Safety and efficacy of preoperative treatment of NSCLC with nivolumab and relatlimab
LBA37. A randomized, multicentric phase II study of preoperative nivolumab plus relatlimab or nivolumab in patients with resectable non-small-cell lung cancer (NEOpredict-Lung)
Martin H. Schuler (University Hospital Essen, Germany) presented results from NEOpredict-Lung, a phase II study of preoperative immune checkpoint inhibitor therapy (PICIT) prior to resection for non-small-cell lung cancer (NSCLC). Patients in Arm A (n=30) received preoperative doses of nivolumab (anti-PD-1), and patients in Arm B (n=30) received preoperative doses of nivolumab plus relatlimab (anti-LAG-3). All patients in the study received standard of care adjuvant treatment after surgery. Treatment related adverse events were mild and moderate, and no patient surgeries were delayed by toxicities. The primary endpoint of the study was met, in that all patients received curatively intended surgery within 43 days of beginning PICIT, and R0 resection rate was 100% for arm A and 97% for arm B. Radiological response rates were 10% (Arm A) and 27% (Arm B) per RECIST and 38% for both arms per PERCIST. Complete or major pathological response was observed in 27% of patients in arm A and 30% of patients in arm B. 12-month overall survival was 92% (arm A) and 100% (arm B), and 12-month disease free survival were 92% (arm A) and 91% (arm B). Although pathologic responses and remissions were observed in both treatment groups, regardless of PD-L1 status, deeper responses were more often observed in patients with PD-L1 positive tumors. Patients with deeper pathologic response (<=50% vital tumor cells in resected lung cancer), exhibited higher levels of CD8+ T cells in peripheral blood. These data suggest that combining immune checkpoint inhibitor therapy is safe and feasible in patients with curatively resectable NSCLC. The NEOpredict-Lung protocol has been expanded to explore the safety and efficacy of increased doses of relatlimab, and combined correlative studies and biomarker analyses are ongoing.
Targeting claudin 6 for treatment of solid tumors
LBA38. BNT211-01: A Phase 1 trial to evaluate safety and efficacy of CLDN6 CAR T cells and CLDN6-encoding mRNA vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumours
Andreas Mackensen (University of Erlangen-Nuremberg, Erlangen, Germany) reported on the first-in-human trial for BNT211, a therapeutic approach for treating patients with claudin 6 (CLDN6)-positive relapsed/refractory solid tumors. CLDN6 is a membrane protein expressed in a variety of tumors, including testicular and ovarian cancers. BNT211 comprises two components: a chimeric antigen receptor (CAR) T cells targeting CLDN6 and a CLDN6-encoding CAR T cell-amplifying RNA vaccine (CARVac) to expand and improve the persistence of CAR T cells. 22 patients were treated; 9 patients received CLDN6 CAR T monotherapy, and 13 patients received combination therapy of CLDN6 CAR T + CARVac. Patients had CLDN6-positive testicular cancer, ovarian cancer, or endometrial cancer. Two patients exhibited dose-limiting toxicities, and most treatment-emergent adverse events were related to lymphodepletion or transaminase/lipase elevations. Cytokine release syndrome (CRS) occurred in 45% of patients: all cases were <= G2, except one case of G3 CRS, and all cases were manageable. One case of G1 ICANS was quickly resolved. 7 of 21 evaluable patients (33%) exhibited a partial response and 7 exhibited stable disease. Disease control rate was 67%. One patient with testicular cancer exhibited a partial response transitioned to a complete response at the 12- week follow-up. Four of the seven responding patients had testicular cancer, and follow-up is ongoing for three of these patients. In five of seven patients with stable disease, some tumor regression was observed, and response was durable at 30 – 46 weeks. Due to the small size of the study, it has not yet been determined whether CARVac improves persistence of CLDN6 CAR T cells because dose-dependent CAR T expansion was observed in all patients 100 days after CAR-T administration, regardless of administration of CARVac. An automated process for production of CLDN6 CAR T cells has been developed, and dose escalation studies of the automated product are ongoing.
PRAME-targeting bispecific proteins for treatment of solid tumors
728O. Results from Phase 1 dose escalation of IMC-F106C, the first PRAME × CD3 ImmTAC bispecific protein in solid tumors
Omid Hamid (Cedars-Sinai, Los Angeles, CA) presented results from a trial of IMC-F106C, an immune mobilizing monoclonal T-cell receptor against cancer (immTAC) targeting CD3 and PRAME, a broadly expressed cancer testis antigen that is expressed in many solid tumors, including lung, ovarian, endometrial, melanoma, and breast. 55 patients were evaluated for safety, and 31 patients were evaluated for efficacy. Patients represented a variety of tumor types (melanoma, ovarian carcinoma, non-small-cell lung cancer, triple negative breast cancer, and endometrial cancer), and all patients had been heavily pre-treated prior to the study. Most adverse events were grades 1 or 2 and were quickly resolved. 31% of patients experienced grade 3 or 4 adverse events, but none experienced grade 3 or 4 cytokine release syndrome. 7 patients exhibited a confirmed partial response (3 with tebentafusp naïve uveal melanoma, 2 with cutaneous melanoma, and 2 with serious ovarian carcinoma). 6 responses are ongoing, with two responses ongoing for over seven months. The majority of patients exhibited tumor response or disease stabilization. Earlier progressive disease was observed in patients with tumors with lower PRAME expression. Changes in ctDNA levels were observed in patients of all tumor types, and the greatest decreases in ctDNA levels were associated with patients who responded to treatment. 4 responders evaluated for ctDNA clearance had >50% reduction, and three exhibited ctDNA clearance. Of particular interest were patients with NSCLC exhibiting ctDNA clearance but a best response of progressive disease. Dose escalation studies of IMC-F106C are ongoing and expanded studies of IMC-F106C as monotherapy and in combination treatment with chemotherapy and checkpoint inhibitors are in progress.
