NIVOLUMAB + IPILIMUMAB SHOWS SUSTAINED BENEFIT FOR MPM
LBA65 - First-line nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with unresectable malignant pleural mesothelioma (MPM): 3-year update from CheckMate 743
Dr. Solange Peters (Laussane University Hospital) presented a three-year update of the CheckMate 743 trial, which investigated the combination of nivolumab and ipilimumab for the treatment of malignant pleural mesothelioma. Patients were randomized to either nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W for up to two years, or chemotherapy for up to six cycles. Since this follow-up occurred at three years, patients had been off treatment for approximately one year.
The overall survival benefit of the immunotherapy combination was sustained at this extended follow-up, with a 4-month improvement in median OS (HR: 0.73). There also continued to be a difference in chemotherapy outcomes in epitheliod versus non-epitheliod histologies. Exploratory biomarker analysis found that patients with a high inflammatory gene signature (incorporating CD8A, PD-L1, STAT-1, and LAG-3) had improved OS relative to those with a low signature when treated with nivolumab + ipilimumab (21.8 vs 16.8 mo). Inflammatory signature levels did not correlate with outcomes on the chemotherapy arm. Benefit was also seen with nivolumab + ipilimumab across all lung immune prognostic index (LIPI) or TMB levels, and no new safety signals were noted. The long-term benefit of combination immunotherapy for MPM has thus been confirmed with this extended follow-up.
COMBINATION OF TORIPALIMAB AND CHEMOTHERAPY BENEFITS FIRST-LINE ESCC
1373MO - JUPITER-06: A randomized, double-blind, phase III study of toripalimab versus placebo in combination with first-line chemotherapy for treatment naive advanced or metastatic esophageal squamous cell carcinoma (ESCC)
The combination of the anti-PD-1 therapy toripalimab with chemotherapy for esophageal squamous cell carcinoma was presented by Dr. Feng Wang (Sun Yat-sen University Cancer Center). The phase 3 JUPITER-06 trial randomized patients with previously untreated advanced/metastatic ESCC to receive either toripalimab or placebo in combination with paclitaxel and cisplatin, followed by toripalimab or placebo maintenance, with the primary endpoints of PFS and OS.
The results of this interim analysis were presented after a median follow up of 7.3-7.4 months in the 514 randomized patients. Overall survival was extended in the toripalimab arm, at 17.0 vs 11.0 months (HR: 0.58). Similarly, PFS by BICR was also improved with the checkpoint inhibitor therapy, with a HR of 0.58. Benefits of toripalimab were seen in patients with varied levels of PD-L1 expression. Safety of the regimen was as expected, with higher rates of immune-related adverse events with toripalimab therapy, as well as a higher rate of AEs leading to discontinuation (11.7% vs 6.2%). Overall, these results may lead to a new first-line option for advanced/metastatic ESCC.
MACROPHAGE REPROGRAMMING DEMONSTRATES EFFICACY IN LATE-STAGE SOLID TUMORS
LBA38 - Bexmarilimab, a novel macrophage re-programmer shows promising anti-tumour activity in phase I/II trial in several last line solid tumour types
Dr. Petri Bono (Terveystalo Helsinki) presented results of the phase 1/2 MATINS trial, which investigated bexmarilimab, an anti-CLEVER-1 antibody, in patients with solid tumors. By targeting CLEVER-1, bexmarilimab can switch tumor-associated macrophages from an M2 to M1 phenotype and increase antigen presentation. Patients (n=110) with ten tumor types were enrolled in this part of the study, which aimed to assess safety, ORR, and clinical benefit rate (CBR).
Across all disease cohorts, there was one partial response and 17 patients with stable disease, for a CBR of 17%. Median PFS was 59 days, and median OS was 151 days. Safety of the agent was favorable, with 25% of patients experiencing any treatment-related adverse event, while only 2% of these were of grade 3-4. Common AEs included fatigue, anemia and abdominal pain. Given these results, the investigators plan future monotherapy and combination trials in key disease types.
You can read more about the role of macrophages in cancer in this recent article from the Journal for ImmunoTherapy of Cancer (JITC).
T-VEC + PEMBROLIZUMAB MISSES PRIMARY ENDPOINT IN MELANOMA
1037O - MASTERKEY-265: A phase 3, randomized, placebo (Pbo)-controlled study of talimogene laherparepvec (T) plus pembrolizumab (P) for unresectable stage IIIB–IVM1c melanoma (MEL)
The phase 3 MASTERKEY-265 study was presented by Dr. Helen Gogas (National and Kapodistrian University of Athens). The study randomized patients with unresectable stage IIIb-IVM1c melanoma without prior treatment (unless BRAF/MEK-inhibitor-eligible) to receive pembrolizumab in combination with either T-VEC or placebo. The co-primary endpoints were PFS and OS, with final PFS results and interim OS results presented in this abstract.
