Staff Writer

Talimogene laherparepvec (T-VEC), an attenuated oncolytic virus, combined with pembrolizumab, an immune checkpoint inhibitor, passed an early safety evaluation for unresectable melanoma, reported investigators at this year&rsquo;s European Cancer Congress (ECC).

Treatment-related grade 3 adverse events occurred infrequently in a small phase Ib trial of combination therapy with T-VEC and pembrolizumab. No patient discontinued treatment due to adverse events, and treatment-related deaths did not occur.

&ldquo;T-VEC plus pembrolizumab was well tolerated, and we observed no dose-limiting toxicity,&rdquo; said Georgina V. Long, BSc, PhD, MBBS, associate professor at the University of Sydney in Australia. &ldquo;Treatment-related adverse events were mostly grade 1/2. The combination of T-VEC and pembrolizumab is feasible and warrants further investigation.&rdquo;

PD-1/PD-L1 inhibitors, such as pembrolizumab, demonstrated activity in advanced melanoma, which has stimulated interest in combination strategies to improve outcomes in patients who have advanced disease. T-VEC is an oncolytic herpes simplex virus type 1 engineered to replicate selectively in tumor cells and express human granulocyte macrophage-colony stimulating factor (GM-CSF).

A recently reported study showed that T-VEC treatment improved durable response in advanced melanoma.

An as-yet unpublished phase Ib study showed that the combination of T-VEC and ipilimumab resulted in an overall response rate of 50%, durable response rate of 44%, and tolerable safety profile in patients with advanced melanoma, added Long.

Investigators enrolled 21 patients with unresectable stage III/IV melanoma and no prior treatment. Those with clinically active brain metastases or active herpetic skin lesions (or a history of complications from herpetic infection) were excluded.

Five weeks prior to initiating pembrolizumab, patients received intralesional T-VEC injection at doses up to 4 mL per treatment (10

PFU/mL every 2 weeks). Pembrolizumab (200) mg was then administered intravenously every 2 weeks at week 0. Dose-limiting toxicity was assessed during weeks 0 to 6.

Treatment continued until disease progression, development of intolerance, injectable tumor disappearance (T-VEC only), or 2 years. The primary endpoint was the incidence of dose-limiting toxicity.

Women accounted for 13 of the 21 patients, and 8 of the 21 had stage III disease at enrollment. About 20% of the patients had

-positive melanoma. All patients received one or more doses of T-VEC and pembrolizumab. Median treatment duration was 13.1 weeks, and seven infusions for T-VEC and 10.1 weeks and five infusions for pembrolizumab.

The most common adverse events of any grade were rash and pyrexia (each reported in 9 patients), fatigue (8), chills and nausea (7 each), headache and vomiting (5 each), diarrhea, arthralgia, and pruritus (4 each), and influenza-like illness and peripheral edema in 3 patients each.

Six patients had grade 3 adverse events, including four patients who had a total of five treatment-related adverse events (one case each of anemia, hyperglycemia, macular rash, headache, and generalized rash). Treatment-related grade 4 adverse events were not reported, said Long.

Analysis of the timing of treatment-related adverse events showed spikes at the start of T-VEC, as well as the initiation of pembrolizumab.

Serious adverse events consisted of one case of grade 5 hypovolemic shock that was not considered treatment related, and one case of grade 1 treatment-related cytokine release syndrome, which occurred early after initiation of pembrolizumab and did not recur.

One case of T-VECassociated treatment interruption occurred during T-VEC monotherapy and two cases during T-VEC plus pembrolizumab. Four pembrolizumab-related treatment interruptions occurred.

Long said the safety data reported at ECC are as of June 10, and efficacy data are still being analyzed. Even so, a phase III continuation of the trial has been planned, comparing the combination to pembrolizumab alone. Pembrolizumab will be started concurrently with T-VEC, and the dosing interval for pembrolizumab will be increased to every 3 weeks.

