ADDITION OF LAG-3 INHIBITION IMPROVES EFFICACY OF ANTI-PD-1 THERAPY IN MELANOMA
Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047)
Evan J. Lipson, MD (Johns Hopkins University) presented results from the RELATIVITY-047 trial, comparing relatlimab plus nivolumab to nivolumab alone for the management of previously untreated advanced melanoma. Both treatments were given at a fixed dose in a single infusion: nivolumab 480 mg with or without relatlimab 160 mg Q4W. PFS served as the primary endpoint in the 714 enrolled patients.
After a median follow-up of 13.2 months, PFS favored the combination arm at 10.1 months compared to 4.6 months with nivolumab monotherapy (HR: 0.75). 1-year PFS rates were also higher with relatlimab + nivolumab at 47.7% vs 36.0%. A PFS benefit was seen regardless of tumor LAG-3 expression level, though there was a slight trend toward LAG-3 expressors. There was a higher incidence of grade 3-4 treatment-related adverse events with the combination (18.9% vs 9.7%), as well as higher rates of treatment discontinuation. Three treatment-related deaths occurred in the combination arm, and two in the nivolumab monotherapy arm. This study represents the first late-stage trial to demonstrate benefit, in terms of PFS, for a fixed-dose combination of LAG-3 and PD-1 inhibition.
Learn more about the biology of LAG-3 in a review from the Journal for ImmunoTherapy of Cancer (JITC).
PD-1 BLOCKADE PLUS CHEMOTHERAPY IMPROVES OUTCOMES IN NASOPHARYNGEAL CARCINOMA
JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC)
Rui-hua Xu, MD, PhD (Sun Yat-sen University Cancer Center) discussed the role of PD-1 inhibition in nasopharyngeal cancer (NPC) in combination with chemotherapy, using toripalimab with gemcitabine and cisplatin. Previously untreated patients (n=289) with R/M NPC were randomized to receive toripalimab or placebo with chemotherapy for up to two years.
PFS was significantly improved in the toripalimab arm, with the median increasing by over three months from 8.0 to 11.7 months. This improvement carried across key subgroups, such as those with varied PD-L1 expression levels. ORR and DOR were also improved with toripalimab (ORR: 77.4% vs 66.4%; DOR: 10.0 vs 5.7 months). Median OS was not yet reached in either arm. While most safety signals were similar in the two arms, there were more any-grade and high-grade immune-related adverse events in patients receiving toripalimab (any-grade: 39.7% vs 18.9%; grade 3+: 7.5 vs 0.7%). However, the encouraging efficacy in terms of PFS and reasonable safety of this regimen mark an important advancement in the treatment of NPC with the potential to impact the standard-of-care after continued follow-up.
Cancers of the head and neck are notoriously difficult to treat with immunotherapy – a recent article in JITC proposes tumor hypoxia as one potential resistance mechanism.
CHECKPOINT INHIBITION SHOWS PROMISE FOR ESOPHAGEAL SQUAMOUS CELL CARCINOMA
ESCORT-1st: A randomized, double-blind, placebo-controlled, phase 3 trial of camrelizumab plus chemotherapy versus chemotherapy in patients with untreated advanced or metastatic esophageal squamous cell carcinoma (ESCC)
Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study
The application of immune checkpoint inhibition in esophageal squamous cell carcinoma (ESCC) was investigated in several studies. Rui-hua Xu, MD, PhD (Sun Yat-sen University Cancer Center) discussed the ESCORT-1st trial of camrelizumab and chemotherapy, while Ian Chau, MD (The Royal Marsden Hospital) presented results from CheckMate 648, investigating nivolumab plus ipilimumab or chemotherapy.
The ESCORT-1st trial compared camrelizumab and chemotherapy to placebo and chemotherapy in 596 patients with previously treated ESCC. After 10.8 months’ follow-up, median overall survival (OS) and progression-free survival (PFS) were significantly improved in the anti-PD-1 arm, with OS of 15.3 vs 12.0 months (HR: 0.70) and PFS of 6.9 vs 5.6 months (HR: 0.56). The median duration of response (DOR) was also longer in the experimental arm, at 7.0 months compared to 4.6 months. Serious treatment-related adverse events were noted in 30.2% of patients in the camrelizumab arm and 23.2% in the placebo arm.
