A treatment regimen of pembrolizumab (Keytruda) plus low-dose ipilimumab (Yervoy) was tolerable and effective for patients with advanced melanoma, with an overall response rate (ORR) of 56%, according to results from the phase Ib KEYNOTE-029 clinical trial.

The rate of grade 3/4 adverse events (AEs) with the combination was 36%, with a 54% incidence of immune-mediated AEs. These findings were similar to what has been seen with other trials exploring the combination of PD-1 and CTLA-4 inhibition, said lead investigator Georgina Long, BSc, PhD, MBBS, medical oncologist at the Melanoma Institute, Australia, during the late-breaking abstract session at the 2015 Society for Melanoma Research Congress.

The KEYNOTE-029 trial included 72 patients with advanced melanoma followed for 18 weeks. Patients were treated in the United States, New Zealand, or Australia with pembrolizumab at 2 mg/kg and four doses of ipilimumab at 1 mg/kg. Nine of the patients in the study (12%) had been previously treated, but none had been treated with checkpoint inhibitor therapies, said Long.

Most of the patients in the KEYNOTE-029 study were male with a median age of 60 years, and 86% were PD-L1 positive. Only 28% of the patients had 

 V600 mutations. Eighty five percent of patients had a good ECOG performance status of 0, and only 21% had elevated LDH levels.

Among treatment-naïve patients (n = 63), the ORR was 57%. Among those who had been previously treated, the ORR was 44%. The disease control rate (ORR plus stable disease) was 79%, noted Long. “Only 14 patients in the study, or 19%, were diagnosed with progressive disease,” she said.

The complete response rate was 4% across the full study. There were no complete responses in those who had undergone previous therapy, said Long.

Thirty-seven patients (51%) had a partial response to treatment. The partial response rates were 52% and 44% in the treatment-naïve and pretreated groups, respectively. Stable disease occurred after treatment in 24% of patients.

Altogether, 72% of the patients received all 4 ipilimumab doses, and only 31% discontinued both treatments before the end of the trial. Most of the discontinuations were due to progression (19%) or AEs (10%), said Long.

“The majority of patients with ongoing adverse events experience thyroid-related side effects,” Long said. Ninety three percent of patients experienced treatment-related AEs, but only 22% were rated as “serious” by the investigators. None led to death. Seventeen percent of AEs led to ipilimumab discontinuation before the end of the trial, and 8% of AEs led patients to discontinue both drugs.

The most frequent AE in the KEYNOTE-029 study was rash, which affected 53% of patients. Thirty one percent of patients experienced fatigue and 28% were diagnosed with pruritis during treatment. Seventeen percent of patients experienced hypothyroidism as a result of treatment.

Grade 3 or 4 immune-mediated AEs affected 17% of patients. The most frequent immune-mediated AEs were hypothyroidism, hypophysitis, and hyperthyroidism. Other common immune-mediated AEs were pneumonitis and colitis, Long noted.

“Hypophysitis was more common in this trial than we’ve seen in similar studies, but it’s difficult to say why that occurred,” Long said. “We were very aware of this side effect during the study, and so that may be one explanation."

The KEYNOTE-029 phase Ib trial was a continuation of a smaller clinical study with the same study medications at the same dosages. Enrollment in the earlier study also included patients with renal cell cancer, said Long. Since only 6 patients in the earlier study experienced dose-limiting toxicity, the trial was expanded to 72 patients—all with advanced melanoma.

The investigators will continue to evaluate the efficacy and safety data resulting from the treatment regimen used in the KEYNOTE-029 trial, noted Long. They plan to analyze these outcomes and correlate them with tumor biomarkers, using an expanded data set of 153 patients, she added.

	Long G. KEYNOTE-029: Pembolizumab (pembro) + low-dose ipilimumab (ipi) for advanced melanoma. Presented at the Society for Melanoma Research 2015 Congress; November 18-21, 2015; San Francisco, CA.

Articles

A treatment regimen of pembrolizumab plus low-dose ipilimumab was tolerable and effective for patients with advanced melanoma.

Pembrolizumab/Ipilimumab Combo Effective in Advanced Melanoma

In the largest-to-date analysis of treatment-naïve metastatic melanoma patients with 

 V600 mutations treated with dabrafenib (Tafinlar) and trametinib (Mekinist), researchers have found that baseline LDH levels and number of disease sites were the most significant factors affecting survival.

