Staff Writer

Treatment with datopotamab deruxtecan phase 1 TROPION-PanTumor01 trial (NCT03401385) showed promising activity through overall response rates (ORRs) in patients with advanced or metastatic triple-negative breast cancer (TNBC), according to cohort data presented during the 2021 San Antonio Breast Cancer Symposium (SABCS).

Among all patients in the TNBC cohort of the trial (n = 44), the ORR by blinded independent central review (BICR) was 34% at a median follow-up of 7.6 months (range, 4-13). This included a confirmed complete response (CR) or partial response (PR) in 14 patients (32%), plus 1 patient (2%) with a CR/PR that was pending confirmation. Seventeen patients (39%) had stable disease (SD), 2 patients (5%) were not evaluable (NE), and 8 patients (18%) had progressive disease (PD). Overall, the disease control rate (DCR) was 77%.

Furthermore, at a median follow-up of 8.8 months (range, 4-13), the ORR was 52% in patients with TNBC who did not receive prior treatment with a Topo I inhibitor-based ADC (n = 27), which included 13 patients (48%) with confirmed CRs or PRS, plus 1 patient (4%) with a CR/PR pending confirmation. Nine patients (33%) had SD, 1 patient (4%) was NE, and 4 patients (15%) had PD. The DCR was 81%.

Additional data showed that the median duration of response was not reached (range, 2.7 to 7.4+ months); the majority of responses were ongoing at the data cutoff.

"There are clear responses or clear tumor regressions in those patients who had prior Topo-based ADCs with at least 1 confirmed PR," lead study author Ian E. Krop, MD, PhD, of Dana-Farber Cancer Institute, said in a presentation during the conference. "However, because a full 30% of the patients on this study had a prior Topo I inhibitor(-based) ADC, and that is the same class of payload as (datopotamab deruxtecan), there is a possibility of cross resistance. Therefore, we did want to look at specifically the subset of patients who had not had 1 of these prior ADCs."

There are currently very limited standard treatments for patients with advanced or metastatic TNBC that considered relapsed/refractory. TROP2 is highly expressed in various malignancies, including breast cancer. In the TROPION-PanTumor01 study, investigators are evaluating the safety and efficacy of the TROP2-directed ADC datopotamab deruxtecan in patients with advanced or metastatic breast cancer, non–small cell lung cancer (NSCLC), and other tumor types.

At the 2021 SABCS, Krop, who is an associate chief in the Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, clinical research director of the Breast Oncology Center, and associate professor of medicine at Harvard Medical School, presented on the data from the TNBC cohort.

Patients enrolling in the trial were required to have relapsed/refractory advanced or metastatic solid tumors, an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1. Additionally, patients needed to be at least 18 years old in the United States or 20 years old in Japan, and be unselected for TROP2 expression. Those with stable, treated brain metastases were permitted.

In the TNBC cohort, 42 of 44 patients received datopotamab deruxtecan intravenously (IV) at 6 mg/kg every 3 weeks, and the other 2 patients received the ADC IV 8 mg/kg every 3 weeks. The decision to use the 6-mg/kg dose, which was selected for expansion across other tumors, as well as in the phase 3 TROPION-Lung01 (NCT04656652) and TROPION-Breast01 (

) studies, was based on clinical results and exposure-response analyses for safety and efficacy.

The primary end points of the trial were safety and tolerability; secondary end points included efficacy, pharmacokinetics, and anti-drug antibodies.

In the TNBC cohort, the median age was 53 years (range, 32-82), and 31 patients (70%) were based in the United States vs 13 patients (30%) in Japan. The majority of patients had an ECOG performance status of 1 (59%) and did not have de novo metastatic disease (68%). Eleven percent of patients had brain metastases.

Furthermore, the median number of prior therapies in the metastatic setting was 3 (range, 1-10), and 68% of patients had at least 2 prior lines of therapy. Previous treatments included taxanes (91%), platinum-based chemotherapy (52%), immunotherapy (43%), PARP inhibitors (16%), and Topo I inhibitor-based ADC (30%).

At the data cutoff date of July 30, 2021, 31 patients (70%) discontinued treatment, including 30 due to disease progression, and 1 patient due to an adverse event (AE). Thirteen patients (30%) remained on treatment at the time of the presentation.