CheckMate 648, on the other hand, enrolled 970 patients with previously untreated ESCC into one of three arms: nivolumab + ipilimumab, nivolumab + chemotherapy, or chemotherapy alone. After a median of 13.0 months, both nivolumab-containing arms demonstrated enhanced OS compared to chemotherapy (HR: nivo + ipi – 0.64; nivo + chemo – 0.54). PFS was also improved with nivolumab + chemotherapy in patients with tumor PD-L1 >= 1% (HR: 0.65), but not for nivolumab + ipilimumab. ORR and DOR were also improved in patients treated with nivolumab regimens.
These two studies point to the role of immune checkpoint inhibition in ESCC, indicating a new approach in the management of this difficult disease.
CLEAR CELL RCC BENEFITS FROM ADJUVANT PEMBROLIZUMAB TREATMENT
Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study.
The KEYNOTE-564 trial of adjuvant pembrolizumab for high-risk clear cell RCC was discussed by Toni K. Choueiri, MD (Dana-Farber Cancer Institute). Patients on the trial (n=994) were randomized to either pembrolizumab for 17 cycles or placebo following nephrectomy and followed for a median of 24.1 months.
At the first interim analysis, adjuvant pembrolizumab was found to significantly improve disease-free survival (DFS), with the median duration not reached in either arm (HR: 0.68). 2-year DFS rates were estimated at 77.3% with pembrolizumab and 68.1% with placebo. Median OS was not reached in either arm as well, though with an estimated HR of 0.54. Safety analysis indicated a similar rate of any-grade adverse events in the two arms, with a higher rate of grade 3+ treatment-related events with pembrolizumab (18.9% vs 1.2%). This trial represents a significant advancement for the adjuvant treatment of high-risk ccRCC and may impact clinical practice in the future.
Learn more about potential biomarkers of response to therapy in RCC in this recent JITC publication.
NEOADJUVANT DURVALUMAB INVESTIGATED FOR TNBC
Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study.
The GeparNUEVO trial was presented by Sibylle Loibl, MD, PhD (German Breast Group). The study randomized patients to receive durvalumab or placebo in combination with an anthracycline/taxane-based neoadjuvant regimen. The primary endpoint was pathologic complete response (pCR) rate in the 174 enrolled patients with triple-negative breast cancer.
The pCR rate was higher in the durvalumab arm, at 53.4% vs 44.2%. Notably, the benefit of durvalumab was only observed in the window group (those patients who received two weeks of treatment prior to core biopsy, OR 2.22). Patients with a pCR, regardless of treatment, demonstrated higher 3-year invasive disease-free survival (iDFS) at 92.0% compared to 71.9% in patients without a pCR. Durvalumab led to improvements in 3-year iDFS (85.6% vs 77.2%), 3-year distant disease-free survival (91.7% vs 78.4%), and 3-year OS (95.2% vs 83.5%) when compared to the placebo arm, driven by patients with pCR. Immunotherapeutic approaches may therefore be optimal choices for neoadjuvant treatment of TNBC.
ADJUVANT ATEZOLIZUMAB SHOWS BENEFIT FOR STAGE II-IIIA NSCLC
IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC)
Heather A. Wakelee, MD (Stanford University) explained the results of an interim analysis of IMpower010, investigating the role of adjuvant atezolizumab in NSCLC. Patients in the trial (n=1280 enrolled) received up to four cycles of chemotherapy after complete resection of their disease and were then randomized (n=1005 randomized) to treatment with atezolizumab or best supportive care. Endpoints were tested hierarchically and included DFS in PD-L1 TC >=1% in stage II-IIIA, DFS in all stage II-IIIA, DFS in ITT, and OS in ITT.
