Five Hits and a Dud:
A Snapshot of the 2015 European Cancer Congress
By Neil Canavan
The European Cancer Congress (ECC) 2015 meeting organizers made sure to remind their attendees that there’s more than cancer immunotherapy (IO) to hear about – innovations with targeted treatments continue to be made, and IO/targeted combinations are in the works. “This has to be a story of working together,” said Caroline Robert, MD, PhD, Institute Gustave Roussy, Paris, at the opening plenary session.
“In the future we are going to do immunogenic targeted therapy, and personalized immunotherapy, and there is no reason to have separate auditoriums to discuss these issues,” said Dr. Robert.
In the meantime, yes, checkpoints and chimeric antigen receptors (CARs) are the stuff of headlines, and rightly so, but many patients don’t respond to these new agents, and the remaining unmet clinical needs will have to be addressed with targeted agents used by themselves, or in immunotherapy combinations.
In that light, this review will touch on two immunotherapy (IO) presentations, and targeted agents showing significant activity in two settings of unmet clinical need.
Metastatic Kidney Cancer
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, with 338,000 new cases, and more than 100,000 deaths worldwide each year. “The five-year survival rate for those diagnosed with advanced kidney cancer is 12.1%, and so more effective treatments are desperately needed for these patients,” said Padmanee Sharma, MD, PhD, professor of immunology, MD Anderson Cancer Center, Houston, presenting her data on the CheckMate 025 trial.
The phase III, CheckMate 025 study compared nivolumab (Nivo), an immunotherapy drug that blocks the interaction between the programmed cell death receptor (PD-1) and its activating ligand (thereby “unmasking” the tumor so that the immune system can then recognize it) and everolimus, the standard of care (SOC) in this disease setting (N=821).
Having recruited its first patients in October 2012, CheckMate was halted in July 2015 due to the abundant evidence of efficacy. “After the interim analysis in July, the DMC [Date Monitoring Committee] concluded that the trial had already met its primary endpoint,” said Dr. Sharma. “It was clear by then that there was superior overall survival among patients being treated with Nivo.”
Randomized in a 1:1 fashion, patients who had previously failed SOC with anti-angiogenic agents were treated with either Nivo, or everolimus, until experiencing disease progression or unmanageable toxicity. Treatment beyond progression was permitted if either drug was tolerated and clinical benefit was noted.
Results showed that the overall response rate to treatment with Nivo was 25%, versus just 5.4% for everolimus. This activity translated into a superior rate of overall survival for the immunotherapy: a median of 25.5 months for Nivo was reported vs 19.6 for everolimus (HR 0.73; p=0.0018) (Figure 1).
“Importantly, survival curves for the two treatment arms separated early and that separation was sustained throughout the remainder of the study,” Dr. Sharma said. Further, the survival advantage was still observed in patients in the poorest risk groups (as gauged by performance status).
While this was all to the good regarding Nivo’s therapeutic efficacy, there was one puzzling finding from CheckMate 025: Nivo activity is not strictly linked to expression of its putative ligand target – the PD-L1 protein. For patients with ≥1% PD-L1 expression the median overall survival was 21.8 months, while for patients with <1% of PD-L1 expression the rate was higher: 27.4%.
“The finding that overall survival was higher among patients treated with Nivo, irrespective of PD-L1 expression, suggests that PD-L1 expression should not be used to determine which patients might respond to the therapy and whether or not to offer it to them,” concluded Dr. Sharma.
Regarding safety, the Nivo cohort experienced fewer serious adverse events, and those seen were consistent with previous use of the drug. The most common events related to Nivo were fatigue (33%), nausea (14%) and pruritus (14%).
Of note, regarding duration of response, even those patients who discontinued Nivo due to intolerability continued to respond favorably.
Due to the remarkable response rate observed in this trial, and the unquestioned unmet medical need, the results for Checkmate 025 were just published in the New England Journal of Medicine.
Five Hits and a Dud:
A Snapshot of the 2015 European Cancer Congress (continued)
RCC: Take Two
Not to be outdone, Toni Choueiri, MD, Dana-Farber Cancer Institute took the stage immediately following Dr. Sharma’s presentation to report on his study, METEOR, conducted in patients with advanced RCC using the drug, cabozantinib.
“I am very excited about the outcome of the study since the results may change the standard of care in patients with advanced kidney cancer who have received prior standard (anti-angiogenic) therapy,” said Dr. Choueiri.
Cabozantinib, a tyrosine kinase inhibitor already approved for use in metastatic medullary thyroid cancer, blocks the signaling of multiple pathways including, RET, MET, VEGFR, KIT, AXL, and FLT-3. These kinases are variously involved in oncogenesis, cell proliferation, and metastasis.
“Increased MET and AXL expression has been associated with poor prognosis, and resistance to VEGFR (SOC) inhibition,” explained Dr. Choueiri. “Resistance in these patients is a major challenge.”
In the phase III METEOR trial, cabozantinib, a small molecule drug, was compared with everolimus in second line treatment for a cohort of patients with advanced RCC who had previously failed standard of care (N=658).