In a pooled analysis of 3 randomized clinical trials with over 600 patients, the researchers concluded that those patients with LDH levels less than the upper limits of normal (ULN), and melanoma affecting less than 3 sites, had a 1-year overall survival (OS) of 90%, and a 3-year OS of 70%.  These patients also showed a superior progression-free survival (PFS) of 61% at 1 year and 33% at 3 years.

“Patients who experienced a complete response also did very well,” said lead researcher Georgina Long, MD, PhD, medical oncologist at the Melanoma Institute Australia. Ninety-five percent of patients with compete responses were alive at 1 year, and 88% were alive at 3 years after treatment. Long presented data from the analysis at the 2015 Society for Melanoma Research Congress.

In the study, researchers looked at outcomes from 2 phase III clinical trials—the COMBI-V study, which compared treatment with dabrafenib plus trametinib versus vemurafenib (Zelboraf) alone, and the COMBI-D trial, which compared dabrafenib plus trametinib treatment with dabrafenib alone. A phase I/II trial with 54 patients that compared dabrafenib with trametinib treatment was also included in the analysis.

The researchers’ aims were to characterize the clinical features associated with progression and their influence on survival post-progression, Long said. After a median follow-up of 20 months, 35% of patients (n = 221) in the studies remained alive and progression-free, and 290 patients had died.

The researchers analyzed baseline factors known to be associated with prognosis in melanoma. These risk factors included age, BMI, target lesion diameter, LDH level, sex, ECOG performance status, number of disease sites, and whether or not the patient had visceral disease.

“After multivariate analysis, there were only 4 factors that affected overall survival and progression-free survival: LDH, ECOG performance status, the number of organ sites affected by melanoma, and sex,” Long said. The strongest risk factor, however, for survival and progression-free survival was LDH level.

“Patients with a normal LDH had a 71% risk reduction for progression and a 77% risk reduction for death,” Long said.

When the researchers analyzed PFS among patients with normal LDH versus those who had LDH ≥ULN, they found that those who had greater LDH levels (n = 219) had a 3-year PFS of just 13%. Those with the highest LDH levels (>2 X ULN, n=70) fared the worst with a 3-year PFS of 2%.

Even when the researchers considered the impact of disease sites combined with LDH levels, they found that abnormal LDH was more likely to adversely affect outcomes. Among patients with normal LDH and melanoma that affected >3 sites, the 3-year PFS was 17%, Long said.

 After multivariate analysis, LDH levels were also a stronger factor in OS than number of disease sites or ECOG status. Patients with a normal LDH (n = 398) had a 3-year OS of 57%, while those with an LDH ≥ULN had a 3-year OS of 7%.

Those with the worst LDH levels (≥2 X ULN, n=70) fared the worst in terms of survival with a 2- and 3-year OS of 7%. Patients with an LDH of 1 to ≤2 X ULN (n = 149) had a 2-year OS of 33% and a 3-year OS of 9%.

The scientists then looked at the factors that affected survival after progression, and found that only the pattern of disease progression affected survival, Long said.

Patients who progressed in their baseline lesions survived for only 10.1 months after progression. Those who developed new non-CNS lesions survived for 9.5 months, and patients who developed new CNS lesions survived 3.8 months after progression. Patients who had baseline lesions and also developed new lesions survived for 4 months after progression, Long said.

“These results show us that it’s not just the kinetics of progression that matter. Survival is not just about speed, it’s also about the pattern of progression that occurs,” Long said.

Long noted that no baseline patient characteristics predicted survival outcomes after progression. “Survival after progression was only affected by what the patients were like at the time of progression,” she said.

“The data on patients with the poorest survival are important, because they will enable us to explore translationally in tumor tissues what targets might affect improve outcomes. It will help us find future target pathways,” Long said.

She noted that the researchers will also be building a model to analyze the influence of LDH levels among patients who had complete responses—and had the longest survival. “We’ll be looking at whether complete responses or LDH levels are more influential in predicting outcomes,” she said.

In the largest-to-date analysis of treatment-naÃ¯ve metastatic melanoma patients with BRAF V600 mutations treated with dabrafenib and trametinib, researchers have found that baseline LDH levels and number of disease sites were the most significant factors affecting survival.