Long GV, Drummer R, Ribas A, et al. Safety data from the phase 1b part of the MASTERKEY-265 study combining talimogene laherparepvec (T-VEC) and pembrolizumab for unresectable stage IIIB-IV melanoma.Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract LBA24.

Andtbacka RH, Kaufman HL, Collichio F, et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.

Articles

Talimogene laherparepvec (T-VEC), an attenuated oncolytic virus, combined with pembrolizumab, an immune checkpoint inhibitor, passed an early safety evaluation for unresectable melanoma.

T-VEC Combined With Pembrolizumab Shows Safety in Melanoma

Two strategies of successive immunotherapy for the treatment of advanced melanoma recently showed similar safety and tolerability, yet substantially different efficacy, according to a late-breaking abstract that was presented at this year&rsquo;s European Cancer Congress.

Nivolumab followed by ipilimumab led to grade 3/4 adverse events (AEs) in half of patients during the first two induction cycles, whereas reversing the order of the drugs was associated with grade 3/4 AEs in 43%. However, beginning with nivolumab led to objective responses in 40% to 50% of patients, which is more than twice the rate observed with an ipilimumab-first strategy.

&ldquo;The nature of adverse events was similar to those previously observed with either agent, alone and in combination, whereas the frequency of adverse events was consistent with previous reports for nivolumab followed by ipilimumab,&rdquo; said F. Stephen Hodi, MD, director of immune-oncology at Dana-Farber Cancer Institute in Boston. &ldquo;Consistent improvement in efficacy outcomes was demonstrated with nivolumab followed by ipilimumab as compared with ipilimumab followed by nivolumab.

A preliminary trial of sequential therapy showed an overall response rate of 19% with ipilimumab followed by nivolumab.

A phase III trial involving patients with untreated melanoma showed an overall response rate of 58% with nivolumab followed by ipilimumab, 44% with nivolumab alone, and 19% with ipilimumab alone.

Hodi and colleagues performed a randomized phase II trial to evaluate the safety and efficacy of 2 strategies of sequential therapy, in order to provide information on the decision making process of sequential treatment. Patients were randomized to nivolumab followed by ipilimumab, followed by nivolumab maintenance therapy, or ipilimumab-nivolumab and maintenance therapy with nivolumab.

The primary endpoint was the incidence of treatment-related grade 3-5 AEs during induction periods. Secondary endpoints included confirmed objective response rate at week 25 and progression rates at weeks 13 and 25. Eligible patients had unresectable stage III/IV melanoma, either untreated or that had progressed after first-line systemic therapy.

The final analysis included 138 randomized patients with a median age of about 60 years. About 85%-90% of patients had no prior therapy. In those randomized to receive nivolumab first, 42% had PD-L1 expression greater than 5% as compared with 23% of the patients who received ipilimumab first.

The results showed a 52% incidence of treatment-related grade 3/4 AEs during induction periods 1 and 2 in the nivolumab-ipilimumab arm and 43% in the ipilimumab-nivolumab arm. Study drug-related deaths did not occur in either group.

Hodi reported that 24% of patients in the nivolumab-ipilimumab group discontinued because of treatment-related grade 3/4 AEs versus 27% in the ipilimumab-nivolumab group.

Among those who received nivolumab first, grade 3/4 AEs included diarrhea in 13%, colitis in 12%, and elevated liver enzymes (ALT) in 10%. No other grade 3/4 AE occurred in as many as 10% of the group. In patients who began with ipilimumab, the most common grade 3/4 AE was colitis, occurring in 21% of patients. No other grade 3/4 AE occurred in more than 7% of patients.

The efficacy summary showed an objective response rate at 25 weeks of 41.2% among those who received nivolumab first versus 20.0% in those who started treatment with ipilimumab. The unconfirmed response rates were 47.7% with nivolumab first and 22.6% with ipilimumab first. At 25 weeks, 38.2% of patients had progressed in the nivolumab-first arm versus 60% with ipilimumab-first group.