Furthermore, datopotamab deruxtecan showed a manageable safety profile with no new safety signals. The most frequent treatment-emergent adverse events (TEAEs) included nausea, stomatitis, vomiting, and fatigue. However, neutropenia and diarrhea were both uncommon. No cases adjudicated as treatment-related interstitial lung disease were observed.

Ninety-eight percent of patients had at least 1 TEAE, 45% of which were considered to be of grade 3 or higher; 23% experienced grade 3 or higher treatment-related TEAEs. Dose reductions due to AEs were required in 18% of patients, and 14% of patients experienced treatment interruption due to AE. One patient discontinued treatment due to AEs, and no fatal AEs were reported.

Krop added that the HR-positive, HER2-negative cohort of TROPION-PanTumor01 is now fully enrolled and data are forthcoming. Datopotamab deruxtecan is also being explored in the phase 1b/2 BEGONIA trial (NCT03742102), which is testing the agent in combination with durvalumab (Imfinzi) as a first-line treatment for patients with metastatic TNBC.

Additionally, the phase 3 TROPION-Breast01 trial is investigating datopotamab deruxtecan in HR-positive, HER2-negative breast cancer. A phase 3 trial of datopotamab deruxtecan in patients with TNBC is being planned, Krop said.

"We have come a long way in TNBC when we're talking about comparing different targeted therapies, when up until a few years ago, there were no targeted therapies at all," Krop said. "This is good progress. There is potential room for looking at this drug both in pretreated patients, like what was seen here, as well as earlier lines of therapy."

1. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan (Dato-DXd) in advanced/metastatic HER2 negative breast cancer: triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-05.

2. Schmid P, Nunes AT, Dry H, et al. BEGONIA: phase 1b/2, open-label, platform study of the safety and efficacy of durvalumab (D) ± paclitaxel (P) with novel oncology therapies for first-line metastatic triple-negative breast cancer (mTNBC): Addition of arm 7, D + datopotamab deruxtecan (Dato-DXd; DS-1062).

. 2021;39(15_suppl). doi:10.1200/JCO.2021.39.15_suppl.TPS1105

Articles

Early results from a phase 1 study show promise for datopotamab deruxtecan for patients with advanced or metastatic triple-negative breast cancer. 

Datopotamab Deruxtecan Demonstrates Highly Promising Efficacy in Advanced or Metastatic TNBC

Clinicians are eagerly awaiting  overall survival (OS) data from the phase 3 KEYNOTE-564 trial (NCT03142334) to confirm adjuvant pembrolizumab’s (Keytruda) role as a potential new standard treatment for patients with renal cell carcinoma (RCC).

Results shared in a webinar during the 2021 European Association of Urology (EAU) Congress showed that at a median follow-up of approximately 24 months, adjuvant pembrolizumab induced a 32% reduction in the risk of disease recurrence or death compared with placebo (HR, 0.68; 

 Per investigator assessment, the median disease-free survival (DFS) was not yet reached in either the pembrolizumab arm (n = 496) or the placebo arm (n = 498).

The OS data are still immature, with 3.6% (n = 18) and 6.6% (n = 33) of events occurring in the pembrolizumab and placebo arms, respectively. The median OS has not yet been reached in either arm but is trending favorably toward the PD-1 inhibitor (HR, 0.54; 

 = .0164); however, this has not crossed the prespecified boundary of statistical significance. The estimated 2-year OS rates are 96.6% with pembrolizumab and 93.5% with placebo.

“These early data from the trial are very promising, with a clear reduction in the disease recurring in patients on pembrolizumab. There are signs as well that the drug may improve survival rates, but we can’t be sure of that for another few years. We’re hopeful that this trial, when complete, will provide a strong case for this drug to be approved for use by the medicines regulator,” said coinvestigator Thomas Powles, MBBS, MRCP, MD, in a press release.

 Powles is a professor of genitourinary oncology and group lead for solid tumor research at Barts Cancer Institute, and director of the Barts Cancer Centre in London, United Kingdom.