Factors Affecting Dabrafenib/Trametinib Outcomes in Melanoma Identified

While BRAF inhibitors have significantly enhanced melanoma treatment, there is still room for advancement. However, making real strides in devising treatments that provide durable tumor control will require an understanding of BRAF resistance mechanisms, according to Keith Flaherty, MD, associate professor of Medicine at Harvard Medical School and director of Developmental Therapeutics at the Massachusetts General Hospital Cancer Center.

“With BRAF monotherapies and combination therapies, we can extend survival in some patients,” Flaherty said in presentation at the 2015 Society for Melanoma Research Congress. “Enhancing patient outcomes also requires understanding the unique genetic wiring in tumors that [do and] do not manifest resistance,” he said.

Scientists have now accumulated 5 to 6 years of follow-up data on melanoma patients treated with BRAF inhibitor therapies. “We know that melanoma is not uniformly complex. And there’s quite a lot of genetic heterogeneity in terms of amplification and deletion events, and number of mutations in melanoma tumors,” Flaherty said.

Flaherty and colleagues have now performed whole genome sequencing on a large cohort of patients who have undergone BRAF inhibitor therapy. “We’re now moving toward correlating genetic differences with clinical outcomes,” he said.

Right now scientists are attempting to learn the mechanisms of resistance from static biomarkers before deploying patients to therapy. It is important that scientists learn to understand the baseline features of tumors and adaptations of tumors during therapy that make them resistant. With this understanding, patients likely to develop resistance can receive more aggressive treatments, Flaherty said.

Scientists now know that the reengagement of the map kinase signaling pathway plays a part in melanoma treatment resistance, including resistance to BRAF inhibitors. Scientists need to develop therapies that can reengage with the map kinase pathway to try to squelch the mechanisms of reactivation, which can make patients resistant even to combination therapies, Flaherty said. Other baseline tumor features, however, may also play a part in resistance.

MITF expression, which is correlated with BCL2A1 expression, is another potential mechanism for the development of resistance, Flaherty noted. In genetic studies on melanoma tumors, those patients who had upregulated BCL2A1 were more likely to have blunted response to BRAF inhibitor therapy, he added.

Patients low in MITF expression, who also are low in the AXL protein coding gene are also more likely to develop resistance. “Patients with low MITF expression with low AXL expression have been shown to have the shortest duration of tumor control,” Flaherty said.

The challenge is to triage patients early in the course of therapy based on the likelihood that their tumors will be resistant. These harder-to-treat patients could then should be treated with doublet therapy, or by adding a MTOR inhibitor or JAK inhibitor to treatment. Both these approaches have shown potential in patient treatment and in the laboratory for overcoming BRAF inhibitor therapy resistance, Flaherty said.

The issue of whether such genetic changes in a tumor could be assessed prior to or during initial therapy has not yet been fully resolved, Flaherty noted. “As we learn more about the genetic mechanisms of resistance, it makes sense to biopsy patient tumors to assess and measure resistance.”

“Another question is what drives persistence after maximal response to BRAF inhibitor therapy. And that’s more difficult to assess in treated patients,” Flaherty said. “In patients who have deep responses to therapy, their metastases are gone in weeks. So biopsies of these tumors are a challenge.”

Eventually, researchers hope to develop blood-based biomarkers that could be correlated with genetic changes in tumors that drive resistance, Flaherty noted. Even if the genetics of resistance are not hardwired, assessing baseline tumor biomarkers will eventually play a part in selecting the best therapeutic approach for each patient, Flaherty said.

If genetic signatures or blood-borne biomarkers of resistance could be assessed at baseline or early on in therapy, then oncologists could immediately use more aggressive therapies with these patients, Flaherty said. “As we continue to develop new therapies, we’ll find additional solutions to the problem of potential therapy resistance,” he added. “Yet there is likely to be no one-size-fits-all approach in terms of overcoming resistance in melanoma patients treated with BRAF inhibitors.

Making real strides in melanoma care requires an understanding of BRAF resistance mechanisms.

Understanding BRAF Resistance Critical to Advancing Melanoma Care

The FDA approval of ipilimumab (Yervoy) for melanoma in 2011 ushered in a new era of antibodies that target immune checkpoints. Since this milestone, several combinations and monotherapies have gained rapid approval, with continued expansion on the horizon, according to James P. Allison, PhD, at the 2015 Society for Melanoma Research Congress.

