in the neoadjuvant setting of TNBC. Data from two clinical trials presented at 2015 SABCS pulled back one layer of the onion regarding neoadjuvant use of carboplatin, but are the data robust enough to change what clinicians do in clinical practice?

The phase II GeparSixto study evaluated the addition of carboplatin to weekly paclitaxel plus non-pegylated liposomal doxorubicin (Myocet) for 18 weeks in TNBC and HER2-positive breast cancer. Patients with TNBC (n = 315) received concurrent bevacizumab, while those with HER2-positive disease received trastuzumab and lapatinib. The carboplatin dose was reduced from area under the curve (AUC) 2.0 to AUC 1.5 to improve tolerability.

In patients with TNBC, carboplatin improved the pathologic complete response (pCR) from 36.9% to 53.2% (

 = .005). However, the pCR improvement was not statistically significant in the HER2-positive subgroup (36.8% vs 32.8%, respectively; 

The study also showed a disease-free survival (DFS) benefit with carboplatin in the TNBC group after a median of 35 months (85.8% vs 76.1%; 

 wild-type tumors, the odds ratio (OR) for pCR was 2.09 in favor of carboplatin treatment compared with controls (50.8% vs 33.1%; 

-mutant patients, the OR for pCR was 1.6 in favor of carboplatin, but the difference was not statistically significant (61.5% vs 50.0%; 

Prior to this study, it was thought that platinum compounds are not active in patients without germline 

 mutations, said Christy A. Russell, MD. She noted that before she saw the GeparSixto findings, she was not in favor of adding carboplatin to neoadjuvant chemotherapy. She commented that the advantage in 

 wild-type TNBC was seen “not only in pathologic complete response rate, but also what appears to be translating into disease-free survival by the addition of carboplatin. And it has now made me think about it a little more. I have not yet added it.”

Joyce A. O’Shaughnessy, MD, pointed out that updated data from the CALGB 40603 trial, also presented at the conference, showed higher pCR, but no DFS improvement when carboplatin is added to once weekly paclitaxel in patients with stage II/III TNBC.

The standard chemotherapy regimen for this trial was weekly paclitaxel 80 mg/m2 for 12 courses plus dose-dense doxorubicin and cyclophosphamide. Patients were randomized in a 2 x 2 schema to receive the standard regimen alone or the standard plus one of these regimens: bevacizumab every 2 weeks for 9 cycles; carboplatin AUC 6 every 3 weeks for 4 cycles; or the combination of bevacizumab and carboplatin.

The pCR rates in the breast, the primary endpoint of the initial study, were 60% for patients receiving carboplatin and 46% in patients who did not receive carboplatin, an increase of 76% (

In follow-up data presented at 2015 SABCS, Sikov and colleagues reported that patients who achieved a pCR on any arm of the study achieved far superior event-free survival and overall survival outcomes compared with those who did not have a pCR.

Panelists discussed the regimen and the dosing in the trials to help give the results more context. One noteworthy difference was the standard chemotherapy used. Myocet is not FDA approved, and thus the standard used in the GeparSixto trial is not representative of a US regimen. The drug is approved in Europe in combination with cyclophosphamide. The standard chemotherapy in the CALGB 40603 study was typical, noted the panelists.

Brufsky theorized that the control arm in the GeparSixto study was likely an inferior regimen, potentially causing carboplatin to exert more of an effect.

An additional factor to consider in these trials is that the dose of carboplatin was lower in the GeparSixto study versus the CALGB 40603 (AUC 1.5 vs AUC 6, respectively). The panelists agreed that these factors, combined with the small sizes of the trials, made it challenging to draw any conclusions about the impact of adding a platinum agent in this setting.

“We really need larger trials powered for disease- free survival,” O’Shaughnessy said. However, she added that it may be appropriate to try adding on carboplatin in patients who are very high risk. “What I’ve done personally, and I think many of us may do, is when you see these poor responders, we tend to add,” agreed Hope S. Rugo, MD. “So, [for] poor responders with triple-negative disease, I’ll add platinum as opposed to starting with it since we already know we get a reasonable pCR rate in those patients.”