Blocking adenosine to improve response to combination therapy for triple-negative breast cancer
LBA17. Primary endpoint results of SYNERGY, a randomized phase 2 trial, first-line chemo-immunotherapy trial of durvalumab, paclitaxel, and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced or metastatic triple-negative breast cancer (TNBC)
Laurence Buisseret (Institut Jules Bordet, Brussels, Belgium) presented results from SYNERGY, a phase 2 to determine whether blocking ectoenzyme CD73 with oleclumab enhanced antitumor response to combination therapy of anti-PD-L1 immunotherapy with chemotherapy in triple-negative breast cancer (TNBC). CD73 is involved in generation of immunosuppressive adenosine in the tumor microenvironment, and overexpression of CD73 is associated with poor prognosis in patients with TNBC. 127 patients with untreated inoperable locally advanced or metastatic TNBC received chemotherapy of paclitaxel and carboplatin. Patients in arm A (n=63) also received durvalumab with oleclumab, and patients in arm B (n=64) also received durvalumab (no oleclumab). 27% of patients in arm A and 32.8% of patients in arm B were CD73 positive. At the 24-week follow-up, clinical benefit rates were not significantly different between the two arms (42.9% for arm A and 44% for arm B), regardless of PD-L1 or CD73 status. Progression free survival was similar in both arms, 6.0 months for arm A, and 7.7 months for arm B. Safety profiles for both arms were similar, and adverse events were manageable. Results from the SYNERGY trial indicate that addition of oleclumab to combination therapy of durvalumab + carboplatin/paclitaxel does not provide clinical benefit in first-line advanced TNBC. Translational studies to better understand mechanisms and predictive biomarkers of response to chemo-immunotherapy in TNBC are ongoing.
Combination therapy as first line treatment of hepatocellular carcinoma
LBA35. Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a randomized, phase Ⅲ trial
Shukui Qin (Bayi Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, China) presented data from a phase III trial comparing the clinical benefits of combining anti-PD-1 therapy (Camrelizumab; C) with an anti-angiogenic tyrosine kinase inhibitor (Rivoceranib, Apatinib ; R) versus a multi-kinase inhibitor (Sorafenib; S) as first-line treatment for unresectable or metastatic hepatocellular carcinoma (HCC). Patients were randomized to receive C+R (n=272) or S (n=269). At a median follow-up of 7.8 months, progression free survival (PFS) with C+R was significantly improved compared to S (5.6 months vs 3.7 months). At a median follow-up of 14.5 months, overall survival (OS) with C+R (22.1 months) was significantly higher than with S (15.2 months). Hazard ratios of PFS and OS favored C+R in all patient subgroups analyzed. Overall response rates (ORR) and disease control rates (DCR) were also significantly improved with C+R 25.4%) compared to S (5.9%). Treatment-related adverse events (TRAEs) of grades 3 or 4 were observed in 80.5% of patients in the C+R arm and 52% of patients in the S arm. TRAEs were manageable: TRAEs led to partial discontinuation of treatment in 24.3% of patients in the C+R arm and 4.5% of patients in the S arm, and all treatment was discontinued in 3.7% of patients in the C+R arm and 4.5% of patients in the S arm. 33.1% of patients who received C+R and 48.3% of patients receiving S went on to receive subsequent anti-cancer treatment, and 33.5% of patients from the S arm received immunotherapy in subsequent treatments. This international trial is the first of its kind to show survival benefits associated with PD-(L)1 inhibitor + anti-angiogenic TKI combination therapy for patients with uHCC. The novel combination of an anti-angiogenic agent with a PD-1 inhibitor established superiority in response rates, PFS, and OS over standard sorafenib monotherapy in HCC. The median survival of 22.1 months in the combination arm is promising but has to be weighed against the increased toxicity rate and 24% of patients discontinuing therapy due to adverse events.
PD-1 blockade as first-line treatment of hepatocellular carcinoma
LBA36. Final Analysis of RATIONALE-301: Randomized, Phase 3 study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma
Masatoshi Kudo (Kindai University, Osaka, Japan), reported results from RATIONALE-301, a phase III study comparing tislelizumab (TIS) versus sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (HCC). Patients were randomized to TIS (n=342) or SOR (n=332). Median overall survival (OS) improved with TIS (15.9 months), compared to SOR (14.1 months; HR=0.85), but the benefit was not statistically significant. Modest OS benefits favoring TIS were observed across all patient subgroups analyzed. Overall response rate with TIS (14.3%) was higher than with SOR (5.4%), and responses with TIS were more durable: median duration of response was 36.1 months with TIS compared to 11.0 months with SOR. Of the responders in this study, treatment is ongoing for 71.4% of patients in the TIS arm and 40.0% in the S arm. Safety profiles for TIS and SOR were comparable to prior reports, and TIS was associated with fewer adverse events >= grade 3 (48.2% vs. 65.4%) and adverse events causing discontinuation of treatment (10.9% vs 18.5%). Tisalizumab did not demonstrate a significant survival benefit over sorafenib, but the meaningful and durable clinical benefits and manageable safety profiles associated with tislelizumab monotherapy indicate that it may be a favorable option for first-line treatment of unresectable HCC.