The standard-of-care treatment for patients with locoregional RCC is surgery; however, nearly half of patients eventually experience disease recurrence. Currently, no standard adjuvant systemic therapy exists that is supported by high levels of evidence worldwide.

In the double-blind, multicenter KEYNOTE-564 study, investigators explored pembrolizumab vs placebo following nephrectomy in patients with clear cell RCC. Specifically, patients’ disease had to meet criteria that categorized them as high risk for recurrence, which included: pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0; pT4, any grade, N0, M0; any pT, any grade, N-positive, M0; or M1 with no evidence of disease after surgery.

Patients had to have undergone nephrectomy within 12 weeks prior to randomization, could not have previously received systemic treatment, and had to have an ECOG performance status of 0 or 1. In addition, a tissue sample had to have been obtainable for PD-L1 assessment.

All patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks or placebo every 3 weeks, both for approximately 1 year.

At 1 year, the estimated DFS rates were 85.7% with pembrolizumab and 76.2% with placebo. At 2 years, these rates were 77.3% and 68.1%, respectively.

Regarding safety, all-grade adverse events (AEs) with pembrolizumab occurred in 96.3% of patients and in 91.1% of those receiving placebo; grade 3 to 5 AEs occurred in 32.4% and 17.7%, respectively. AEs led to death in 2 patients treated with pembrolizumab and in 1 patient receiving placebo.

1. Powles T. Pembrolizumab (pembro) vs. placebo as post nephrectomy adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): randomized, double-blind, phase 3 KEYNOTE-564 study. Presented at: 36th Annual EAU Congress; July 8-12, 2021; Virtual.

2. New use of old drug reduces risk of kidney cancer returning. News release. European Association of Urology. July 10, 2021. Accessed August 17, 2021. https://bit.ly/3ldbQ9A

Results shared in a webinar during the 2021 European Association of Urology Congress show the potential of adjuvant pembrolizumab for the treatment of renal cell carcinoma.

Adjuvant Pembrolizumab Excites in RCC, Even While Awaiting OS Data

According to findings from the ongoing S1619 trial, neoadjuvant cisplatin-pemetrexed plus atezolizumab (Tecentriq), followed by maintenance atezolizumab may be safe and effective for patients with resectable pleural mesothelioma.

The findings were presented at the 2021 World Conference on Lung Cancer by Boris Sepesi, MD, of the University of Texas MD Anderson Cancer Center.

“When we speak about mesothelioma that is potentially surgically resectable, that is the patient population that we sort of consider potentially curable, although we know that recurrences occur,” explained Sepesi. “The median survival in patients who undergo multimodality therapy that includes surgery range in different studies between 17 and 25 months… The aim of this study was really to test chemotherapy plus immunotherapy in surgically resectable mesothelioma based on the fact that these are occasionally immunogenic tumors that express PDL1 expression, which is associated with worse outcomes.”

The study sought to assess whether adding anti-PD-L1 inhibitors to neoadjuvant cisplatin-pemetrexed, followed by maintenance immunotherapy after surgical resection and adjuvant radiation would enhance T-cell activation against microscopic disease and potentially increase overall survival (OS) in patients with malignant pleural mesothelioma.

Overall, 21 patients successfully completed neoadjuvant therapy, although 7 were unable to proceed to surgical resection. Of those 7, 2 patients reported severe toxicity, 4 experienced disease progression, and 1 death occurred due to non-immune related renal and respiratory failure.

There were 18 patients with stable disease or partial response who were able to receive surgical resection, and 16 patients registered to receive maintenance atezolizumab for 1 year. Thus far, median progression-free survival is 18 months and OS has not been reached.

Participants were evaluable if they had received at least 2 cycles of the triplet neoadjuvant therapy, were chemo-naïve, had mesothelioma, and extended surgical staging. A total of 28 patients were screened between November 2017 and May 2020 with the intention of obtaining 24 eligible patients.

Patients were then administered the triple-combination regimen with the following dosage: 75 mg/m2 cisplatin, 500 mg/m2 pemetrexed, and 1200 mg IV atezolizumab every 3 weeks. As long as patients did not experience disease progression, they continued to resectable surgery. Following surgery, they were to be treated with 1 year of maintenance atezolizumab.