Data from a separate study presented at 2015 SABCS examined the use of capecitabine in the adjuvant setting.

The phase III CREATE-X trial enrolled patients with pathologic residual invasive disease following surgery and neoadjuvant therapy with an anthracycline, taxane, or both. It included hormone receptor (HR)—positive and HR-negative subsets, the latter of which included some patients with triple-negative disease. Patients were randomized to standard treatment with or without 8 cycles of capecitabine. The primary endpoint was DFS.3 The 3-year overall DFS rate was 82.8% with capecitabine compared with 74.0% in the standard therapy arm. The benefit with capecitabine was less pronounced in the HR-positive group (n = 561; HR, 0.84). Those with HR-negative disease (n = 296) had a 42% reduction in the risk of recurrence with capecitabine (HR, 0.58).

The subset of patients with TNBC showed the most benefit, said O’Shaughnessy. “My personal opinion is that it is something worth discussing with patients,” she added, noting that more clinical studies are needed to confirm the benefit. Rugo commented on the dose of capecitabine, noting that the drug metabolizes differently in some ethnic populations. “I might have had two patients ever tolerate 2500 mg/m

 of capecitabine, and that’s the dose they gave, and their dose intensity was very good,” she said. “And we know that the metabolism of capecitabine is different in many, not all, Asian people based on differences in pharmacogenomics.”

O’Shaughnessy stated that previous trials have shown a systemic benefit with capecitabine in triple-negative disease. Brufsky asked the panelists whether the evidence to date convinces them to use adjuvant capecitabine. Rugo and Sara A. Hurvitz, MD, both said they would consider using capecitabine in patients with significant residual disease following good neoadjuvant therapy. “I think it warrants a discussion with patients who have had standard therapy and have a lot of residual disease if they are hormone receptor—negative,” Hurvitz said.

The discussion turned to the use of eribulin mesylate in metastatic disease. The results from the phase III 301 study found that eribulin mesylate was not superior to capecitabine in locally advanced or metastatic breast cancer following treatment with anthracycline and taxane chemotherapy.

However, subsequent subanalyses revealed certain subgroups did show a benefit.

Those with triple-negative disease had a median overall survival of 14.4 months with eribulin mesylate compared with 9.4 months with capecitabine. (HR = 0.70; 95% CI, 0.55-0.91; 

“It truly is that new drug we needed after the anthracycline, taxane, capecitabine [therapies],” O’Shaughnessy said. “And now we have a non— cross-resistant drug both in the ER-positive and the triple-negative [patients].”

Rugo stated that there is a learning curve with using the drug because of the risk of mucositis. She uses a lower dose than the package insert dose of 1.4 mg/m

. She said she has started patients at .4 mg/m

, and gradually increased the dose by .1 mg/m2, and has “had it be a treatment which works when people’s livers are failing and gives them another 8 months of life,” Rugo remarked.

In liver failure, Rugo and O’Shaughnessy agreed that the bilirubin level should guide the starting dose, not the Child-Pugh score. “I’ve given it to people with bilirubins of 6 and 7, but then you should really be giving .4 [mg/m

],” said Rugo. “And you still are going to get mucositis, and it’s really pretty impressive, but it works.”

Another study presented at the SABCS conference was the phase Ib KEYNOTE-028 trial, which showed that the PD-1 inhibitor pembrolizumab had an overall response rate of 12% in PD-L1 positive patients with ER-positive/HER2-negative advanced breast cancer. Among those with TNBC, the ORR was 18.5%.