After a follow-up of 32.8 months, patients in the atezolizumab arm displayed significant DFS improvement in the PD-L1+ population (not reached [NR] vs 35.3 months), as well as in all randomized patients with stage II-IIIA disease (42.3 vs 35.3 months). However, there was no significant difference in DFS in the full ITT population (NE with atezolizumab vs 37.2 months with BSC; p: 0.0395). Overall survival could not yet be tested. Adverse events occurred more commonly in the atezolizumab arm with any-grade events in 92.7% vs 70.7% of patients, grade 3-4 events in 21.8% vs 11.5%, and grade 5 events in 0.8% in the atezolizumab arm. This study indicates a probable role for adjuvant immunotherapy in stage II-IIIA NSCLC.
ADJUVANT PEMBROLIZUMAB OUTPERFORMS INTERFERON OR IPILIMUMAB IN MELANOMA
Final analysis of overall survival (OS) and relapse-free-survival (RFS) in the intergroup S1404 phase III randomized trial comparing either high-dose interferon (HDI) or ipilimumab to pembrolizumab in patients with high-risk resected melanoma
Adjuvant treatment options for high-risk melanoma were compared in a trial presented by Kenneth F. Grossmann, MD, PhD (University of Utah). Three regimens were compared: pembrolizumab (Q2W for 1 year), high-dose interferon alfa-2b (1 year) or ipilimumab (Q3W then Q12W for 3 years). Primary endpoints of the study included relapse-free survival (RFS) and OS among all patients and OS in patients with PD-L1-positive tumors.
At 3.5 years after the final patient (n=1345) was randomized, treatment with pembrolizumab resulted in improved RFS when compared to the pooled control arms of ipilimumab or interferon (HR: 0.74). Differences were not seen for OS in either the full study population (HR: 0.84) or the PD-L1-positive population (HR: 0.88). High-grade adverse events were less frequent in the pembrolizumab arm, with grade 3-5 events in 19.5% of patients compared to 49.2% with ipilumumab and 71.2% with interferon. Therapy targeted to the PD-1 pathway was received by 39% of patients in the control arm as subsequent therapy, potentially confounding OS results. Thus, while pembrolizumab only demonstrated an RFS and not OS benefit, the improved safety profile may merit consideration in adjuvant management of melanoma and reinforces that anti PD-1 are standard therapies in the adjuvant setting.
NEOADJUVANT AND ADJUVANT PEMBROLIZUMAB MAY BENEFIT HIGH-GRADE SEROUS CARCINOMA
Efficacy and safety results from neopembrov study, a randomized phase II trial of neoadjuvant chemotherapy (CT) with or without pembrolizumab (P) followed by interval debulking surgery and standard systemic therapy ± P for advanced high-grade serous carcinoma (HGSC): A GINECO study
Isabelle L. Ray-Coquard, MD, PhD (Centre Leon Berard) discussed the addition of pembrolizumab to chemotherapy for neoadjuvant and adjuvant therapy for ovarian, tubal or peritoneal HGSC. Patients received chemotherapy (carboplatin-paclitaxel) +/- pembrolizumab for four cycles prior to interval debulking surgery, followed by chemotherapy (2-4 cycles) with optional bevacizumab (15 months) +/- pembrolizumab for up to two years. The complete resection rate (CRR) at IDS was the primary endpoint.
The CRR was improved with pembrolizumab compared to the pre-defined hypothesis, at 74%. At the same time, the CRR in the control arm was 70%, which was higher than anticipated. A higher ORR was noted in patients treated with pembrolizumab, at 73.3% vs 62.1%, and the rate of grade 3+ adverse events was also higher in the pembrolizumab group (75% vs 67%). Median PFS was similar between the two arms, at 19.3 months with pembrolizumab and 20.8 months with placebo. It should be noted that this was a non-comparative trial, so the placebo arm is not designed for comparison with the pembrolizumab arm. Biomarker studies and long-term follow-up are ongoing, in order to fully assess the role of immunotherapy in the peri-surgical management of HGSC.