Within this pool of potential participants, 25 received at least 2 cycles of neoadjuvant cisplatin-pemetrexed-atezolizumab.

The median age of participants was 68 years. The majority of participants were Caucasian, and the patient pool was predominantly male. Four patients planned on receiving

extrapleural pneumonectomy (EPP) surgery, while 24 planned on receiving pleurectomy and decortication surgery (P/D).

The primary end point of the trial was to assess the safety and tolerability profiles, as well as better understand the feasibility, of

neoadjuvant cisplatin-pemetrexed-atezolizumab treatment followed by surgery and maintenance atezolizumab. For the treatment to be considered safe or tolerable, there would be no reported grade 4 or 5 immune-related adverse events (irAEs). To be considered feasible, 75% of patients (18/24) needed to complete at least 1 dose of maintenance therapy.

The final analyses will separately assess patients who received EPP surgery and those who received P/D surgery for their resectable operation. Of the 18 that successfully received resection surgery, 17 received P/D and 1 received EPP. So far, 16 patients have registered to receive maintenance atezolizumab for 1 year. There are still 3 patients undergoing treatment with maintenance atelozimab therapy.

Investigators concluded that the triplet combination appeared to be reasonably tolerated in the patient population. There was only 1 patient who reported grade 4 or 5 AEs. Notably, that patient did experience multiple grade 4 AEs and 1 grade 5 AE. That patient experienced severe acute renal injury, sepsis, pneumonitis, and respiratory failure.

The most common neoadjuvant therapy-related AEs were nausea (n = 20), fatigue (n = 15), neutropenia (n = 11), anemia (n = 12), anorexia (n = 11), and vomiting (n = 7). Researchers also observed cases of hyponatremia (n = 5), creatinine increase (n = 6), constipation (n = 7), dysgeusia (n = 5), and infusion-related reactions (n = 3).

“These are some preliminary survival results which at this point seem rather encouraging although the median follow up is not the same as in some of the previous trials,” said Sepesi. “Some of these results are comparable to, [or] perhaps, slightly better to historical cohorts, but we will have to complete the trial, and complete the adequate follow-up to be able to make any conclusions from this regimen.”

“As always with mesothelioma, this trial highlights the challenging nature of the new adjuvant therapy, because of the heterogeneity of the disease, as well as how patients react as well as the difficult and complex surgical therapy,” he concluded. “However, I think this is a step forward in terms of complex treatment of mesothelioma.”

While Sepesi chose to refrain from speculating on the benefit of adding atezolizumab to the regimen, in a post-presentation discussion, he noted that future research will also need to look at patients based on nodal status (N0 vs N+) since those outcomes are different in surgically managed mesothelioma.

There are still 3 patients undergoing the therapy in this trial.

Tsao A, Qian L, Cetnar J, et al. A trial of neoadjuvant cisplatin-pemetrexed with atezolizumab combination and maintenance for resectable pleural mesothelioma. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021; Virtual. Absract OA13.01

Findings from the S1619 trial signal that a neoadjuvant triplet is safe and effective for the treatment of resectable mesothelioma. 

Neoadjuvant Cisplatin-Pemetrexed plus Atezolizumab Shown Safe and Effective for Resectable Mesothelioma

Treatment with olaparib (Lynparza) in combination with pembrolizumab (Keytruda) demonstrated continued antitumor activity in patients with post-docetaxel metastatic castration-resistant prostate cancer (mCRPC), according to results from the phase 1b/2 KEYNOTE-365 trial presented at the American Urological Association 2021 Annual Meeting.

“With a minimum of 11.4 months follow-up, pembrolizumab plus olaparib demonstrated antitumor activity and an acceptable safety profile for men with molecularly unselected, docetaxel-pretreated mCRPC,” said author Luke T. Nordquist, MD, FACP, medical oncologist and CEO of the Urology Cancer Center & GU Research Network, Omaha, Nebraska.