By contrast, the PD-L1 inhibitor avelumab was less effective against mixed phenotypes of breast cancer in the JAVELIN trial.7 The ORR for ER-positive disease was 2.8% (2 of 72 patients) compared with 8.6% in triple-negative disease (5 of 58 patients). The response rate was higher among patients with TNBC with >10% PD-L1 expression in immune cells within the tumor; the response rate in this category was 44.4% (4 of 9 patients). The PD1/PD-L1 immunotherapy response rates are not as impressive as what has been observed in other cancers, noted the panelists. “One of the theories right now is that the reason melanoma and renal cell cancer are so responsive is that they have a lot of neoantigen diversity, and breast cancer and prostate cancer don’t,” Brufsky said. The panelists agreed that more factors likely must be considered to making immunotherapy work in breast cancer than focusing on PD-L1 expression. One variable to consider is the role of tumor-infiltrating lymphocytes, and their impact on prognosis, Russell noted.

“The area of immune therapy is going to be very exciting to look at, and I think we are all hoping to crack the nut on triple-negative disease,” Hurvitz said. “We have to get better at distinguishing disease subtypes and developing targeted therapies.

			von Minckwitz G, Loibl S, Schneeweiss A, et al. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Presented at; 2015 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 8-12, 2015. Abstract S2-04.

			Sikov WM, Berry DA, Perou CM, et al. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: outcomes from CALGB 40603 (Alliance). Presented at: 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract: S2-05.

			Toi M, Lee S-J, Lee ES, et al. A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). Presented at: 2015 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 8-12, 2015. Abstract S1-07.

			Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S6-6.

			Kaufman PA, Cortes J, Awada A, et al. A phase III, open-label, randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes: subgroup analyses. 

			Rugo HS, Delord J-P, Im S-A, et al. Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1—positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. Presented at: 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S5-07.

			Dirix LY, Takacs I, Nikolinakos P, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract: S1-04.

The antibodyâ€“drug conjugate sacituzumab govitecan
(IMMU-132) received a breakthrough therapy
designation based on phase II trial data showing
a response rate of 31% in heavily pretreated patients
with metastatic TNBC. However, treatment
advances are lagging behind those seen in other
breast cancer phenotypes.

Studies Mark Progress Against Triple-Negative Breast Cancer

Emerging data showing improved survival with targeted and immunotherapeutic approaches are rapidly altering the standard of care for patients with melanoma. For 

-positive patients with metastatic or unresectable melanoma, the standard of care includes a BRAF inhibitor in combination with a MEK inhibitor. For patients with or without 

 mutations, there are immunotherapeutic options available in frontline and in resistant disease settings.

Questions remain, however, in terms of how to optimally sequence and/or combine both targeted agents and immunotherapies. And, for 

-mutant disease, when is it appropriate to switch from a targeted approach to an immunotherapeutic one?

 Peer Exchange, melanoma experts, led by moderator Keith T. Flaherty, MD, discussed the latest evidence in metastatic melanoma, and how they apply it to their practices in order to make these nuanced treatment decisions.

In December 2015, the PD-1 inhibitor pembrolizumab gained two new melanoma indications: one as a frontline treatment in patients with advanced melanoma, regardless of BRAF status; the other, as a treatment for patients refractory to the CTLA-4 inhibitor ipilimumab

. The FDA also recently expanded its approval for the PD-1 immune checkpoint inhibitor nivolumab to include it as a frontline treatment for patients with 

Jeffrey S. Weber, MD, PhD, commented that the “tail of the curve” with ipilimumab, nivolumab, and pembrolizumab, shows there is a long-lasting treatment effect with these immunotherapies.

“If you get beyond 3 years in remission, partial, complete, or with stable disease, you’re probably going to stay there for a long time…I’ve been treating patients with ipilimumab for 14 years and I occasionally get an e-mail, or a letter, or a postcard from a patient I treated 13, 14 years ago when I was in Los Angeles, and they’re alive and doing well.” Weber said.

In clinical practice, optimal sequencing with the anti-PD-1 and anti-CTLA-4 antibodies remains unclear. Despite initial approvals with both pembrolizumab and nivolumab as second- line therapies following ipilimumab treatment, there is evidence that PD-1 inhibition upfront may be a better approach. Jason J. Luke, MD, referred to CheckMate-064 data, presented at the 2015 European Cancer Congress meeting, showing a confirmed objective response rate (ORR) by modified RECIST criteria at week 25 of 41.2% in patients who received nivolumab followed by ipilimumab compared with 20.0% in patients receiving the 2 therapies in the opposite sequence.