Results for efficacy in this difficult-to-treat population were striking; the overall response rate was 21% for cabozantinib treatment vs 5% for everolimus; and the progression-free survival (PFS) was 7.4 months for cabozantinib vs 3.8 months for the comparator (for both: p<0.001) (Figure 2).
A sub-analysis showed an even greater response in patients who received sunitinib as prior treatment; the PFS was 7.4 months for cabozantinib vs 3.8 for everolimus (HR=0.41).
Though the trial is ongoing, this interim analysis suggested a strong trend for improved overall survival.
“This is a great day for kidney cancer patients,” Dr. Choueiri said. "We now have two new drugs with two distinct mechanisms of action to choose from.”
The clinical challenge ahead is, of course, which do you pick? As yet, the data do not say.
Not everyone was beating up on everolimus: the RADIANT-4 trial managed to demonstrate the drug as having superior efficacy as compared with placebo in a cohort of patients with neuroendocrine tumors (NETs) of lung or gastrointestinal origin.
“Everolimus has previously shown activity in pancreatic NET and is approved as a standard treatment option in that setting,” said RADIANT-4 investigator, James Yao, MD, of the MD Anderson Cancer Center, explaining the rationale for using the drug. “Unfortunately, effective therapeutic options for patients with advanced, progressive, nonfunctional NET of lung or GI are very limited. In fact, there are no agents approved that have demonstrated activity in patients with lung NET.”
In this phase III study, RADIANT-4 randomized 302 patients with NETs in a 2:1 fashion, everolimus vs placebo. The most common tumor sites in this population were lung (30%), and ileum (24%). Patients were treated until disease progression or intolerable adverse events occurred.
Results for treatment with everolimus showed an improved PFS of 11.0 months vs 3.9 months for placebo (HR=0.48; p<0.0001). “This means a 52% reduction in the relative risk of progression or death with everolimus,” said Dr. Yao.
As with METEOR, this trial is also ongoing, and like that investigation, an interim analysis of RADIANT-4 suggests an overall survival benefit for everolimus (HR=0.64; p=NS).
“The benefit was demonstrated early, with early separation of the curve at the two month time point and was durable, with curves separated for more than 18 months," Dr. Yao noted.
The next update on overall survival will be reported in 2016.
Moving on from everolimus but staying with NETs, Philippe Ruszniewski, MD, Chief of Division of Gastroenterology and Pancreatology, Beaujon Hospital, Paris, reported on his use of the radio-therapeutic, 177Lu-DOTATATE (Lutathera) in patients with mid-gut NETs.
“NETs are a group of tumors originating in the neuroendocrine cells of many different organs,” said Dr. Ruszniewski. “These cancers are rare, but they are the second most common type of GI malignancy, and incidence is on the rise.” Indeed, the incidence of NET has grown by almost 500% since 1973.
The SOC for mid-gut NETs is front-line use of somatostatin analogues. Failing that, there are no approved treatment options.
Lutathera, administered as an IV, is a peptide receptor radionuclide therapy composed of lutetium chelated to a targeting peptide. The targets are somatostatin receptors which are overexpressed in 80% of NETs. Once bound by tumor cells, the drug is internalized and thereby causes radiation-induced DNA damage, followed by cell death.
For this phase III investigation, patients with advance mid-gut NET were randomized to Lutathera + Octreotide LAR (SOC), or SOC alone (N=230).
Presenting an interim analysis of this study, Dr. Ruszniewski reported that the overall response rate was 19% for Lutathera vs 3% for SOC (p<0.0004). As for PFS, the median threshold had yet to be reached at the time of data analysis, but was 8.4 months for SOC alone (p<0.0001). Though not yet statistically significant, a numerical superiority for overall survival was also seen with Lutathera. “This appears to be a major advance in this patient population,” said Dr. Ruszniewski.
Adverse events were reported as, “not a big issue,” though low grade thrombocytopenia and neutropenia were observed.
This presentation was a two-year overall survival (OS) update of a phase III trial that has already reported its primary endpoint (https://obroncology.com/obrgreen/print/ESMO-Redux-All-Stars-and-Also-Rans). The present analysis included a further 11 months of data.
As revisited by Caroline Robert, MD, PhD, the COMBI-v study compared the doublet of dabrafenib/trametinib with vemurafenib monotherapy in patients with unresectable, or metastatic BRAF-mutation positive melanoma (1:1 randomization; N=704).
At two years, the OS for the doublet was 51% vs 38% for monotherapy, translating into a median survival of 25.6 months for the combination vs 18.0 months for vemurafenib alone (p<0.001).
“This is the longest overall survival reached in a randomized study in this patient population – the longest ever,” concluded Dr. Robert. She added that, in her opinion, the data supported the use of dabrafenib + trametinib as standard of care in this disease setting.
IMPRINT did not leave a favorable impression.
The phase III IMPRINT trial featured the drug IMA901, a vaccine cocktail with 10 different tumor-associated peptides that was administered with the immune system booster, GM-CSF, to a population of patients with advanced RCC currently receiving sunitinib (N=339).
In brief, the trial did not meet its endpoint of improved overall survival.
As stated by the study's authors: “Methods to significantly improve the magnitude and polarization of immune responses would need to be identified before further development of IMA901 in mRCC is indicated.”
And so it goes.