Safety and efficacy of perioperative immune checkpoint blockade for renal cell carcinoma
LBA67. Phase III RandOmized Study Comparing PErioperative Nivolumab (nivo) versus Observation in Patients (Pts) with Renal Cell Carcinoma (RCC) Undergoing Nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial
Mohamad Allaf (Johns Hopkins School of Medicine) reported results from PROSPER, a phase III trial investigating the benefits of perioperative nivolumab (nivo) prior to nephrectomy followed by adjuvant nivo versus nephrectomy alone in patients with high-risk renal cell carcinoma (RCC). Patients in the surgery + nivo arm (n=404) received nivolumab prior to surgery, followed by nivolumab treatment post-surgery. Due to the nature of the trial design, 353 patients began neoadjuvant treatment, 359 patients received surgery, and 314 patients started adjuvant therapy. Patients in the control arm (n=415) received surgery followed by standard of care surveillance. 387 patients in the control arm received surgery. At the 71.8% information time, inefficacy results were presented, and the trial was stopped early due to futility. Recurrence free survival (RFS) was similar between the two arms (HR = 0.97), and median RFS was not reached. HR for RFS were close to 1 for each patient subgroup analyzed. Preliminary values of overall survival of the two arms were not significantly different between the two arms (HR = 1.48). Approximately 12% of patients from both arms withdrew from the study, and 20% of patients in the nivo arm experienced at least one adverse event of grade 3-4. Radiomic, pathomic, and biomarker analyses from this study will be applied to inform design of future trials investigating neoadjuvant immunotherapy for RCC, and patient subsets will be further analyzed for future research.
Analysis of the predictive and prognostic potentials of two PD-L1 IHC assays
1735O. PD-L1 expression on immune cells by SP142 co-localises with dendritic cells and is associated with improved overall survival (OS) with atezolizumab in patients with untreated metastatic urothelial cancer (mUC)
Enrique Grande Pulido (MD Anderson Cancer Center, Madrid, Spain) presented a post-hoc analysis of the association of two PD-L1 IHC assays, SP142 and 22C3, and survival benefits in biomarker evaluable patients from the IMvigor130 trial. The phase III IMvigor 130 study previously showed survival benefits with atezolizumab monotherapy (arm B) compared to chemotherapy (arm C) for first-line treatment of patients with metastatic urothelial cancer who had high PD-L1 expression by the SP142 IHC assay. Analysis of cellular components associated with PD-L1 staining showed that SP142 preferentially colocalized with dendritic cells compared to other myeloid subsets. The SP142 PD-L1 assay was found to be prognostic: patients with tumors staining for PD-L1 by 22C3 (CPS>=10) exhibited shorter median overall survival (OS) compared to patients with tumors staining for PD-L1 by SP142 (IC2/3) for both arms B and C. The SP142 PD-L1 assay was also found to be predictive: among patients who received atezolizumab (arm B), median OS was higher for patients with IC2/3 tumors (SP142 assay; 18.93 months) compared to patients with CPS>=10 tumors (22C3 assay; 14.62 months). Longer OS was associated with higher PD-L1 scores (SP142 IC2/3 and 22C3 CPD>=10), and shortest median OS was observed in patients with tumors staining 2+ or 3+ for 22C3 but not SP142. These data suggest that PD-L1-expressing dendritic cells may be involved in mechanism behind the survival benefits associated with atezolizumab in SP142 IC2/3 tumors vs IC0/1 tumors and reinforce preclinical data that demonstrate the importance of PD-L1 dendritic cells in the anti-cancer immune response.
Monitoring epigenetic changes in peripheral blood to evaluate systemic and tumor-specific biomarkers
LBA74. Genomic biomarkers in peripheral blood (PB) from patients (pts) enrolled in the JAVELIN Bladder 100 trial of avelumab first-line (1L) maintenance in advanced urothelial carcinoma (aUC)
Thomas B. Powles (Queen Mary University of London, London, United Kingdom) reported on biomarker analyses from the JAVELIN Bladder 100 trial of avelumab as first-line maintenance for advanced urothelial carcinoma (aUC). The goal of this study was to identify blood biomarkers associated with epigenetic changes or chromatin conformation signatures (CCSs) in the tumor genome architecture that identify patient subpopulations that could benefit from immune checkpoint inhibitor therapy. Peripheral blood from 496 patients in the JAVELIN Bladder 100 trial was analyzed by the EpiSwitch PCR assay to identify three-dimensional loops in the chromatin structure of white blood cells. Tumor immune activity was scored using a gene expression signature, and association of CCS with tumor immune activity was determined via univariate and multivariate analyses of a training set of 80 specimens. 25 CCSs were identified, and one CCS was near POU2F2, a transcription factor involved in B cell maturation and T cell-dependent humoral immunity. Patients lacking the POU2F2 CCS had elevated scores for tumor immune activity, elevated levels of dendritic cells, and increased expression of genes associated with tertiary lymphoid structures (TLSs). The POU2F2 CCS was associated with reduced POU2F2 expression and TLS biomarkers, suggesting the CCS negatively regulates expression of POU2F2. Patients with tumors expressing higher levels of POUS2F2 exhibited better survival outcomes with maintenance avelumab (HR=0.69), and patients with the absence of the POUSF2 CCS in peripheral blood also exhibited better survival outcomes with maintenance avelumab (HR 0.62). Patients with low tumor mutation burden (TMB) and the absence of the POU2F2 CCS also exhibited better survival outcomes with maintenance avelumab (HR=0.44), suggesting that expression of POU2F2 and promotion of TLS formation may compensate for the decreased immunogenic environment in TMB-low tumors. Although this model needs statistical validation, these data indicate that CCS may be potentially predictive of outcomes with maintenance avelumab.