“I think there are pretty good data now that suggest that anti-PD-1 antibody, absent other particular caveats, really ought to be the frontline therapy,” Luke stated. “I have to say that my personal opinion right now is I prefer to use a single-agent anti-PD-1 antibody upfront because it’s robust, you get response rates, you get disease control, and you don’t have this massive increase in toxicity profile.”

Rene Gonzalez, MD, expressed a divergent viewpoint.

“I would quibble a little bit with that for two reasons,” he said. “One, is we have the really long tail with ipilimumab that nothing comes even close to, IL-2 maybe. But, the other thing is we don’t know how long to treat people with PD-1 [inhibitors]. One of the beauties of ipilimumab is you get your 4 doses, and you’re done.”

There appear to be higher response rates and more immediate disease control with the PD-1 inhibitors than with ipilimumab, said Flaherty.

Weber, who was a lead investigator on the CheckMate-064 trial, also supported using a PD-1 inhibitor prior to the CTLA-4 inhibitor. “They all got the same therapy. Very few patients dropped out,” added Weber. “The only difference was the sequence.”

It is also important to consider who is most likely to benefit from its use. In a patient with bulky disease who has a high lactate dehydrogenase (LDH) level and is rapidly progressing, “I think we’d all agree, those patients are less likely to respond to anything, particularly ipilimumab,” said Weber.

Another area of debate pertains to the duration of therapy with the PD-1 inhibitors. The FDA approvals did not specify a duration, leaving it open to interpretation. Flaherty asked the panelists whether they stop giving therapy in patients who are still responding.

Luke remarked that it is reasonable to consider stopping therapy if a patient is stable for more than 3 to 6 months, a follow-up PET scan shows no hypermetabolic activity, and a biopsy shows no residual tumor.

Weber said that he typically would not stop treatment with nivolumab or pembrolizumab until at least 12 months on therapy, but would not go beyond 2 years. For a patient, it can be viewed as a lifeline. “It’s a tough one, because put yourself in the patient’s shoes,” Weber remarked. “You’ve been getting this drug either every 2 weeks, or every 3 weeks in the case of pembrolizumab, for 2 years, and then somebody comes in the room and says, well, listen, I think you look great, it’s OK, you can stop.”

Data from CheckMate-069, which showed a 60% reduction in the risk of progression or death with the combination of nivolumab and ipilimumab versus ipilimumab alone, led to the approval of the combination in patients with 

wild-type unresectable or metastatic melanoma. With the combination, the ORR was 61% compared with 11% with ipilimumab alone. The ORR was independent of PD-L1 status.

The combination was also associated with significantly higher rates of grade 3/4 adverse events, 54% with the doublet versus 24% with the monotherapy. An FDA decision is pending on a full approval for the combination in patients who are previously untreated, the application for which is based on the phase III CheckMate-067 trial.

The PD-1/CTLA4 combination approach may be the right one in patients who need a rapid response, noted Luke, such as a younger patient who has brain metastases. However, in most patients, he is more comfortable using anti-PD-1 frontline monotherapy. Different patients have differing tolerances for the toxicities. Some prefer “the kitchen sink” approach, he said. “The question becomes, can we find patients where we don’t have to expose them to the toxicity? We don’t know how to answer it yet,” said Luke.

The toxicities with the combination are more frequent and more severe, added Gonzales. Weber pointed out that the very steep and immediate response makes the combination “a perfect therapy for a 

 wild-type patient who has aggressive, high LDH bulk, rapidly growing disease, or even a 

Although the toxicities can be more intense, much of the reaction is biochemical, such as grade 3 hyperamylasemia with no symptoms, noted Weber. Grade 3/4 colitis or diarrhea can be very problematic, however.

Given the known intensity of the toxicities with the combination, Flaherty asked the panel to share their thoughts regarding whether 4 induction doses of ipilimumab/nivolumab are necessary.