The median change in tumor burden at 13 weeks was -27% in the patients who started treatment with nivolumab and +10% in those who started with ipilimumab. The median change from baseline to 25 weeks was -50% with nivolumab first and -17% with ipilimumab first.

&ldquo;The data from this study, including planned correlative biomarker analyses that are underway, may help inform the choice of initial treatment approaches in advanced melanoma,&rdquo; Hodi added.

Recent studies have demonstrated high response rates in advanced melanoma treated with nivolumab, as well as 10-year survival exceeding 20% in patients treated with ipilimumab. The activity of the two drugs stimulated interest in combination strategies to achieve even better outcomes.

The FDA is currently reviewing a supplemental biologics license application for nivolumab plus ipilimumab in previously untreated patients with advanced melanoma, based on phase III data. An earlier application was submitted based on phase II data, which was also being reviewed by the FDA. The agency will make a decision regarding the application by January 23, 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; Vienna, Austria. Abstract 23LBA.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.

Two strategies of successive immunotherapy for the treatment of advanced melanoma recently showed similar safety and tolerability, yet substantially different efficacy.

Nivolumab Followed by Ipilimumab Proves More Effective in Advanced Melanoma

Over a fifth of patients with previously treated advanced nasopharyngeal carcinoma showed a measurable response, when treated with pembrolizumab, an immune checkpoint inhibitor, according to a study that was reported at this year&rsquo;s European Cancer Congress.

Two-thirds of patients in the study had some degree of reduction in target lesion size. The median duration of response was 10.8 months. The objective response rate with pembrolizumab in nasopharyngeal carcinoma was 22.2%, which consisted of all partial responses. Another 15 patients had stable disease, resulting in a disease control rate of 77.8%.

&ldquo;This is the first demonstration of robust clinical activity of a PD-1 inhibitor in patients with recurrent metastatic nasopharyngeal carcinoma,&rdquo; said lead investigator Chiun Hsu, MD, a head and neck cancer specialist at National Taiwan University Hospital in Taipei. &ldquo;Pembrolizumab showed a manageable safety profile, and further investigation of advanced nasopharyngeal carcinoma is planned.&rdquo;

Nasopharyngeal carcinoma is uncommon in the United States and Europe, but it is a major cancer problem in certain parts of Asia. For example, Southern China has an incidence of 26.9 cases per 100,000, compared with less than 1/100,000 in the United States and 0.1-2.2/100,000 in Europe.

Options for frontline curative therapy consist of radiation therapy for patients with stage I disease and chemoradiation for stages IIa to IVa/b. Patients who have recurrent or metastatic disease have limited options, consisting primarily of palliative chemotherapy, mostly with platinum-based combinations. Patients with advanced nasopharyngeal carcinoma have a median survival of 5 to 11 months, Hsu said.

Elevated PD-L1 expression is common in cancers associated with Epstein-Barr virus (EBV) infection, such as nasopharyngeal carcinoma. PD-L1 expression in nasopharyngeal carcinoma is upregulated by EBV-induced activation of the LMP1 and interferon-gamma pathways, Hsu continued. As such, PD-1 and PD-L1 expression might correlate with poor prognosis in patients with nasopharyngeal carcinoma.

Investigators evaluated pembrolizumab activity in a phase Ib multi-cohort study involving patients with PD-L1 positive advanced solid tumors, which includes 44 patients with recurrent or metastatic nasopharyngeal carcinoma. All but three of the patients tested positive for PD-L1 expression.

Subsequently, 27 patients with advanced nasopharyngeal carcinoma were enrolled in the trial. The patients received pembrolizumab 10 mg/kg IV every 2 weeks. Patients who achieved complete or partial response continued at the same dose until disease progression or development of intolerable toxicity. Patients with confirmed disease progression discontinued pembrolizumab.

All but 2 of the patients had received at least 1 prior line of therapy for advanced disease, and a third of the patients had received 5 or more prior regimens.

The cohort had a median follow-up of 12.9 months and a median time to response of 1.8 months. In patients with stable disease, the median duration was 5.6 months. Median progression-free survival (PFS) was 5.6 months. PFS was 49.7% at 6 months and 28.9% at 12 months.