The KEYNOTE-365 trial (NCT02861573) was launched to assess the efficacy and safety of the olaparib/pembrolizumab regimen in patients with mCRPC. Prior results shared from cohort A showed promising clinical activity in molecularly unselected patients who had previously received docetaxel. 2,3

In the study, at a mean follow-up of 19.3 months (range, 11.4-45.9), patients received 200 mg of pembrolizumab intravenously every 3 weeks and 400 mg or 300 mg of olaparib orally twice daily, until disease progression, unacceptable toxicity, or withdrawal of consent. Standard bone scanning, CT, or MRI were also performed every 9 weeks for 54 weeks, and then every 12 weeks until disease progression. Primary end points were prostate-specific antigen (PSA) response rate, objective response rate determined by RECIST v1.1 through a blinded independent central review, and safety. Secondary end points included time to PSA progression, disease control rate, duration of response, radiographic progression-free survival, and overall survival.

“Cohort A of KEYNOTE-365 examined specifically the safety and efficacy of the combination of pembrolizumab and olaparib in molecularly unselected patients with mCRPC,” Nordquist said.

Patients were enrolled if they had molecularly unselected, docetaxel-pretreated mCRPC that had progressed within 6 months of screening. They also must have been treated previously no more than once with chemotherapy for mCRPC and no more than twice with second-generation hormonal therapies.

Of the 104 patients who enrolled, 102 were treated and 92 discontinued their treatment, mainly due to the progression of their disease (51%). Median age of enrolled patients was 69.5 years (range, 47-84), 29 patients (28.4%) were PD-L1 positive, 34 (33.3%) had visceral disease, and 58 (56.9%) had measurable disease. Twenty-four patients (23.5%) had previously been treated with abiraterone (Zytiga) only, 24 (23.5%) had previously been treated with enzalutamide (Xtandi) only, and 46 patients (45.1%) had previously been treated with both.

PSA response rate in all patients with a PSA measurement at baseline (n = 102) was 14.7% (95% CI, 8.5-23.1) and in the 58 pts who had measurable disease, confirmed objective response rate was 6.9% (95% CI, 1.9-16.7; 4 partial responses).

“The overall disease control rate was 26% for the total population, and clinical activity was consistent across PD-L1 and HR mutation subgroups,” Nordquist said.

Additionally, investigators found the median time to PSA progression was 4 months (range, 3.0-4.9 months), the median duration of response was not reached (range, 7.2+ to 37.8+ months), the disease control rate was 26.5% (95% CI, 18.2-36.1), the median radiographic progression-free survival was 5.2 months (range, 4.1-6.5) and the median overall survival was 14.4 months (range, 10.4-17.9).

There were high rates of treatment-related adverse events (TRAEs), which occurred in 93 patients (91.2%). The most frequent AEs (≥30%) were anemia (41.2%), nausea (41.2%), decreased appetite (30.4%), and fatigue (30.4%). A smaller, but significant rate of grade 3-5 TRAEs occurred in 49 patients (48.0%). Six patients (5.9%) died of AEs and 2 deaths were treatment related.

“The safety profile of pembrolizumab plus olaparib in combination is consistent with individual profiles of each agent. These results do support further evaluation of this combination in mCRPC,” concluded Norquist.

The phase 3 KEYLYNK-010 trial (NCT03834519) will further investigate pembrolizumab plus olaparib by comparing their efficacy vs abiraterone or enzalutamide in abiraterone- or enzalutamide-pretreated patients with mCRPC who have experienced disease progression on or after docetaxel for mCRPC.

1. Nordquist LT, Yu EY, Piulats JM, et al. Pembrolizumab (Pembro) plus olaparib in patients with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): updated results from KEYNOTE-365 cohort A with a minimum of 11 months of follow-up for all patients. Paper presented at the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-14

2. Yu EY, Piulats JM, Gravis G, et al. KEYNOTE-365 cohort A updated results: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). 

 2020;38(suppl 6):100. doi:10.1200/JCO.2020.38.6_suppl.100

3. Yu EY, Massard C, Retz M, et al. Keynote-365 cohort a: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). 

2019;37(suppl 7):145. doi:10.1200/JCO.2019.37.7_suppl.145

An update from KEYNOTE-365 trial shows the promising efficacy of olaparib in combination with pembrolizumab for patients with post-docetaxel metastatic castration-resistant prostate cancer.








Olaparib Combined With Pembrolizumab Signals Antitumor Activity in mCRPC

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.

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.