Luke commented that anyone who has toxicity that requires steroids should probably not receive more ipilimumab, but restarting anti-PD-1 therapy depends on the situation. The evidence suggests the responses last well past treatment. “Most of the side effects happen very quickly…a lot of [patients] came off very early from treatment, and yet they’re ongoing in response far later,” Luke said. “So, I don’t think that we need to push all these doses.”

Weber pointed out that patients in the Check- Mate-064 trial who had toxicities with ipilimumab were able to continue with nivolumab. “I think you could have combination toxicity, much of which may well be the ipilimumab, stop, recover, and then go to the nivolumab maintenance,” Weber said.

Weber explained that testing for PD-L1 expression is more helpful in some cancers than in others. For example, in nonsquamous non-small cell lung cancer, PD-L1 status is predictive, while in squamous disease it is not. In melanoma, PDL1 status can give an indication of who is more likely to respond. However, “as a marker to decide whom you shouldn’t treat, PD-L1 staining falls short, certainly in melanoma,” said Weber.

In November, the FDA approved the BRAF/ MEK combination of vemurafenib/cobimetinib for patients with 

-positive metastatic or unresectable melanoma, based on the phase III coBRIM study. The study showed a median progression- free survival of 12.3 months with the combination versus 7.2 months for vemurafenib alone.

 Also in November, the FDA granted a full approval to the combination of dabrafenib and trametinib in patients with unresectable or metastatic 

-mutated melanoma after the combination demonstrated a nearly 8-month extension in overall survival when compared with vemurafenib in the COMBI-v trial and a more than 6-month overall survival compared with dabrafenib alone in the COMBI-d trial.

 “All three of those studies were positive in the sense that it without a doubt showed that combination therapy is better than single-agent BRAF inhibitor,” said Gonzales. “They are the new standard of care in terms of targeted agents for melanoma.”

Pembrolizumab and ipilimumab have indications that are independent of 

 status. The approval of the nivolumab/ipilimumab combination is limited to 

 wild-type disease. Weber pointed out that the evidence suggests “there is no difference in 

 wild-type patients in how well they respond to the combination.” A recent retrospective analysis by Larkin et al showed that nivolumab had similar efficacy and safety in both 

 wild-type disease. In addition, the efficacy and safety outcomes were similar regardless of prior BRAF inhibitor or ipilimumab treatment.

Gonzales commented on the difficulty of knowing when to switch a patient from BRAF/MEK therapy to immunotherapy. “When I’ve started a BRAF/MEK combination on a patient and he’s had a great response, when do I switch him? Do I switch him to ipilimumab/PD-1 [inhibitor] combination…in the hopes of getting that durable remission?” Gonzales said.

Luke commented that he uses the BRAF/MEK inhibitor combination therapy as the backbone. “I know I can always go to it,” said Luke. “If patients come off of other things, we’re going to go back to it, get this back under control for a few months, and then we can think of what else can we try to do.”

Gonzales noted that the data with the combination of ipilimumab/nivolumab have prompted him to more often consider switching some patients to immunotherapy from the BRAF/MEK combination. “And I think my bar is falling as to when I do that because with BRAF/MEK combination, half the patients will die in about 2 years,” Gonzales said. “And so I’m not worried about the half that go beyond that, but it’s the front end of that curve that we might be able to impact better now rather than later.”

“I think in the context of some of this data that we’re getting now that a sizable fraction of patients do very, very well for a long time on targeted therapy,” Luke stated. “I think we need to push back on that message that everyone needs to get on [an anti PD-1 therapy]. There are other drugs that are very effective.”

			Broderick J. FDA approves two new indications for pembrolizumab in advanced melanoma. OncLive.com. http://goo.gl/7yv1wV. Published December 18, 2015. Accessed January 2, 2016.

			Inman S. FDA approves frontline nivolumab for advanced melanoma. OncLive.com. http://goo.gl/0XltAI. Published November 24, 2015. Accessed January 2, 2016.