Efficacy and safety of bempegaldesleukin plus nivolumab for advanced melanoma
785O. PIVOT IO 001: first disclosure of efficacy and safety of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) vs NIVO monotherapy in advanced melanoma (MEL)
Adi Diab (The University of Texas MD Anderson Cancer Center) presented efficacy and safety data from PIVOT IO 001, a phase III study comparing bempegaldesleukin (BEMPEG), an interleukin-2 prodrug combined with nivolumab (BEMPEG + NIVO) vs. nivolumab monotherapy (NIVO) for advanced melanoma. Previous studies indicate a role for BEMPEG in mitigating IL-2 toxicity and in activation and expansion of CD8+ T cells and NK cells. At a median follow-up of 19.3 months, overall response rate (ORR) for BEMPEG+NIVO (n = 391) was 27.7% vs 36.0% for NIVO (n=392). No patient subgroup analyzed favored BEMPEG+NIVO regarding ORR. Disease control rates were 56.1% with BEMPEG+NIVO and 58.5% with NIVO. At a median follow-up of 11.6 months, median progression free survival (PFS) was 4.17 months with BEMPEG+NIVO and 4.99 months with NIVO. No patient subgroup analyzed favored BEMPEG+NIVO regarding PFS. Median overall survival (OS) was 29.67 months with BEMPEG+NIVO and 28.88 months with NIVO. Drug-related adverse events (AEs) of grades 3 or 4 were higher for BEMPEG+NIVO compared to NIVO (21.7% vs 11.5%), and one adverse event of special interest, ischemic cerebrovascular events were more common with BEMPEG+NIVO compared to NIVO (2.6% vs 0.8%). The primary endpoints of ORR, PFS, and OS were not met for this study; BEMPEG+NIVO did not exhibit increased efficacy compared to NIVO, and it was associated with increased toxicity when compared to NIVO. Ongoing biomarker analyses to assess changes in peripheral blood and the tumor microenvironment will be used to further interpret study results.
Using tumor-infiltrating lymphocytes for treatment of advanced melanoma
LBA3. Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: results from a multicenter, randomized phase 3 trial
John B.A.G. Haanen (Leiden University, Amsterdam, Netherlands) presented results of a phase III trial (NCT02278887) comparing the use of tumor-infiltrating lymphocytes (TILs) vs. ipilimumab for treating patients with unresectable stage IIIC –IV melanoma. Of the 168 patients in the trial, 86% were refractory to anti-PD-1 treatment. Patients randomized to the TIL arm (n=80) underwent resection of the melanoma lesion for TIL production and subsequently received infusion of TILs after lymphodepletion and high-dose interleukin 2. Patients randomized to the ipilimumab arm (n=82) received standardized doses of ipilimumab, with no surgery or lymphodepletion. At a median follow-up of 33.0 months, median progression free survival for TIL (7.2 months) was significantly higher than PFS for ipilimumab (3.1 months). Progression free survival favored TIL over ipilimumab for all patient subgroups. Overall response rate for TIL was 48.8%, with 20% complete responses, compared to an ORR of 21.4% and 7.1% complete responses for ipilimumab. Median overall survival for TIL and ipilimumab were 25.8 months and 18.9 months, respectively. Treatment related adverse events >=3 occurred in all TIL patients and 57% of ipilimumab patients, and adverse events were manageable. Health-related quality of life scores were significantly higher for TIL compared to ipilimumab, with a mean score difference of 7.7. These data provide further support of TIL therapy as a new treatment option for patients with advanced melanoma, including patients refractory to PD-1 blockade.
Adding immunotherapy to preoperative chemoradiotherapy for advanced non-small cell lung cancer
950O. Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable lung cancer: the INCREASE trial
Idris Bahce (Amsterdam University Medical Center Amsterdam, Netherlands) presented results from the INCREASE trial, a single-arm prospective phase II study to investigate whether addition of ipilimumab + nivolumab (IPI-NIVO) to neoadjuvant chemoradiotherapy (CRT) modulated the tumor microenvironment and increased pathological responses in patients with locally advanced non-small cell lung cancer (NSCLC). 26 patients with T3/4 and N0-N2 NSCLC participated in the trial, and 24 of those patients completed surgery. Pathologic complete response (pCR) was observed in 63% of patients who underwent surgery. The major pathologic response rate was 79% in patients who completed surgery. Radiological response rates were lower than pathologic response rates, with a partial response rate of 12.5%. Grade 3-4 treatment-related adverse events occurred in 67% of patients, and management of adverse events and toxicities was manageable. Surgery was not delayed for any patients in the study. Neoadjuvant treatment was associated with increased levels of CD8+ effector T cells in peripheral blood, especially in patients who exhibited pCR. Patients in the INCREASE trial also exhibited increased levels of activated CD8+ T cells in tumor-draining lymph nodes compared to matched control patients. Results from this study suggest a regimen of preoperative chemo-radio-immunotherapy is safe, provides deeper pathologic response, and enhances T cell activation for patients with borderline resectable NSCLC.
Investigating the role of IL-1 beta in non-small cell lung cancer
LBA49. CANOPY-A: Phase III study of canakinumab (CAN) as adjuvant therapy in patients (pts) with completely resected non-small cell lung cancer (NSCLC)
Edward B. Garon (David Geffen School of Medicine at University of California Los Angeles) presented results from CANOPY-A, a phase III study to test the efficacy and safety of canakinumab (CAN), a high-affinity anti-IL-1 beta antibody as adjuvant therapy in patients with completely resected non-small cell lung cancer (NSCLC). An exploratory analysis of the CANTOS study showed that CAN was associated with significant reductions in NSCLC incidence and mortality, suggesting that inhibition of the IL-1 beta pathway may reduce the rates of progression, invasiveness, and metastasis of lung cancers. Patients with completely resected stage IIA – III A/B NSCLC received CAN (n=693) or placebo (PBO; n=689) post-surgery. Most patients in the trial had received prior chemotherapy and/or radiotherapy. Canakinumab did not significantly improve disease free survival (DFS) compared to placebo; median DFS was 35.0 months and 29.7 months, respectively, HR was 0.94. Because no significant changes in DFS were observed, overall survival was not formally assessed. Patient subgroup analyses did not show any meaningful differences between the two arms. Treatment-related adverse events were slightly higher with CAN (38.9%) compared to PBO (31.5%), and adverse events interrupted dosing in 13.4% of patients in the CAN arm, compared to 11.0% in the PBO arm. Although the primary endpoint (DFS) of this study was not met, exploratory biomarker analyses from CANOPY-A are ongoing, including tumor molecular profiling and longitudinal analysis of circulating inflammatory markers, in order to provide insights to the role of inflammation and IL-1 beta in NSCLC.