“A few years ago, the best you could hope for in advanced melanoma was to improve survival a little bit, but now we have immunotherapies that provide durable responses that last decades,” said Allison, professor and chair of immunology at MD Anderson Cancer Center.

“Immunotherapies are successful because they have specificity, memory, and adaptability,” he said. “These agents don’t just recognize certain peptides on cancer, but can recognize many different mutations—as well as changes in cancer cells&mdash;that contribute to the development and persistence of tumors.”

The advent of immune checkpoint inhibition has not only altered treatment paradigms for patients with cancer, but it has also changed the way that researchers think about new therapies. Traditionally, targeted therapies and vaccines have been directed against a single mutation or peptide on the cancer cell; however, with the checkpoint inhibitors there are more factors at play.

“Immunotherapies, such as checkpoint inhibitors, don’t target tumor cells, and our research work does not involve using vaccines or cytokines to turn on the immune system,” Alison said. “Checkpoint inhibitor therapies work by blocking inhibitory pathways, in order to create an anti-tumor response.”

In effect, the checkpoint inhibitors that Allison has researched work to unleash or “take the brake off” the immune system. “This approach was a radical departure, so it was at first difficult for us to be taken seriously,” he said.

Allison’s research was the first to show that CTLA-4-targeted agents, when combined with a GM-CSF tumor cell vaccine, could eradicate melanoma. “It leads to cure in experiments we’ve now done in thousands of mice. And the cure rate in these experiments is never less than 85%,” Allison said.  

The fully human antibody ipilimumab has now been used to treat over 50,000 patients with melanoma and other cancers, including those that affect the prostate, kidney, bladder, ovarian and lungs. The longest surviving patient treated with ipilimumab remains alive 10 years after undergoing initial therapy for melanoma metastasized to the lungs, Allison noted.

Ipilimumab results in objective responses in several tumor types, and the adverse events that accompany treatment—colitis hepatitis, and hypophysitis&mdash;can generally be managed with steroids, said Allison.

After follow-up of over 10,000 patients treated with ipilimumab, researchers now know that the use of this agent can lead to long-term survival in about 22% of cases. “I think we can think about starting to apply the word cure to these patients,” Allison said.

Allison’s work, which led to the approval of ipilimumab, has also illuminated the mechanisms and efficacy of PD-1 inhibitors. Now, just 4 years after the first checkpoint inhibitor was approved, there are two PD-1 inhibitors indicated for metastatic melanoma.

The next step in advancing cancer treatment with checkpoint inhibitors is to expand research into the use of these agents in combination, according to Allison. When checkpoint inhibitors are combined, their efficacy increases and patient survival improves. “The effect of combining these treatments is not synergistic, but additive,” Allison said.

In the phase III CheckMate-067 trial, the combination of nivolumab and ipilimumab demonstrated an objective response rate of 57.6% in patients with advanced melanoma. On top of these responses, 13.1% of patients treated with the combination had stable disease.

“With this treatment, two thirds of patient had some response. And among those who had an objective response, half had 80% or more tumor shrinkage,” Allison said.

Researchers now hope to improve available therapies so that 50% of those treated with combination checkpoint inhibitors experience long-term survival, Allison said. Next, these combination strategies are likely to move into other types of cancer, such as lung cancer and renal cell carcinoma.

“Eventually, we expect that these immunotherapies will be combined with more standard therapies in combating tumors such as renal cell cancers—so that we can increase treatment efficacy and improve outcomes,” Allison said. “There are many new opportunities for using checkpoint inhibitor therapies outside of melanoma.”

	Allison J. Immune checkpoint blockade in cancer therapy: New insights, opportunities and prospects for a cure. Presented at the Society for Melanoma Research 2015 Congress; San Francisco, CA; November 18-21, 2015.

Since the approval of the first checkpoint inhibitor, ipilimumab, several combinations and monotherapies have gained rapid approval, with continued expansion on the horizon.

James Allison Predicts 'Cures' With Checkpoint Inhibitor Combinations

With the FDA approval of the first oncolytic immunotherapy—talimogene laherparepvec (T-VEC; Imlygic)&mdash;in October, the stage has been set for increased research into these agents, according to Robert Andtbacka, MD, associate professor in the division of Surgical Oncology at the Utah School of Medicine and a research investigator with the Huntsman Cancer Institute.