After a median follow-up of 31 months, the PFS endpoint was not met, as the median PFS for the T-VEC arm was 14.3 months compared to 8.5 months with placebo (HR: 0.86). In subset analyses, patients treated in the USA, those with normal LDH and sum of lesion diameters of less than 5 cm had favorable outcomes in the combination arm. The overall survival data are not mature, through the current HR is 0.96, which crossed the futility boundary. Safety of the combination regimen was consistent with individual agent profiles, with grade 3+ adverse events in 21.2% and 16% of patients in the T-VEC and placebo arms, respectively.
ADJUVANT PEMBROLIZUMAB IN STAGE 2 MELANOMA SHOWS INITIAL PROMISE
LBA3 - Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial
The adjuvant portion of the KEYNOTE-716 study was presented by Dr. Jason Luke (UPMC Hillman Cancer Center). This trial enrolled patients with stage 2b/2c melanoma after complete resection to receive either adjuvant pembrolizumab or placebo for up to 17 cycles. The primary endpoint was RFS per investigator.
A total of 976 patients were enrolled and followed for a median of approximately 14 months. The RFS HR was 0.65 (p = 0.00658) in favor of pembrolizumab, although the median was not reached in either arm. The 12-month RFS was 90.5% with pembrolizumab and 83.1% with placebo. The rate of distant recurrence was numerically lower with pembrolizumab treatment than with placebo. Treatment-related adverse events of grade 3-4 occurred in 16.1% of patients receiving pembrolizumab and 4.3% of the placebo arm. No significant difference in quality of life was reported across the follow-up period. Overall, these results demonstrate the benefit of adjuvant immunotherapy treatment for stage 2 melanoma, and further follow-up is awaited.
The role of adjuvant nivolumab in stage III-IV melanoma was discussed in a recent article in JITC.
HIGHER-DOSE IPILIMUMAB WITH LOW-DOSE NIVOLUMAB FOUND SUPERIOR IN ADVANCED UC
LBA31 - High- vs low-dose pre-operative ipilimumab and nivolumab in locoregionally advanced urothelial cancer (NABUCCO cohort 2)
Dr. Jeroen Van Dorp (Netherlands Cancer Institute) presented results from the NABUCCO trial, specifically from cohort 2, which investigated two regimens of combination ipilimumab and nivolumab for stage III urothelial cancer. Arm A of this cohort was treated with nivolumab 1 mg/kg + ipilimumab 3 mg/kg, while arm B received nivolumab 3 mg/kg + ipilimumab 1 mg/kg. The primary endpoint was pCR rate, with safety as a key secondary goal.
The pCR rate favored regimen A, with higher-dose ipilimumab. The pCR rate in arm A was 43%, compared to 7% with arm B. Adverse events were more common in arm A, with grade 3-4 adverse events in 33% of patients in arm A and 20% of patients in arm B. These results are in contrast to those seen with other diseases, such as melanoma, wherein response rates are similar with the two combination regimens, potentially pointing to the importance of blocking the CTLA-4 pathway in urothelial cancer.
The Society for Immunotherapy of Cancer recently published a clinical practice guideline on urothelial cancer, which you can find in JITC.
PD-L1-HIGH TNBC BENEFITS FROM PEMBROLIZUMAB + CHEMOTHERAPY
LBA16 - KEYNOTE-355: Final results from a randomized, double-blind phase 3 study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC
The final results of KEYNOTE-355 were presented by Dr. Hope Rugo (University of California – San Francisco Comprehensive Cancer Center). This trial randomized 847 patients with metastatic triple-negative breast cancer (TNBC) to receive pembrolizumab + chemotherapy or placebo + chemotherapy as first-line treatment. The co-primary endpoints were PFS and OS in patients with PD-L1-positive disease (CPS >= 10) and in the entire population.
After a median follow-up of 44.1 months, the final overall survival data were mature. A significant improvement in OS was observed in patients with PD-L1 positive disease (CPS >=10) treated with pembrolizumab, with a median OS of 23.0 months compared to 16.1 months with placebo (HR: 0.73, p = 0.0093). No significant difference was found when comparing OS for patients with CPS >= 1, with median OS of 17.6 and 16.0 months with pembrolizumab or placebo, respectively. Similarly, no difference was noted in the ITT: median OS was 17.2 months with pembrolizumab and 15.5 months with placebo. Other outcomes, such as PFS and safety, mirrored prior reports from this trial. In conclusion, patients with PD-L1-high TNBC benefit from the addition of pembrolizumab in front-line treatment.
The Society for Immunotherapy of Cancer recently published a clinical practice guideline on the use of immunotherapy for breast cancer, which can be found in JITC.