Immune checkpoint inhibitors as second-line therapy for dMMR/MSI colorectal cancer
LBA23. Avelumab versus standard second-line treatment chemotherapy in metastatic colorectal cancer (mCRC) patients with microsatellite instability (MSI): the SAMCO-PRODIGE 54 randomised phase II trial
Julien Taieb (Université de Paris, France) presented results from the SAMCO-PRODIGE 54 trial comparing the efficacy and safety of avelumab (anti-PD-L1) therapy to the standard chemotherapy for second-line treatment of mismatch repair-defective/microsatellite instability-high metastatic colorectal cancer (dMMR/MSI mCRC). 122 patients with dMMR/MSI mCRC who progressed on cytotoxic first-line chemotherapy with or without targeted agents were randomized to receive avelumab (n=61) or chemotherapy of FOLVOX or FOLFIRI +/- targeted agent (n=61). Overall response rate (29.5% vs 26.3%) and disease control rate (70.5% vs 77.3%) was not significantly different with avelumab compared to chemotherapy. At 24 months, progression free survival (PFS) was 25% with avelumab compared to 3% with chemotherapy (p=0.025 as calculated by the Qui and Sheng test). Avelumab was associated with durable response, as disease was controlled for over 18 months in the majority of responders. Adverse events >= 3 were observed in 31.7% of patients with avelumab and 53.1% of patients with chemotherapy. Comparison of 12-month PFS rates of the SAMCO-PRODIGE 54 trial (second-line treatment with anti-PD-L1; 31%) to KEYNOTE-177 (first-line treatment with anti-PD-1; 50%) suggests SAMCO-PRODIGE 54 may have included more patients with tumors resistant to immune checkpoint inhibitors, indicating that immune checkpoint inhibitors may be most effective against dMMR/MSI mCRC when used as soon as possible in the course of treatment. Results indicate that that avelumab is safe and effective as second-line treatment for dMMR/MSI mCRC, and more investigation is needed regarding resistance to immune checkpoint inhibitors in dMMR/MSI mCRC. Overall survival, quality of life, and biomarkers from tumor, blood, and stool will be further analyzed to identify predictors of response and resistance to immunotherapy.
Adjuvant nivolumab plus ipilimumab after nephrectomy for renal cell carcinoma
LBA4. Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: results from the randomized, phase 3 CheckMate 914 trial
Robert J. Motzer (Memorial Sloan Kettering Cancer Center, New York) reported primary analysis for part A of CheckMate 914, a two-part phase III trial evaluating adjuvant nivolumab + ipilimumab (NIVO+IPI) vs placebo (PBO; part A) or adjuvant nivolumab (NIVO) monotherapy vs NIVO+IPI vs PBO (part B) in mutually exclusive patients with surgically resected stage II/III clear cell renal cell carcinoma (RCC) at high risk of post-surgical relapse. Patients in the study had previously received a radical or partial nephrectomy and had no clinical/radiological evidence of residual disease. At 4 to 12 weeks after surgery, patients received NIVO+IPI (n=405) or PBO (n=411). At a median follow-up of 37.0 months, no significant difference in RFS was observed between the two arms. Median disease-free survival (DFS) per BICR was not met with NIVO+IPI and 50.7 months with PBO (HR 0.92). Treatment-related adverse events (TRAEs) were observed in 88.9% of patients in NIVO+IPI and 56.8% of patients in PBO, and TRAEs >= grade 3 were reported in 28.5% of patients in NIVO+IPI and 2.0% of patients in PBO. The rate of treatment discontinuation due to adverse events was considerably higher with NIVO+IPI (29.0%) compared to PBO (1.0%). Further analyses of Arm A of CheckMate 914 are ongoing to provide a better understanding of outcomes related to adjuvant nivolumab + ipilimumab. Part B of CheckMate 914, comparing adjuvant nivolumab monotherapy to adjuvant nivolumab + ipilimumab and placebo is ongoing.
LBA5. Primary results of the phase 3 KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC)
Jean-Pascal Machiels (Cliniques Universitaires Saint-Luc, Bruxelles, Belgium) presented results from KEYNOTE-412, a phase III study investigating the safety and efficacy of pembrolizumab (pembro) + chemoradiation therapy (CRT) vs placebo + CRT in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Patients with newly diagnosed, treatment-naïve LA-HNSCC were randomized to pembro + CRT followed by maintenance pembro (n=402) or placebo + CRT followed by maintenance placebo. Event-free survival (EFS) trended in favor of pembro + CRT compared to placebo + CRT (HR 0.83), but the difference was not statistically significant. At the 24-month and 36-months follow-ups, EFS rates were 63.2% and 57.4% with Pembro + CRT and 56.2% and 52.1% with placebo + CRT. HR for EFS were close to 1 for each patient subgroup analyzed. PD-L1 expression may be an informative predictive biomarker; in patients with tumors of PD-L1 CPS >=1, the 24 months EFS rate was 63.7% (pembro + CRT) and 56.3% (placebo + CRT), and OS rate at 36 months was 71.4% (pembro + CRT) and 70.2% (placebo + CRT). Post hoc analyses of patients with tumors of PD-L1 CPS >= 20 yielded similar results, with the 24 months EFS rate was 71.2% (pembro + CRT) and 62.6% (placebo + CRT), and OS rate at 36 months was 79.1% (pembro + CRT) and 73.0% (placebo + CRT). Adverse events >= grade 3 were observed in 92.2% of patients in the pembro + CRT arm and 88.4% of patients in the placebo + CRT arm, and adverse events led to discontinuation of some component of treatment in 41.2% (pembro + CRT) and 33.2% (placebo + CRT) of patients. Although differences between pembro and placebo were not statistically significant, pembrolizumab + CRT was associated with favorable trends toward improved EFS in patients with LA-HNSCC, and adverse events were manageable.
Does preoperative treatment with immune checkpoint inhibitors improve patient outcomes for melanoma?