The most frequent all-grade adverse events (AEs) with pembrolizumab were pruritus (25.9%), fatigue (18.5%), hypothyroidism (18.5%), hepatitis (11.1%), hepatitis (11.1%), herpes zoster (11.1%), pneumonitis (11.1%), rash (11.1%), and maculo-papular rash (11.1%). The most common grade 3-5 AEs were hepatitis (7.4%) and pneumonitis (7.4%). There was one treatment-associated death related to bacterial sepsis.

&ldquo;Advanced nasopharyngeal carcinoma is a severe form of head and neck cancer often associated with a poor prognosis,&rdquo; Hsu said in a statement. &ldquo;These data presented at ECC represent the potential for new approaches to treat this type of cancer, for which there are currently limited treatment options, and further support the need for additional research into how Keytruda may work for certain types of head and neck cancer.&rdquo;

Approved in the United States and Europe for use in treatment-refractory metastatic melanoma, pembrolizumab has been evaluated as monotherapy and in combinations for more than 30 different types of tumors, Hsu noted. The drug has demonstrated substantial antitumor activity in multiple cancers.

Hsu C, Lee S, Ejadi S, et al. Antitumor activity and safety of pembrolizumab in patients with PD-L1-positive nasopharyngeal carcinoma: Interim results from a phase 1b study. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 2801.

Over a fifth of patients with previously treated advanced nasopharyngeal carcinoma showed a measureable response, when treated with pembrolizumab, an immune checkpoint inhibitor.

Pembrolizumab Shows Response in Metastatic Nasopharyngeal Carcinoma

Failure-free survival (FFS) for patients with follicular lymphoma has had a lack of improvement, fueling interest in new treatment strategies that may offer promise for better outcomes, said lymphoma specialist Nathan Fowler, MD, in a presentation at this year&rsquo;s Society of Hematologic Oncology (SOHO) annual meeting.

Over the past 25 years, new regimens for follicular lymphoma have led to better overall survival. However, even the most intensive regimens have failed to push FFS much beyond 5 years.

Within the last decade or so, emerging information about the microenvironment of follicular lymphoma has provided a basis for exploring new approaches to increase FFS.

&ldquo;We&rsquo;ve learned a lot about the key role that the B-cell receptor plays,&rdquo; said Fowler, an associate professor of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center. &ldquo;We know a lot more about T-cell signaling and T-cell activation in the microenvironment, as well as certain other cells and the tumor vasculature.&rdquo;

Ibrutinib, the BTK inhibitor, offers one example of potential new approaches for treatment of follicular lymphoma. Having demonstrated efficacy in chronic lymphocytic leukemia and mantle cell lymphoma, ibrutinib was evaluated in a phase I study of follicular lymphoma.

At a daily dose of 2.5 mg/kg, 55% of patients had objective responses, half of which were complete responses. At double the dose, the overall response rate was the same, but a third of patients achieved complete responses. Median duration of response and progression-free survival (PFS) were 10.3 and 13.4 months, respectively, with 2.5 mg, and increased to 12.3 and 19.6 months with the higher dose.

A subsequent phase II study that consisted of 40 patients produced an overall response rate of 28%. A waterfall plot, however, showed that about 70% of patients had some degree of tumor shrinkage associated with inhibition of the BTK pathway.

&ldquo;I think that explains why despite an overall response rate of 28%, the progression-free survival was a year. A lot of patients who had stable disease maintained stable disease for quite some time with ibrutinib,&rdquo; said Fowler.

A planned phase III study has an accrual goal of 400 patients with relapsed follicular or marginal zone lymphoma. All patients will receive bendamustine-rituximab or R-CHOP chemoimmunotherapy plus either ibrutinib or placebo. The trial has a primary endpoint of PFS.

Additionally, investigators recently completed a trial of frontline ibrutinib-rituximab combination therapy in follicular lymphoma. The primary outcome measure was objective response rate, and results could be reported at the American Society of Hematology annual meeting in December, according to Fowler.