BENEFIT OF PEMBROLIZUMAB IN MSI-HIGH CRC MAINTAINED
Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC)
The final OS data from the KEYNOTE-177 study were presented by Thierry Andre, MD (Sorbonne Université and Hôpital-Saint Antoine). Patients with untreated MSI-high/MMR-deficient colorectal cancer were randomized to either pembrolizumab Q3W for 2 years or investigator’s choice. Patients in the control arm could cross-over to pembrolizumab upon disease progression. Notably, 36% of patients in the control arm crossed over to pembrolizumab treatment, with another 24% receiving anti-PD-1 pathway therapies off-study, resulting in an effective crossover rate of 60%.
There was a trend toward improved OS with pembrolizumab treatment, with median OS not reached in the pembrolizumab arm compared to 36.7 months in control (HR: 0.74; p: 0.0359). The investigators attributed the lack of significance to the sizable portion of patients in the control arm receiving subsequent immunotherapy. PFS and ORR also favored pembrolizumab treatment (median PFS: 16.5 vs 8.2 months; ORR: 45.1% vs 33.1%). Responses were more durable with pembrolizumab, with the median DOR not yet reached. This study therefore represents a potential standard-of-care treatment regimen for patients with MSI-H/dMMR colorectal cancer.
A recent study in JITC describes prognostic factors for patients with MSI-high CRC treated with immunotherapy.
TCR THERAPY LEADS TO RESPONSES IN SARCOMAS
SPEARHEAD-1: A phase 2 trial of afamitresgene autoleucel (Formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma
Sandra P. D’Angelo, MD (Memorial Sloan Kettering Cancer Center) discussed a trial of afamitresgene autoleucel (an autologous TCR-engineered T cell product targeting MAGE-A4) for patients with various types of previously-treated sarcoma. Thirty-seven patients had been treated at data cut-off, mostly with synovial sarcoma.
Across evaluable patients, the overall response rate was 39.4%, including two complete responses in patients with synovial sarcoma. Disease control rate was 84.8%, and the median duration of response was not yet reached. Responses were noted across MAGE-A4 expression levels, as well as administered cell doses. Cytokine release syndrome of any grade occurred in 59% of patients, mostly Grade 1-2. Additionally, no ICANS events were reported. The potential of adoptive cellular therapy for sarcoma treatment is evident from this study, though long-term follow-up is awaited.
HPV-SPECIFIC VIRAL THERAPY SHOWS IMMUNOLOGIC EFFECTS
First report of the safety/tolerability and preliminary antitumor activity of HB-201 and HB-202, an arenavirus-based cancer immunotherapy, in patients with HPV16+ cancers
Virus-based therapies for HPV-associated malignancies were investigated by Alan Loh Ho, MD (Memorial Sloan Kettering Cancer Center) and colleagues. Two live-attenuated viruses that express non-oncogenic HPV16 E7E6 fusion protein were investigated: HB-201, a lymphocytic choriomeningitis virus, and HB-202, a Pichinde virus. Patients with HPV-associated cancers, mainly head and neck cancers, were treated with different regimens and doses of HB-201 monotherapy or HB-201 and HB-202 alternating therapy, given IV with or without initial intratumoral administration.
While 84% of patients experienced a treatment-emergent adverse event, no dose-limiting toxicities occurred. The only grade 3+ adverse event attributed to the therapy was fatigue. Thirty-eight patients were dosed across the different regimens, and 18 are still on treatment. The most promising results were noted with the regimens that included intravenous dosing every three weeks, with a disease control rate of 72.7% with HB-201 monotherapy and DCR of 100% with dual therapy. Across all patients with HNSCC, two PRs were noted, though 34.5% of treated patients demonstrated any tumor regression. High levels of HPV-specific T cells were seen after these treatments, indicating a promising immune response that can be optimized through further work.
ONCOLYTIC VIRUS THERAPY SHOWS POTENTIAL FOR TREATMENT OF T CELL LYMPHOMA
Clinical activity of systemic VSV-IFNβ-NIS oncolytic virotherapy in patients with relapsed refractory T-cell lymphoma
Joselle Cook, MBBS (Mayo Clinic) discussed an initial investigation of an oncolytic virus therapy in patients with hematologic malignancies. VSV-IFNb-NIS was administered to patients with R/R multiple myeloma, T cell lymphoma, or acute myeloid leukemia, at single doses ranging from 5x109 TCID50 to 1.7x1011 TCID50 with the primary goal of defining the maximum tolerated dose. Fifteen patients were treated.