Oncolytic immunotherapies, such as T-VEC, are genetically modified viruses or plasmids that can invade tumors and replicate—killing cancer cells and spurring an overall immune response as well, Andtbacka said in a presentation at the 2015 Society for Melanoma Research Congress. In research on patients treated with T-VEC and other oncolytic immunotherapies, melanoma patients showed responses in injected and non-injected tumorous lesions, as well as responses at sites of distant metastases, such as the lung and liver.

“Most of us believe these responses are immune-mediated and not virus-mediated,” Andtbacka said. Analyses of lesions treated with oncolytic immunotherapies show that these treatments induce antigen-specific immunity with increased levels of CD4 regulatory T cells, CD8 suppressor T cells, and myeloid-derived suppressive T cells. New phase I/II trials also show that oncolytic immunotherapies may enhance the effect of other immunomodulatory agents, such as the checkpoint inhibitor therapy, ipilimumab, Andtbacka noted.

In the phase III OPTiM clinical trial, which led to the approval of T-VEC, durable responses (≥6 months) and objective overall responses in T-VEC—treated stage IIIB-IV melanoma patients were compared to results after treatment with GM-CSF. In the study, 295 patients were treated with intralesional injections of T-VEC and 141 received subcutaneous injections of GM-CSF.

Results revealed that the durable response rate was 16.3% in T-VEC patients vs. 2.1% in GM-CSF patients. The objective response rate was also superior among T-VEC patients—26.4% compared with 5.7% for GM-CSF.

T-VEC also appeared to prompt a global immune response, since 10.8% of patients treated with the agent had a complete response. Although tissue samples from the study were not analyzed, later studies have shed light on the mechanisms through which oncolytic immunotherapies incite a global immune response.

“Treatments such as T-VEC increase the exposure of tumor cell antigens to the immune system—which explains the complete responses seen in the OPTiM clinical trial,” Andtbacka said.

Other oncolytic therapies now being investigated include other viruses, as well as plasmids. The phase II CALM trial of CVA21, an oncolytic therapy that utilizes the Coxsackie virus, has also shown promising results in stage IIIC and IV melanoma patients. Among 54 evaluable patients, 38.6% experienced a complete or partial response or stable disease after 24 weeks of treatment. The 1-year survival was 75.4% with no grade 3/4 events. Among patients with lung and liver lesions, the partial response rate was notable—37.5%, Andtbacka said.

The investigators in the CALM trial analyzed the biology of the tumors injected with CVA21, and found that after just 3 injections, the number of lymphocytes within the tumors had significantly increased. Subsequent biopsies also revealed that the tumors showed increased infiltration of T cells. “As a result, these agents are being investigated in combination with checkpoint inhibitor treatments such as ipilimumab [Yervoy] as a means of improving response and survival,” Andtbacka said.

Limited data sets in combination trials of T-VEC with ipilimumab or pembrolizumab [Keytruda]—such as the initial results from the MASTERKEY-265 phase 1b study&mdash;indicate that these combined regimens improve tumor response. The improved tumor response rates have also been achieved without undue toxicity, Andtbacka said.

In an effort to understand the systemic immunity conferred by oncolytic agents such as T-VEC and CVA21, investigators initiated the phase I STORM study. In the study, patients with advanced non&shy;—small cell lung cancer, bladder cancer, prostate cancer, and melanoma were treated with intravenous CVA21—rather than local injections of the oncolytic immunotherapy agent. CVA21 was well tolerated in the study, and most adverse events were grade 1, Andtbacka said. Although it is too soon to assess efficacy, patient tumor and blood samples did shed light on the local and systemic immune effects of CVA21.

The investigators of the STORM study first documented an increase in viral RNAs within tumors. Their results also showed an increased viral load among prostate cancer and melanoma patients in the study, which may indicate that the genetically modified viruses in the bloodstream were able to recognize, hone in, and kill tumor cells, Andtbacka said.

“Agents such as CVA21 have the potential to induce responses in injected and non-injected lesions and to induce an overall immune response that could affect even metastatic lesions,” Andtbacka noted. “Since they can increase T-cell infiltration into tumors, oncolytic immunotherapies could be used as a rescue strategy to reconstitute the tumor microenvironment in patients resistant to checkpoint inhibitor therapies,” he added.