LBA6. Neoadjuvant versus adjuvant pembrolizumab for resected Stage III-IV melanoma (SWOG S1801)
Sapna Patel (The University of Texas MD Anderson Cancer Center, Houston, Texas) presented results from SWOG S1801, a randomized phase II study comparing adjuvant therapy (AT) vs. neoadjuvant therapy (NAT) with pembrolizumab (PEM) in patients with resectable stage IIIB-IV cutaneous, acral, and mucosal melanomas without brain metastases. Patients in the AT arm (n=159) received PEM after surgery, and patients in the NAT arm (n=154) received PEM before and after surgery. Radiation therapy after surgery was allowed for both treatment arms. At a median follow-up of 14.7 months, EFS was significantly higher with NAT compared to AT (HR 0.58), and two-year EFS rates were 72% (NAT) and 49% (AT). Overall survival HR was 0.63. Benefits of NAT compared to AT were observed in all patient subgroups analyzed. Partial responses and complete responses were observed in patients at all stages of disease. Of patients with submitted pathology reports, 21% of patients in the NAT arm achieved pathologic complete response. The rate of PEM- or surgery-related adverse events were similar in both arms. One patient in the NAT arm was unable to receive surgery due to toxicity and 12 due to disease progression. 44 patients in the AT arm and 9 patients in the NAT arm experienced a melanoma recurrence after starting adjuvant therapy. Results from this study suggest that neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma, suggesting that treatment with immune checkpoint blockade prior to surgery enhances anti-tumor immunity without delaying curative surgery.
Neoadjuvant immune checkpoint inhibitors for advanced mismatch repair-deficient colon cancer
LBA7. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study
Myriam Chalabi (Netherlands Cancer Institute, Amsterdam, Netherlands) reported results from NICHE-2, which investigated the safety and efficacy of neoadjuvant immune checkpoint blockade (ipilimumab + nivolumab) prior to surgical resection in patients with high risk (T4 and/or N2) stage III mismatch repair-deficient (dMMR) colon cancer (CC). NICHE-2 builds upon the finidings of NICHE-1, which has shown that neoadjuvant immune checkpoint blockade is effective in non-metastatic dMMR CC. 112 patients were treated in this single-arm study, and 107 were included in efficacy analysis. Immune-related adverse events of grades 3 or 4 were observed in 4% of patients, and 2% of patients experienced a >=2-week delay in surgery due to adverse events. All patients underwent surgery, with 100% R0 resections. Pathologic response was observed in 99% of (106/107) patients, with a major pathologic response in 95% of patients and pathologic complete response (pCR) in 67% of patients. At a median follow-up of 13.1 months, no patients exhibited disease recurrence. PCR rate for patients with Lynch Syndrome (n=32) was 78%, compared to 58% for patients with sporadic tumors, suggesting neoadjuvant immune checkpoint blockade is especially beneficial for this patient population. 3-year disease-free survival data for NICHE-2 are expected in 2023, but the data presented provide strong support for neoadjuvant immunotherapy as a new standard of care for the management of dMMR CC.
Investigating the association of pre-treatment ctDNA and other clinical factors with disease recurrence in patients with melanoma
788O. Association of pre-treatment ctDNA with disease recurrence and clinical and translational factors in patients with stage IIIB-D/IV melanoma treated with adjuvant immunotherapy (CheckMate 915)
Georgina V. Long (The University of Sidney, Australia) presented a retrospective analysis from the phase 3 CheckMate 915 study, which compared treatment of nivolumab + ipilimumab with nivolumab in patients with stage IIIB-D/IV resected melanoma. Post-resection pre-treatment plasma from 1127 patients (61% of the intent to treat population) was evaluated for ctDNA status and level using a patient-specific panel of up to 200 variants. Regression models were used to evaluate the association between ctDNA status and recurrence-free survival (RFS) alone and in combination with baseline clinical factors and biomarkers. Pre-treatment ctDNA prevalance was approximately 16%, and this rate was similar across most demographics and the two treatment arms. Higher ctDNA prevalence was observed in patient populations with higher stage III substages of melanoma (11% IIIB, 18% IIIC, 41% IIID) and with higher ECOG performance status (16% PS0, 23% PS1). The presence of pre-treatment ctDNA was associated with poorer recurrence free survival (HR 1.87) and poorer distant metastases-free survival (HR 2.86). No significant interaction between baseline ctDNA status and treatment arm (nivolumab + ipilimumab and nivolumab monotherapy) was observed. Improved association with recurrence was observed when baseline ctDNA status was combined with other baseline factors and biomarkers, including tumor mutation burden (TMB), and interferon gamma (IFN gamma) signature. Patients with high TMB or high IFN gamma signature showed increased rates of recurrence-free survival (RFS) and combining baseline ctDNA status with TMB and IFN gamma signature further improved RFS prediction. This study is the largest assessment of ctDNA in an adjuvant melanoma setting and establishes ctDNA as a useful predictor of outcome for advanced melanoma, especially regarding recurrence and metastasis. Longitudinal ctDNA analyses are ongoing and will be used to inform further risks of recurrence.