NEOADJUVANT IMMUNOTHERAPY MAY BENEFIT DMMR SOLID TUMORS
1758O - Neoadjuvant pembrolizumab in localized/locally advanced solid tumors with mismatch repair deficiency
Dr. Kaysia Ludford (MD Anderson Cancer Center) presented a phase 2, single-center trial of neoadjuvant pembrolizumab in solid tumors with mismatch repair deficiency. Patients were treated with two cycles of pembrolizumab and then evaluated for clinical benefit. If patients were benefitting, they were eligible for an additional six cycles of pembrolizumab prior to resection. The primary endpoints of the trial were safety and pCR rate.
Thirty-five patients were enrolled in the trial, and 15 have undergone surgery. The majority of patients had colorectal cancer. The best overall response rate across all evaluable patients was 75%, including 25% CR. Among the patients who underwent surgery, the pCR rate was 69%. Correlative studies indicated that decreases in ctDNA levels after treatment indicated a greater likelihood of response. This study indicates that tumors with deficient MMR may benefit from neoadjuvant treatment with immune checkpoint blockade.
CLAUDIN18.2-TARGETED CAR T THERAPY DEMONSTRATES RESPONSES IN GI CANCERS
1372O - CLDN 18.2-targeted CAR-T cell therapy in patients with cancers of the digestive system
Dr. Changsong Qi (Peking University Cancer Hospital) investigated the use of Claudin18.2-targeted CAR T therapy in patients with gastrointestinal cancers. Tumors had to have expression of CLDN18.2 and the trial included both dose escalation and expansion cohorts. A total of 37 patients, mostly with gastric cancer, were enrolled and treated with CAR T therapy, at doses ranging from 2.5 x 108 cells (RP2D) to 5 x 108 cells.
All patients in the trial experienced grade 3-4 hematologic toxicities, mostly attributed to the conditioning regimen. CRS occurred in 95% of patients, all of grade 1-2. No immune effector cell-associated neurotoxicity syndrome (ICANS) was reported. One dose-limiting toxicity of gastrointestinal hemorrhage occurred. The ORR was 48.6%, and the disease control rate was 83.3%. Amongst patients with gastric cancer who had progressed on at least two prior therapies, the ORR was 61.1%, and the median PFS and OS were 5.6 and 9.5 months, respectively. Further investigation of this CAR T treatment is ongoing, to better understand the potential of this treatment.
Read more about the challenges and opportunities for cell therapies in solid tumors in this recent JITC article.
THERAPEUTIC VACCINATION SHOWS PROMISE IN ADVANCED NSCLC
LBA47 - Activity of OSE-2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (IO): Final results of Phase 3 Atalante-1 randomised trial
The final results of the Atalante-1 trial were presented by Dr. Benjamin Besse (Institut Gustave Roussy). The trial allocated patients with NSCLC to receive OSE2101 (an anti-cancer vaccine) or standard-of-care chemotherapy. The last line of therapy for all patients had to be an immune checkpoint inhibitor. The primary endpoint of the trial was overall survival. The trial was stopped prematurely per IDMC recommendations in light of the COVID-19 pandemic. This resulted in the population of interest (PoI) serving as the primary population for analysis, which included patients with secondary resistance to immunotherapy per the SITC definitions.
A total of 219 patients were enrolled, with 118 of these in the PoI. The median OS in the PoI was 11.1 months with OSE2101 treatment, compared to 7.5 months with chemotherapy (HR: 0.59, p=0.02). Improvements in both post-progression survival (7.7 vs 4.6 months) and time to worsening ECOG performance status (8.6 vs 3.3 months) were noted with the vaccine treatment. Disease control rates and PFS were similar across arms. A higher rate of grade 3+ treatment-related adverse events was seen in the chemotherapy arm, at 35%, compared to 11% in the OSE2101 arm. Overall, this study lends further support to the use of therapeutic cancer vaccination.
BLOOD-BASED TMB-HIGH NSCLC PATIENTS HAVE SIMILAR OUTCOMES WITH ATEZOLIZUMAB OR CHEMOTHERAPY
1281O - Atezolizumab (atezo) vs platinum-based chemo in blood-based tumour mutational burden-positive (bTMB+) patients (pts) with first-line (1L) advanced/metastatic (m)NSCLC: Results of the Blood First Assay Screening Trial (BFAST) phase III cohort C
Dr. Rafal Dziadziuszko (Medical University of Gdansk) described the results of cohort C of the BFAST trial, which compared atezolizumab to chemotherapy as first-line therapy in patients with metastatic NSCLC and high blood-based tumor mutational burden (bTMB). Using the clinical trial assay, high bTMB was defined as >= 16, and moderate as bTMB >= 10. 471 patients were enrolled in the study and evaluated for PFS as the primary endpoint.