With the FDA approval of the first oncolytic immunotherapy-talimogene laherparepvec (T-VEC; Imlygic)-the stage has been set for increased research into these agents.

Novel Agents, T-VEC Combos Mark Next Phase of Oncolytic Immunotherapy Era in Melanoma

There were few differences in quality of life (QoL), global health, and symptom burden between patients with melanoma who were treated with nivolumab (Opdivo) plus ipilimumab (Yervoy) or either agent alone, according to a recent analysis of patient-reported outcomes from the phase III CheckMate-067 trial.

After one year of follow-up, patients in the nivolumab plus ipilimumab arm of the CheckMate-067 trial experienced no clinically meaningful change in health-related QoL—even though they showed significant improvements in survival. Additionally, patients treated with nivolumab alone or ipilimumab alone showed no significant changes in QoL compared to baseline, said Dirk Schadendorf, MD, during a presentation at the 2015 Society for Melanoma Research Congress.

“The nivolumab plus ipilimumab treatment arm had the highest frequency of adverse events, but these adverse events did not seem to affect patient-reported QoL outcomes,” said Schadendorf, director of the department of dermatology, the West German Cancer Center at the University Hospital in Essen, Germany.

In the CheckMate-067 study, 945 patients with advanced melanoma were treated with nivolumab alone, ipilimumab alone, or the combination of nivolumab plus ipilimumab. Results revealed that patients in the combination arm showed improved progression-free survival (PFS). The median PFS with the combination was 11.5 versus 6.9 months with nivolumab alone and 2.9 months with ipilimumab alone.

Adverse events (AEs) were more frequent with the combination treatment, with 55% of patients in nivolumab plus ipilimumab having grade 3/4 AEs versus 16.3% with nivolumab alone and 27.3% with ipilimumab. Additionally, over 29% of patients in the combination arm experienced a treatment-related AE leading to treatment discontinuation.

Despite the higher incidence, AEs in the CheckMate-067 study were short-lived. The median time for resolution of grade 3/4 AEs was 1.7 to 4.2 weeks, Schadendorf said.

To assess patient-reported QoL, researchers used the EORTC QLQ30 cancer specific QoL questionnaire and the EQ-5D scale, which assesses health status and global health. The EQ-5D includes a visual analog scale (VAS) in which patient rate their health status on a scale from 0 to 100, as well as a descriptive system which asks participants to rate 5 dimensions of their health in terms of self-care, mobility, usual activities, pain/discomfort and anxiety/depression.

Schadendorf noted that patient characteristics were well balanced among the treatment arms at baseline, suggesting that it is unlikely that pre-existing patient health outcomes affected the results.

Reductions were seen in EORTC scores across all arms (

 ≤.01); however, these findings were not deemed to be clinically meaningful (≤10 points change). At week 5, there was reduction of 2.7, 4.3, and 3.1 points for nivolumab alone, nivolumab plus ipilimumab, and ipilimumab alone, respectively. Scores returned to baseline levels by week 25 in the nivolumab alone arm and by week 31 in the combination and ipilimumab alone arms.

The EQ-5D scores improved at week 13 with nivolumab alone (

 = .042), which persisted throughout the trial. However, in the ipilimumab containing arms, EQ-5D scores initially worsened before returning to baseline by week 13 for the combination and by week 19 for ipilimumab alone. VAS scores were stable for the nivolumab-containing arms and worsened with ipilimumab until week 23.

“Even among patients who suffered severe toxicities such as colitis, treatment did not appear to have a significant effect on quality of life,” Schadendorf said. “Do the results in this study indicate that patients don’t care about toxicity when they receive a large survival benefit, or is it that QoL wasn’t affected because the toxicities were short-lived?” he asked.

One shortcoming of the analysis was that patients who discontinued treatment were not included in QoL assessment, Schadendorf said. To account for this, data are being analyzed that include patients who progressed or discontinued. Additionally, patients will continue to be followed in the study to assess whether the tumor control benefits observed in CheckMate-067 will affect long-term patient QoL outcomes, he said.

“One possible explanation for our findings in this study could be that the tools we have now—utilized in our analysis&mdash;are not very useful for assessing QoL in patients treated with newer immunotherapy agents,” Schadendorf said. “Yet these are the only instruments we have that are validated, and it could take years to obtain new and better validated tools.”