Neoadjuvant immune checkpoint blockade for resectable cutaneous squamous cell carcinoma
789O. Neoadjuvant cemiplimab in patients (pts) with stage II–IV (M0) cutaneous squamous cell carcinoma (CSCC): Primary analysis of a Phase 2 study
Neil Gross (The University of Texas MD Anderson Cancer Center, Houston, Texas) presented preliminary results from a phase II single-arm trial investigating the use of neoadjuvant cemiplimab for resectable Stage II-IV cutaneous squamous cell carcinoma (CSCC). This study builds upon a prior pilot study that demonstrated a 55% pathologic response rate with neoadjuvant cemiplimab therapy for resectable CSCC. Part 1 of the study, which involved neoadjuvant cemplimab followed by curative-intent surgery, was reported. At data cutoff, 79 patients were enrolled in the study, 62 patients received all four doses of cemiplimab prior to surgery, and 70 patients underwent surgery. Pathologic complete response (pCR) was observed in 50.6% of patients, and major pathologic response (MPR) was observed in 12.7% of patients. Combined pathologic response rate was 63.3%. Regarding radiological response, objective response rate per RECIST 1.1 was similar to the combined pathologic response rate at 68.4%. Complete response rate was 6.3%, and partial response rate was 62.0%. The differences in complete response rate indicates that cancer cells were likely detected by imaging after surgery. Of the 16 patients that were designated as having stable disease by imaging, 44% of those patients had a complete or major pathologic response. Nine patients did not receive surgery, two of those due to progressive disease. 87.3% of patients experienced adverse events (AEs), 17.7% of patients experienced AEs >= Grade 3, 1.3% of patients discontinued treatment due to AEs, and four patients (5.1%) died due to AEs. The safety profile was similar to previous anti-PD-1 monotherapy studies. Patients with pCR and MPR exhibited a higher tumor mutational burden compared to patients who did not attain pCR/MPR, but the difference between the groups was not significant. MPR and pCR were observed in patients with PD-L1-negative and PD-L1-positive tumors. The combined pathologic response rate (pCR +MPR) of 63.3% in patients with stage II-IV CSCC is the highest observed in a multi-center anti-PD-1 neoadjuvant immunotherapy study for any solid tumor type. The clinical benefits associated with neoadjuvant avelumab along with its manageable safety profile, suggests that neoadjuvant immune checkpoint blockade could potentially enable function-preserving surgery in some cases of advanced CSCC. Longer term follow-up studies, including disease free survival and quality of life analyses are ongoing.
BEMPEG plus nivolumab does not improve outcomes for patients with advanced clear-cell renal carcinoma
LBA68. Bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) compared to the investigator’s choice of Sunitinib or Cabozantinib in previously untreated advanced renal cell carcinoma (RCC): Results from a Phase 3 randomized study (PIVOT-09)
Nizar Tannir (The University of Texas MD Anderson Cancer Center, Houston, Texas) presented results from the PIVOT-09 study, a phase III randomized trial comparing bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) vs the investigators choice of targeted tyrosine kinase inhibitor (TKI) for first-line treatment of advanced/metastatic clear-cell renal cell carcinoma. BEMPEG is a pegylated IL-2 prodrug, designed to preferentially bind to IL-2R beta gamma, mitigating adverse events associated with IL-2. Patients with advanced or metaststic clear-cell renal cell carcinoma (ccRCC) were randomized to the BEMPEG + NIVO arm (n=256) and TKI arm (n=258). Patients in the TKI arm received sunitinib or cabozantinib. At follow-up of a median of 15.5 months, the BEMPEG + NIVO arm showed a lower response rate than the TKI arm (23.0% vs 30.6%). Complete response was observed in 2.0% and 2.7% of patients, and progressive disease was observed in 29.7% and 13.6% of patients in the BEMPEG+NIVO and TKI arms, respectively. Median overall survival was 29.0 months for BEMPEG+NIVO and not reached for the TKI arm. In the subgroup of patients (n=51) with PD-L1-positive tumors (PD-L1 >= 1%), increased survival was associated with BEMPEG+NIVO over TKI. Treatment-related adverse events occurred in 26.8% of patients in the BEMPEG+NIVO arm, and 7.7% of patients discontinued treatment due to adverse events for BEMPEG or NIVO. Grade 5 TRAEs occurred in 1.0% of patients. The safety profile for BEMPEG+NIVO was consistent with previously reported findings. In comparison with TKI-therapy, BEMPEG+NIVO did not improve outcomes for patients with treatment-naïve advanced/metastatic clear cell RCC.
Antibody-drug conjugates combined with immune checkpoint blockade for urothelial cancer
LBA73. Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC)
Jonathan E. Rosenberg (Memorial Sloan Kettering Cancer Center, New York) presented results from Cohort K from study EV-103, which compared enfortumab vedotin (EV) monotherapy and EV + pembrolizumab (P) as first-line treatment for cisplatin-ineligible locally advanced or metastatic urothelial cancer (la/mUC). EV, a nectin-4-directed antibody-drug conjugate, and P have independently shown survival benefits as second- or third-line treatment of la/mUC, and preclinical studies indicate that checkpoint inhibitors may augment EV-mediated cell death. 149 cis-platin ineligible patients with la/mUC participated in the study. 76 were treated with EV+P, and 73 were treated with EV. Confirmed overall response rates were 64.5% with EV+P and 45.2% with EV. 97/1% of patients exhibited tumor response, and patient responses were seen as early as the first assessment at 9 weeks. There were no differences in response rates based on PD-L1 status. Median Duration of response was not reached for EV+P and 13.2 months for EV. Progression free survival (PFS) and overall survival (OS) data are ongoing and will likely change over time. At a median follow-up of 15 months, PFS could not be determined with EV+P and 8 months with EV. OSwas 22.3 months with EV+P and 21.7 months with EV. 94.6% of tumors from patients in the EV+P arm expressed Nectin-4, and response was seen across the spectrum of Nectin-4 expression levels. Treatment-related adverse events occurred in 63.2% of patients in the EV+P arm and 47.9% of patients in the EV arm. Skin reactions and peripheral neuropathy occurred more frequently in the E+P arm. EV+P shows a high response rate and a tolerable safety profile, and randomized trials of EV+P are ongoing. Data presented suggest EV+P as a potential option for first-line treatment of la/mUC in patients who are cis-platin ineligible.