			Hodi FS, Gibney G, Sullivan R, et al. An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064). Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract 23LBA.

			Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. 

			Bristol-Myers Squibb announces regulatory update for Opdivo (nivolumab) in advanced melanoma [press release]. Princeton, NJ: Bristol-Myers Squibb Company; November 27, 2015; http://goo.gl/z1LBnj. Accessed January 2, 2016.

			Larkin JMG, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma.

			Robert C, Karaszewska B, Schachter J, et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3301.

			Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. 

			Larkin J, Lao CD, Urba WJ, et al. Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF wild-type advanced melanoma: a pooled analysis of 4 clinical trials. 

Questions remain in terms of how to
optimally sequence and/or combine both targeted
agents and immunotherapies in melanoma.

Experts Grapple With Nuances of Navigating New Frontier in Melanoma

With scores of subtypes and a paucity of molecular markers, soft tissue sarcoma (STS) remains a complex and challenging tumor type to treat yet significant strides being made in the field are likely to alter the therapeutic paradigm, according to experts who participated in a recent OncLive Peer Exchange

The program, entitled “Multidisciplinary Treatment of Advanced Soft Tissue Sarcomas,” delved into promising new agents and therapeutic strategies that are helping to extend survival and improve quality of life for patients with STS. Led by moderator Brian A. Van Tine, MD, PhD, the panel also discussed the complexities associated with diagnosis and treatment of STS, and the importance of individualizing care.

“This field, for the first time in a very long time…has an influx of potential new drugs that are going to very quickly start changing the landscape of how the non-surgeons approach the tumors,” stated Van Tine, director, Sarcoma Program Barnes and Jewish Hospital Washington University in St. Louis.

Indeed, the armamentarium expanded in October with the FDA’s approval of trabectedin (Yondelis) for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have previously received anthracycline- based chemotherapy.

With fewer than 12,000 annual diagnoses in the United States and 50 or more subtypes, STSs are both rare and heterogeneous. Multidisciplinary care, which may include a pathologist, radiologist, surgeon, oncologist, a gastroenterologist, nurse, geneticist, and social worker, is of particular importance in this complex group of diseases, the Peer Exchange panelists said.

Some of the most common STS subtypes fall under the categories of leiomyosarcoma, liposarcoma/ adipocytic sarcoma, and nondescript spindle cell sarcoma.

randa Obtaining a clear and accurate histological diagnosis prior to starting treatment is essential, since each subtype can differ in underlying biology, clinical behavior, and response to treatment, according to Robin L. Jones, MD, MRCP.

The system in the United Kingdom, where Jones practices, differs from the system in the United States, in that all sarcoma patients in the United Kingdom are referred directly to a sarcoma center following an STS diagnosis, explained Jones, Medical Oncologist Royal Marsden Hospital Institute of Cancer Research London, England. “The complexity both in terms of heterogeneity, rarity, and the wide variety of anatomic primary sites just make it very, very challenging [to treat],” Jones said.

According to the French grading system, tumors are graded as low, intermediate, and high, based on tumor differentiation, tumor necrosis, and mitotic count. This assessment has important implications in terms of prognosis, Jones stated.

Also, prior to any intervention, it is important to conduct chest imaging, as the chest is the most common site for STS tumors to metastasize,new said R. Lor Randall, MD, FACS. Radiological images and clinical features, together with a report from a pathologist experienced with STS, are needed to make a definitive diagnosis prior to beginning treatment.

“As a surgeon I need to understand the biology, the medical oncology, the radiation therapeutics available, the leading-edge thought,” noted Randall, director, Sarcoma Services medical director, Surgical Services, Huntsman Cancer Institute. “The physicians that are involved more in the systemic management also need to understand the local control issues, because we know that surgery and radiation therapy are backbones…for curing and managing sarcomas.”

The medical and surgical teams need to be in communication with the pathologist about the location and behavior of the tumor, agreed Andrew J. Wagner, MD, PhD, senior physician, Adult Oncology, Dana-Farber Cancer Institute. The pathologist’s findings help drive the decisions regarding other testing that may need to be done.