A trial of the PI3 kinase inhibitor idelalisib offered another demonstration of how objective response rate does not necessarily tell the entire story about a drug&rsquo;s activity. Patients with rituximab- and alkylator-refractory indolent non-Hodgkin lymphoma received idelalisib 150 mg twice daily until disease progression (

. 2014;370:1008-1018). The overall response rate was 57% (54% in patients with follicular lymphoma), but few patients failed to derive some degree of benefit in terms of tumor regression, associated with a median PFS of about a year.

Based on these data, idelalisib was granted an accelerated approval by the FDA in 2014 for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma who were previously treated with &ge;2 systemic therapies.

Although not as toxic conventional therapy, many new drugs do have specific toxicities that can be severe in some instances, Fowler noted. For example, more than 40% of the patients in the idelalisib trial had diarrhea, which was grade 3/4 severity in almost 15% of cases. The diarrhea may persist for as long as a patient continues the drug.

Not to be overlooked among targeted therapies are newer agents that home in on the CD20 pathway targeted by rituximab, whose activity was demonstrated in a pivotal trial reported almost 20 years ago.

Fowler says this is a very active pathway, and he adds that there are good drugs currently being approved with additional activity that target the CD20 pathway.

Investigators recently completed a multicenter randomized trial to evaluate bendamustine alone or with the anti-CD20 antibody obinutuzumab (Gazyva) in patients with indolent lymphomas refractory to both rituximab and another CD20-targeting agent. As reported at the 2015 ASCO Annual Meeting this past June, the addition of obinutuzumab to bendamustine was associated with a significant 45% reduction in the PFS risk, despite the fact that the dose of bendamustine was 25% lower than in the monotherapy arm.

Fowler was the principal investigator in a phase II study of a regimen that has gained widespread attention in the lymphoma community because of impressive response rates. The so-called R2 (lenalidomide-rituximab) regimen was evaluated in 110 patients with indolent lymphomas. In the subgroup of 50 patients with follicular lymphoma, the regimen resulted in an overall response rate of 98%, including complete responses in 87% and PET-negative disease in more than 90% (ASH Annual Meeting Abstracts. 2012;120[21]:901).

&ldquo;We now have a median progression-free survival of almost 44 months, and 80% of our patients with follicular lymphoma remain in remission,&rdquo; said Fowler.

Prolonged responses also were seen in patients with small lymphocytic lymphoma, as well as marginal zone lymphoma, though not quite as good as those seen in patients with follicular lymphoma.

The results were subsequently validated in another phase II trial that enrolled only patients with follicular lymphoma.

The collective results led to a 1000-patient phase III trial of the R2 regimen. Patients were randomized to rituximab plus investigator&rsquo;s choice of chemotherapy or to the R2 combination. Accrual was completed several months ago.

In an effort to improve on results obtained with the R2 regimen, Fowler and colleagues have launched a trial of lenalidomide plus obinutuzumab in patients with relapsed indolent NHL. Phase I has been completed and patient accrual has begun in phase II of the investigation.

Investigation of immune checkpoint inhibitors also has expanded to follicular lymphoma. In a phase II trial, the investigational anti&not;PD-1 drug pidilizumab was combined with rituximab in relapsed follicular lymphoma

. 2014;15:69-77). Objective responses were observed in 19 of 29 (66%) patients, including complete responses in 15 (52%) patients.

Failure-free survival (FFS) for patients with follicular lymphoma has had a lack of improvement, fueling interest in new treatment strategies that may offer promise for better outcomes.

Staff Writer | Authors

Articles

T-VEC Combined With Pembrolizumab Shows Safety in Melanoma

Nivolumab Followed by Ipilimumab Proves More Effective in Advanced Melanoma

Pembrolizumab Shows Response in Metastatic Nasopharyngeal Carcinoma

New Approaches to Increase Failure-Free Survival in Follicular Lymphoma