	Schadendorf D, Long G, Larkin J, et al. Patient reported outcomes (PROs) from a phase 3 study of Nivolumab (NIVO) alone or combined with Ipilimumab (IPI) versus IPI in patients with advanced melanoma. CheckMate 067. Presented at the Society for Melanoma Research 2015 International Congress; November 18-21, 2015; San Francisco, CA.

There were few differences in quality of life, global health, and symptom burden between patients with melanoma who were treated with nivolumab plus ipilimumab or either agent alone.

QoL Similar With Checkpoint Combo Versus Single-Agents in Melanoma

Predictive genetic signatures and novel combination strategies may be the key to improving the often dramatic responses seen with immune checkpoint inhibitors, according to Antoni Ribas, MD, PhD, during a satellite symposium presented by the Society for Immunotherapy of Cancer (SITC) that took place before the opening of the 2015 Society for Melanoma Research Congress.

“It’s really remarkable that patients with late-stage melanoma, for instance, would get notable improvements in overall survival from treatments such as nivolumab. But these responders are still in the minority,” said Ribas, professor of Medicine, Surgery and Molecular and Medical Pharmacology at the Jonsson Comprehensive cancer Center at the University of California, Los Angeles. “Our job now is to select patients who are poised to respond to PD-1/PD-L1 blockade therapies.”

Ribas noted that recent studies have attempted to increase the efficacy of PD-1/PD-L1 blockade by combining treatments. Recent clinical trials have shown improved progression-free survival (PFS) in melanoma with combinations of CTLA-4 and PD-1 agents, but the price has been an increased incidence of serious adverse events, he noted.

In the CheckMate-067 trial, for example, patients with advanced melanoma treated with nivolumab plus ipilimumab had a median PFS of 11.5 months versus 6.9 months with nivolumab alone and 2.9 months with ipilimumab alone.

Yet, more patients who underwent the combination therapy suffered serious grade 3/4 adverse events. Grade 3/4 adverse events affected 55% of patients in the combination arm of CheckMate-067, as compared with just 16.3% of those who were administered nivolumab alone and 27.3% of patients who underwent ipilimumab therapy alone.

(NEJM) in 2011, patients with previously untreated metastatic melanoma also derived survival benefits from the combination treatment of ipilimumab plus the chemotherapy agent dacarbazine.

More recent clinical trials have also highlighted reduced mortality in advanced melanoma with other checkpoint inhibitor therapies. In a clinical trial published in 

 in January 2015, patients with previously untreated melanoma without 

 mutations treated with nivolumab had less risk of mortality than those who underwent treatment with dacarbazine (HR, 0.42).

“There are some patients in these clinical trials who are benefiting from targeting single checkpoints. And by using single checkpoint inhibitor therapies we can also reduce serious adverse events,” Ribas said. Yet increasing the number of patients who can benefit from single checkpoint inhibitor therapy requires understanding the biology of tumor response to these treatments, he added.

In patients who don’t respond to checkpoint inhibitor therapies, tumors may be able to protect themselves from T-cell infiltration through genetic mutations that trigger an adaptive PD-1/PD-L1 expression, according to recent research by Ribas and others. In other non-responder patients treated with checkpoint inhibitor therapies, T-cells may increase in the patient’s bloodstream, but they don’t make it into the tumor.

Biopsies of tumors taken before treatment with checkpoint inhibitors could identify genetic signatures that could set off an adaptive PD-1/PD-L1 response, said Ribas. Treatment could then be targeted to those likely to respond to single molecule checkpoint inhibitor therapy. Other methods of improving response to checkpoint inhibitor therapies could include increasing the T-cell infiltration of tumors through immune-activating antibodies, oncolytic viruses, macrophage inhibitors or targeted therapies, Ribas said.

“When we perform the initial decision-making in the use of checkpoint inhibitor therapies in patients, we should be taking biopsies to find out if there are T-cells in the tumor that could be turned off by PD-1/PD-L1 expression,” Ribas said. Biopsies after initial treatment can also reveal if there are no T-cells in the tumor, although they may be present elsewhere in the patient’s body.

“The idea is to use the right treatment for the right patient by understanding the biology of the tumor and its environment,” Ribas said.