Multidisciplinary care is essential from the time of diagnosis, added Jonathan C. Trent, MD, PhD, director, UM Sylvester Comprehensive Cancer Center, “because some of these sarcomas, particularly the small cell sarcomas, can grow quite rapidly.”

	Neoadjuvant/Adjuvant Therapeutic Considerations

“[Multidisciplinary care] also provides the opportunity to look at new approaches and new treatments in a group setting,” noted Wagner.

The standard of care for smaller, lower grade lesions is wide local excision followed by surveillance. For more aggressive lesions, adjuvant and/or neoadjuvant treatment, often with radiotherapy, may be warranted, noted Randall. Chemotherapy may be initiated prior to surgery for cytoreduction.

It is often possible to transition an unresectable tumor to one that is resectable using chemotherapy or targeted therapy to shrink the tumor, said Trent. However, chemotherapy is not used with certain histologies because the tumors are known to be resistant to chemotherapy.

Wagner noted that it is important to consult with the surgeon before deciding whether to use neoadjuvant therapy. One key question to ask the surgeon is whether it will help to shrink the tumor. “The radiation is really important for tumors, to help with margins and local control, but the problem sometimes with giving neoadjuvant chemotherapy is that you can introduce toxicity, and in some cases, it’s not effective and the tumor worsens, instead of reducing in size,” he said.

The phase III GeDDIS trial sought to determine whether a chemotherapy doublet used in relapsed settings would be more effective than single-agent doxorubicin as first-line treatment in advanced unresectable or metastatic STS.

 The trial randomized 257 patients to receive doxorubicin or gemcitabine/docetaxel. The primary endpoint was progression-free survival (PFS) rate (PFR) at 24 weeks.

The PFR was 46.1% for single-agent doxorubicin and 46.0% for the combination. PFS was 23 weeks versus 24 weeks for doxorubicin and docetaxel/ gemcitabine, respectively.

The results showed a similar PFS at 24 weeks, at which point doxorubicin was found to be superior, said Shreyaskumar R. Patel, MD, medical director, Sarcoma Center, The University of Texas MD Anderson Cancer Center. These study results indicated that doxorubicin should remain the standard of care in this setting, added Patel.

Single-agent doxorubicin was also found to have fewer toxicities compared with the combination. The associative toxicities are an important consideration, said Patel, and care should always be individualized and involve the patient’s preferences.

Cancer is constantly evolving, and managing toxicities is part of treating the disease, stated Randall. “While the Holy Grail is cure, it’s really maintenance,” he said. “Like managing diabetes, we want to get to the goal where we can keep people’s quality of life high and their tumor burden low, but we may not truly be curing a lot of people.”

Another trial in the first-line setting, the EORTC 62012 study, assessed whether dose intensification of doxorubicin with ifosfamide would improve survival of patients with advanced STS compared with doxorubicin alone.

The study found no improvement in overall survival, but found an improvement in response rate and PFS with the combination.

 Jones noted that the combination was associated with more toxicities and thus may be most appropriate in patients with rapidly progressing disease, inoperable locally advanced disease, or high tumor burden.

The phase III PALETTE study examined the effect pazopanib, an oral tyrosine kinase inhibitor of VEGF receptors, versus placebo on PFS in 369 patients with metastatic non-adipocytic STS who had failed standard chemotherapy.

The results showed a median PFS of 4.6 months with pazopanib compared with 1.6 months with placebo (HR, 0.31; 

 <.0001), but no significant improvement in overall survival.

 The study showed promising activity in synovial sarcoma and leiomyosarcoma, and also had activity in solitary fibrous tumors, said Trent.

Without molecular markers to guide therapy considerations, STS specialists must rely on histology-based subsetting, noted Patel. In synovial sarcoma, for example, if the patient received doxorubicin/ ifosfamide upfront, pazopanib would likely be second line, he said. In other settings, anthracycline-based therapy would be front line, gemcitabine/docetaxel second line, and pazopanib third line.