No dose-limiting toxicities were observed, and most adverse events were hematologic in nature. CRS was most common at the highest dose level, at grade 1 in 6.7% and grade 2 in 46.6% of patients. Responses were only seen in patients with T cell lymphoma, including two partial responses – one lasting three months at dose level 2 and another lasting six months at dose level 4. Additionally, one patient achieved a complete response lasting at least a year post-therapy at dose level 4 (the highest dose). This patient exhibited the highest peak interferon response, at a level fifteen times that of other patients at 48 hours post-therapy. Viremia was observed in patients only out to 72 hours, and neutralizing antibodies were evident by day 8. The investigators are planning future combination studies to further improve the efficacy of this therapy.
CD20 CAR T THERAPY AFTER CD19 CAR T SHOWS HIGH RESPONSE RATE
Safety and efficacy of a novel anti-CD20 chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) patients after failing CD19 CAR-T therapy
Aibin Liang, MD, PhD (Tongji Hospital) presented a study of a CD20-targeted CAR T therapy, C-CAR066, in patients with R/R DLBCL, FL or MCL who had previously been treated with a CD19 CAR T therapy. Patients received cyclophosphamide/fludarabine pre-conditioning prior to infusion.
C-CAR066 was successfully manufactured for all ten enrolled patients. CRS occurred in 9/10 patients, with only one case being grade 4. No ICANS was observed. Other common toxicities included expected hematologic events, related to lymphodepletion. The best overall response rate was 100%, which included 7/10 patients achieving a complete response. However, by data cut-off, 4/10 patients had disease progression, including all patients with a best response of PR. Two of the relapses resulted in CD19- and CD20-negative disease. Treatment of patients with prior CD19 CAR exposure using a CD20-targeted CAR T therapy may therefore be a viable approach, meriting future research.
One critical component of adoptive cell therapies is the lymphodepletion regimen – a recent JITC article compared several regimens in current clinical use.
BCMA BISPECIFICS DEMONSTRATE EFFICACY IN REFRACTORY MULTIPLE MYELOMA
Efficacy and safety of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MM)
Updated phase 1 results of teclistamab, a B-cell maturation antigen (BCMA) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM)
BCMA has emerged as a promising target for multiple myeloma therapies, including T cell engaging bispecifics. Two such agents were investigated in phase 1 trials presented by Nizar J. Bahlis, MD (Arnie Charbonneau Cancer Institute) and Amrita Y. Krishnan, MD (City of Hope). Dr. Bahlis discussed the use of elranatamab, an IgG2a BCMA-CD3 bispecific, while Dr. Krishnan presented data using teclistamab, an IgG4 BCMA-CD3 antibody.
Elranatamab was administered subcutaneously (SC) weekly at increasing doses to the thirty enrolled patients. The most common adverse events with this treatment were hematologic in nature or injection site reactions. CRS and neurotoxicity occurred in 73% and 20% of patients, respectively, and were all grade 1-2. The ORR at doses above 215 ug/kg was 70%, including 30% of patients with CR or sCR. At the RP2D (1000 ug/kg), the ORR was 83%. Notably, three of four patients with prior BCMA-targeted therapy responded to elranatamab treatment. Follow-up is still short with this trial, but the probability of EFS at six months was 92.3%.
The recommended phase 2 dose of teclistamab was 1500 ug/kg SC weekly with step-up dosing. Forty patients received this dose and were followed for a median of 6.1 months. CRS occurred in 70% of these patients receiving teclistamab. Notably, CRS onset was later with SC dosing than prior experience with IV administration of the same agent (next day vs same day of infusion). Other notable toxicities included hematologic effects and infections. The ORR at the RP2D was 65% with the median DOR not yet reached. At 7 months, 85% of patients were still on-treatment.
Taken together, these studies point toward a new class of effective therapies for highly refractory multiple myeloma, which are poised to impact the clinic in the future.