After a median follow-up of 6 months, the median PFS for the atezolizumab arm was 4.5 months and 4.3 months in the chemotherapy arm, for patients with bTMB >= 16 (HR: 0.77, not significant). Notably, the PFS curves crossed around 4 months after treatment started, with chemotherapy favored initially and atezolizumab thereafter. OS was not significantly different between arms, with median values of 13.3 and 10.3 months for atezolizumab and chemotherapy, respectively. In subgroup analysis, PFS was improved with atezolizumab in patients with non-squamous histology but not in those with squamous cell cancers. In an exploratory biomarker analysis, bTMB by the more recent companion diagnostic assay (FoundationOne) showed more favorable results. Further refinements in TMB are anticipated in the near future.
IMMUNE-INFLAMED TNBC TUMORS MAY BENEFIT FROM ATEZOLIZUMAB + CHEMOTHERAPY
LBA12 - Predictive value of gene-expression profiles (GEPs) and their dynamics during therapy in the NeoTRIPaPDL1 trial
Biomarker analyses from the NeoTRIPaPDL1 trial were presented by Dr. Giampaolo Bianchini (IRCCS Ospedale San Raffaele). The trial randomized patients to receive nab-paclitaxel/carboplatin with or without atezolizumab as neoadjuvant therapy for TNBC. The present analysis investigated the association of pCR with various biomarkers.
The IO score, which incorporates many immune-related genes, correlated with pCR rates in patients treated with atezolizumab, as patients with a positive score had improved outcomes relative to those with a negative score (OR: 3.64). No correlation was observed in the chemotherapy arm with the IO score. A number of signatures were linked with resistance to atezolizumab, including angiogenesis, lipid metabolism and glutamine metabolism. Additionally, the investigators found that patients with quick responses to immunotherapy (“super-responders”, those with no tumor cells evident on day 1 of cycle 2) had tumors with unique biology. This included higher levels of immune cell and signaling pathways. Overall, this study outlines the importance of an inflamed tumor for successful cancer immunotherapy.
CEMIPLIMAB + CHEMOTHERAPY BENEFITS ADVANCED NSCLC WITHOUT ACTIONABLE MUTATIONS
LBA51 - EMPOWER-Lung 3: cemiplimab in combination with platinum doublet chemotherapy for first-line (1L) treatment of advanced non-small-cell lung cancer (NSCLC)
Dr. Miranda Gogishvili (High Technology Medical Centre) presented the EMPOWER-Lung 3 trial, which enrolled patients with advanced NSCLC to receive first-line treatment with either cemiplimab or placebo plus four cycles of chemotherapy. The primary endpoint was OS. 466 patients were enrolled in the trial.
This phase 3 randomized trial met its primary endpoint of OS: median 21.9 vs 13.0 months; HR, 0.71 (95% CI, 0.53–0.93); p=0.014 and secondary endpoint of PFS: median 8.2 vs 5.0 months; HR, 0.56 (95% CI, 0.44–0.70); p<0.0001. PROs were also superior in the cemiplimab arm. In a subset analysis of PD-L1 status, while cases with PD-L1 >=50% and 1-49% both fared well with cemiplimab plus chemotherapy, in those with PD-L1 <1%, the OS HR for the combination was 1.01 (0.63-1.60). Safety analysis was consistent with expectations for combinations of anti-PD-1/platinum chemotherapy regimens. This regimen will likely join the therapeutic options available in non-oncogene-driven advanced NSCLC.
ADJUVANT ATEZOLIZUMAB BENEFITS EARLY-STAGE NSCLC
LBA9 - IMpower010: sites of relapse and subsequent therapy from a Phase 3 study of atezolizumab vs best supportive care after adjuvant chemotherapy in stage IB-IIIA NSCLC
The IMpower010 trial was presented by Dr. Enriqueta Felip (Vall d’Hebron Institute of Oncology). The trial enrolled patients with completely resected stage Ib-IIIA NSCLC to receive atezolizumab or best supportive care following up to four cycles of cisplatin-based chemotherapy.
This trial is the first positive phase 3 study of adjuvant checkpoint immunotherapy after surgical resection and adjuvant chemotherapy in patients with early-stage NSCLC, showing a 34% reduction in risk of disease recurrence or death with adjuvant atezolizumab in the PD-L1 TC >=1% stage II-IIIA population (HR, 0.66; 95% CI: 0.50, 0.88) and potentially changing the standard of care in this population. This presentation focused on rates and sites of relapse. Time to relapse favored the atezolizumab arm in the PD-L1 TC >=1% stage II-IIIA population, with minimal differences seen in the all-randomized stage II-IIIA and ITT populations. Of note, in subset analysis there was no difference in CNS recurrence rates between the two study arms, in contrast to data with adjuvant osimertinib in the ADAURA trial in patients with EGFR-mutated NSCLC. Overall, the IMpower010 regimen represents a landmark study in the adjuvant therapy of early stage NSCLC.