An ongoing Children’s Oncology Group clinical trial is investigating the effect of adding pazopanib to chemotherapy and radiation therapy in the neoadjuvant setting in patients with newly diagnosed non-rhabdomyosarcoma STS that can be removed through surgery, noted Randall. The four-arm trial compares (a) pazopanib plus chemoradiation, (b) chemoradiation, (c) pazopanib plus radiation, and (d) radiation alone.

Pazopanib, which is approved for the treatment of patients with advanced STS who have received prior chemotherapy, carries a black box warning for liver toxicities. The drugs in this class share similar toxicities, including potential elevations in alanine transaminase, aspartate aminotransferase, and bilirubin, said Wagner. Other potential toxicities include hypertension, diarrhea, palmar/plantar erythrodysesthesias, and oral dysesthesia.

A clonazepam mouthwash can help counteract the mouth pain. Patients should be monitored carefully; if toxicities occur, the drug should be suspended or held until improvement, and the dose reduced, Wagner added.

Trabectedin, a marine compound derived from the sea squirt, has been available in the European Union and many other countries for more than 5 years, explained Jones.

A drug application was approved by the FDA in October 2015, based on phase III open label data from a randomized trial of trabectedin compared with dacarbazine in patients with advanced leiomyosarcoma and liposarcoma in more than 500 patients previously treated with anthracycline and ifosfamide or chemotherapy.

Treatment with trabectedin was associated with a 45% reduction in the risk of disease progression or death compared with dacarbazine (HR, 0.55; 

The RECIST response rates have consistently been in the 8% to 10% range, said Patel. “I think there is a group of patients who can tolerate this treatment for a very long time,” added Patel. “There are subsets like myxoid liposarcoma that are more sensitive to this drug than others. So, the drug clearly has had a role.”

Fatigue can be a major problem, said Jones, and liver toxicity is important to monitor. Very rarely, the drug can cause rhabdomyolysis. The dose may need to be modified, added Wagner.

Community oncologists should be aware that if the liver function tests show an obstructive pattern with alkaline phosphatase elevations, those are the patients who can have life-threatening toxicities, said Patel.

The real key is figuring out how to make optimal use of pazopanib and trabectedin, said Trent. It should be “a personalized decision based on patients’ expected toxicities, expected tolerance, and other factors that may be specific to that individual patient,” he said.

		Table. Key Results in Pivotal Trabectedin Trial

ORR consists of complete and partial responses.

		NE indicates not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

		Yondelis [prescribing information]. Horsham, PA: Janssen Products, LP; 2015.

Solid tumors, particularly sarcomas, tend to be hypoxic, explained Jones. Evofosfamide is activated in the hypoxic region of the tumor. The drug, an alkylating agent formerly known as TH-302, appears to be safer than the biologically equivalent dose of ifosfamide, noted Trent. Certain toxicities are associated with evofosfamide, including skin rash. It can also activate melanocytes, said Van Tine, increasing skin pigmentation in some individuals.

Patel noted that the available data suggest that this drug is “a kinder, gentler ifosfamide.”

Evofosfamide could end up replacing ifosfamide, or it could be reserved for select patients who are not candidates for ifosfamide, said Patel.

An ongoing phase III study is comparing evofosfamide in combination with doxorubicin versus doxorubicin alone in an estimated 620 patients with locally advanced or metastatic STS.

The results from the trial and postmarketing data, if the drug were approved, would help determine patient selection for the regimen.

Olaratumab is a monoclonal antibody that targets PDGFR-α. Phase I/II data are very promising, noted Van Tine. The study compared olaratumab plus doxorubicin with doxorubicin alone. The final PFS analysis showed that the combination was associated with a median PFS of 6.6 months compared with 4.1 months with doxorubicin (

 = .0615), which investigators said met the primary endpoint.

With scores of subtypes and a paucity of molecular markers, soft tissue sarcoma remains a complex and challenging tumor type to treat yet significant strides being made in the field are likely to alter the therapeutic paradigm.

Tara Petersen

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