Pembrolizumab + lenvatinib as first-line treatment for non-clear cell renal carcinoma
1448O. Phase 2 KEYNOTE-B61 Study of pembrolizumab (pembro) + lenvatinib (lenva) as first-line treatment for non-clear cell renal cell carcinoma (nccRCC)
Laurence Albiges (Institut Gustave-Roussy, Villejuif, Cedex, France) reported the first results of KEYNOTE-B61, a single-arm phase II study evaluating pembrolizumab (pembro )+ lenvatinib (lenva) as first-line treatment of non-clear cell renal cell carcinoma. This study builds upon results from KEYNOTE-581 and KEYNOTE-427, which showed first-line pembro + lenva improved outcomes for patients with clear cell RCC and first-line pembro showed anti-tumor activity for nccRCC, respectively. 147 patients with previously untreated advanced nccRCC participated in the study. Treatment efficacy was determined for 82 patients had been enrolled in the trial >= 24 weeks before the data cutoff. At a median follow-up of 8.2 months, confirmed ORR was 47.6%; 3 patients achieved complete response, and 36 exhibited partial responses. Disease control rate was 79.3%, and 86.5% of patients exhibited tumor shrinkage. Median duration of response, overall survival (OS), and progression free survival (PFS) have not been reached. The six-month PFS and OS rates were 72.3% and 87.8%, respectively. Response was seen across all histologic subtypes. No new safety signals were observed; treatment-related adverse events occurred in 86.4% of patients, and TRAEs >= grade 3 occurred in 34.7% of patients. Based on these preliminary results, pembro + lenva shows promising anti-tumor activity and manageable safety for patients with treatment-naïve advanced nccRCC, indicating its potential as first-line treatment for nccRCC. KEYNOTE-B61 is ongoing, and further follow-up data will be provided when available.
An immunotherapy doublet combined with a tyrosine kinase inhibitor for patients with renal cell carcinoma of intermediate or poor risk
LBA8. Phase 3 study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313)
Toni K. Choueiri (Dana-Farber Cancer Institute, Boston, MA) presented initial results from the COSMIC-313 phase III trial which evaluated safety and efficacy of cabozantinib (C) in combination with nivolumab + ipilimumab (N+I) vs. N+I in patients with previously untreated advanced renal cell carcinoma (aRCC) who were of IMDC intermediate or poor risk. C is a tyrosine kinase inhibitor (TKI) and has been shown to promote an immune-permissive environment and may enhance response to immune checkpoint inhibitors. 855 patients with previously untreated clear cell aRCC were randomized to C+N+I (n=428) or placebo+N+I (P+N+I; n=427). Progression free survival (PFS) was significantly improved with C+N+I compared to P+N+I (HR 0.73). Median PFS was not reached with C+N+I and was 11.3 months with P+N+I. Extended PFS was consistently observed in all patient subgroups analyzed and favored C+N+I. Overall Response Rate was 43% for C+N+I vs 36% for P+N+I. Three patients in each treatment arm achieved a complete response, and 8 and 20 patients in C+N+I and P+N+I, respectively, exhibited a partial response. In the C+N+I arm, 90% of patients experienced any type of tumor reduction, and 55% experienced a reduction >= 30%. Median duration of response was not yet reached for either group. When patients were subdivided into groups based on IMDC risk level, C+N+I improved PFS and ORR in patients with intermediate risk but not with poor risk. Treatment-related adverse events (TRAEs) occurred in 99% of patients in C+N+I (73% of grade 3 or 4) and 91% of patients with P+N+I (41% of grade 3 or 4). TRAEs led to discontinuation of all treatment in 12% of patients in the C+N+I arm vs 5% in the P+N+I arm. Cabozantinib in combination with nivolumab + ipilimumab provided significant gains in PFS, compared to placebo with nivolumab + ipilimumab, as first line treatment for patients with advanced clear cell renal cell carcinoma, especially in patients of intermediate IMDC risk. Improvement was also observed in ORR, and the safety profile was relatively manageable. The COSMIC-313 trial was the first of its kind to use an immunotherapy combination as the control standard of care. Follow-up for the secondary endpoint of overall survival is ongoing.
Comparing atezolizumab with chemotherapy for patients with NSCLC ineligible for a platinum doublet regimen
LBA11. IPSOS: Results from a Phase 3 study of first-line (1L) atezolizumab (atezo) vs single-agent chemotherapy (chemo) in patients (pts) with NSCLC not eligible for a platinum-containing regimen
Siow Ming Lee (University College London, United Kingdom) presented results from IPSOS, a randomized phase III study comparing atezolizumab (atezo) vs single-agent chemotherapy (chemo) for patients with non-small cell lung cancer (NSCLC) ineligible for first-line platinum doublet chemotherapy. 453 patients with advanced/metastatic NSCLC without driver mutations and were ineligible for platinum-double chemotherapy (ECOG performance status >= 2 and/or 70+ years of age with preexisting comorbidities) were randomized 2:1 to atezo (n=301) or chemo (vinorelbine or gemcitabine; n=151) treatment groups. At median follow-up of 41.0 months, overall survival (OS) was significantly improved with atezo compared to chemo (HR 0.78). OS of patient subgroups consistently improved with atezo compared to chemo, regardless of histology, ECOG performance status, or PD-L1 expression. The two-year overall survival rate was doubled with atezo compared to chemo (24.3% vs 12.4%), and overall response rate was also higher (15.6% vs 7.9%). 4 patients in the atezo arm and no patients in the chemo arm achieved a complete response. 20.2% of patients in the atezo arm went on to receive subsequent anti-cancer therapy, compared to 29.8% of patients in the chemo arm. 18.5% of patients in the chemo arm went on to receive checkpoint inhibitor immunotherapy as subsequent treatment. Grade 3 or 4 treatment related adverse events were observed in 16.3% of patients in the atezo arm and 33.3% of patients in the chemo arm. Adverse events led to discontinuation of treatment at similar rates, 13.0% for atezo vs 13.6% for chemo. Patients in the atezo arm were also more likely to self-report maintenance of quality of life compared to the chemo arm. IPSOS is the first study to show first-line treatment of NSCLC with atezolizumab improved overall survival in platinum-ineligible patients, potentially providing more treatment options for a traditionally poor-prognosis population.