			Ribas A. Checkpoint inhibitor therapy. Presented at: Tumor Immunology 101: A Navigation Guide for the Growing Field of Cancer Immunotherapy. The Society for Immunotherapy of Cancer (SITC) Satellite Symposium. November 18, 2015.

			Wolchok JD, Chiarion-Sileni V, Gonzales R, et al: Efficacy and safety results from a phase III trial of nivolumab alone or combined with ipilimumab versus ipilimumab alone in treatment-naive patients with advanced melanoma (CheckMate 067). 2015 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2015.

			Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. 

			Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. 

Predictive genetic signatures and novel combination strategies may be the key to improving the often dramatic responses seen with immune checkpoint inhibitors.

Researchers Seek to Improve Responses With Checkpoint Inhibitors

Although PD-1 and CLTA-4 checkpoint inhibitors have grabbed the attention of scientists and oncologists in recent years, a wide variety of novel checkpoint and immune blocker/activator therapies may soon hold promise.

“There’s a long and growing list of regulatory and activating immunotherapy targets that may hold promise in cancer treatment, although we have yet to develop their potential in the clinic,” said Margaret K. Callahan, MD, PhD, assistant attending medical oncologist in the department of Medicine at Memorial Sloan Kettering Cancer Center.

Scientists are already developing therapies against these novel immunotherapy targets—including agonist antibodies and checkpoint molecules. Many of these immunotherapies are in clinical development, and some have even shown promise in early phase I studies, Callahan said.

Callahan spoke at a lecture on novel checkpoint and immune blockers/activators and tumor immunology at a satellite symposium presented by the Society for Immunotherapy of Cancer (SITC). The SITC satellite symposium took place before the opening of the 2015 Society for Melanoma Research Congress.

Most novel checkpoints and immune blockers/activators known today target T-cell activation, noted Callahan. Yet they drive an immune response, not just through T-cell recognition, but also when a second costimulatory signal occurs through molecules such as CD28 protein antibody or the GITR/GITRL interaction.  

Callahan highlighted a few novel checkpoints and immune blockers/activators in her presentation, including the CD137 molecule (4-1BB ligand). CD137 is a positive regulator of T-cell activation, and at least 1 agent is in development that targets CD137. The agent that has the most promise, urelumab, has shown antitumor activity in preclinical data, but also has significant liver toxicities, according to recent research.

“There are a lot of nuances in how these molecules regulate T-cells and how they are expressed. So these agents that target these molecules could be quite different, and their effects can be quite different,” Callahan said.

Another promising target for cancer therapies is the CD27 molecule, which is expressed on most T cells. Anti-CD27 therapies have shown promise in small clinical trials and have produced patient responses in phase I studies on Hodgkin lymphoma, as well as disease stability in solid tumors, Callahan said. 

Preclinical studies on agents that target the LAG3 molecule—a negative regulatory molecule&mdash;have also shown potential for reducing unabated cancer growth in mice. In preclinical studies, the power of anti-LAG3 agents has been increased by pairing them with PD-1 inhibitor therapies. In some of these animal studies, a majority of the mice exposed to cancerous cells and then treated with anti-LAG3 agents plus anti&shy;—PD-1 inhibitor therapies, were protected against tumor growth.

“In terms of therapies that can rev up the immune system, PD-1 and CLTA-4 checkpoint inhibitor therapies are just the tip of the iceberg,” Dr. Callahan said. As the number of agents with cancer treatments increase, however, the numbers of combination immunotherapies will also increase, she cautioned.

“There are dozens, if not hundreds, of combinations of therapies that target novel immunotherapy molecules, which we could try out in the clinic. We need to be thinking about the framework that will surround our work in combining these treatments,” Callahan said.

Although the biology of many new and novel immunomodulatory agents provides useful information, how they may act in combination with each other during patient treatment can still be unknown.

Even though the action and efficacy of an individual agent can be understood by researchers, and it makes sense theoretically to combine them, such combinations may still not work together well in the clinic, Callahan noted.

“Even though we may know what the individual toxicities are, it can also be a surprise when we get into the clinic, and find that combination treatments have unacceptable complications or adverse events,” she added.

There is a wide variety of novel targets and corresponding checkpoint and immune blocker/activator therapies that may soon show promise in cancer care.  

Barbara Boughton