Results from GDFATHER-1/2, the first in-human trial of visugromab, a GDF-15 neutralizing antibody
118O. Definitive results for NSCLC and bladder cancer cohorts in the phase 2a trial of visugromab (CTL-002) in advanced/metastatic anti-PD/PD-L1 relapsed/refractory solid tumors (GDFATHER-trial)
Ignacio Melero (University of Navarra, Pamplona, Spain) presented results for the non-small cell lung cancer (NSCLC) and bladder cancer cohorts of the GDFATHER-trial investigating visugromab/CTL-002, a GDF-15 neutralizing antibody in combination with nivolumab for patients with disease refractory to anti PD-(L)1 therapy. GDF-15, a tumor-derived immunosuppressant, is involved in feto-maternal tolerance and cancer-mediated immunosuppression and is correlated with poor prognosis in patients, as it blocks antitumoral immune response. Most patients had received two or three prior lines of therapy, and all patients had disease that was relapsed or refractory to prior anti-PD-(L)1 treatment. The dose escalation (phase I) phase of the trial included 25 patients, and the phase IIa included an expansion cohort of 149 patients. Among the total 174 patients, almost all treatment-related adverse events were of grade 1 or 2, but there was one treatment-related fatal adverse event (multi-organ failure). Treatment with visugromab and nivolumab was associated with increased density of CD4+ and CD8+ T cells and increased CD8+ T cell activation within the tumor microenvironment. High levels of circulating GDF-15 were correlated with some key immune-signatures indicating poor infiltration of T cells in the tumor and poor T cell function, especially in non-squamous NSCLC and bladder cancer, which were thus identified as key GDF-15 immunosuppressed tumors. Among the 27 patients with NSCLC, four exhibited partial responses (overall response rate [ORR] of 14.8%). Among 27 patients with bladder cancer, the ORR was also 14.8% and included one complete response (still ongoing after more than one year) and three partial responses. ORR associated with the combination of visogrumab with nivolumab was comparable to ORR observed among checkpoint inhibitor (CPI)-naïve patients receiving second-line CPI therapy, suggesting that visugromab reinvigorates and deepens CPI activity. Biomarker analysis indicated that baseline serum concentrations of GDF-15 were highly variable and circulating levels of GDF-15 negatively correlated with T cell infiltration of tumors, suggesting that GDF-15 plays a role in establishing an immunosuppressive tumor microenvironment. Results from the GDFATHER trial indicate that the combination of visogrumab with nivolumab is well-tolerated and exhibits promising anti-tumor activity. Several controlled trials of visogrumab combined with CPI and standard of care agents in major tumor types are being planned for the next year.
Primary results from LUMINANCE, a real-world study of durvalumab combined with platinum-etopiside for extensive-stage small cell lung cancer
LBA2. First-line (1L) durvalumab plus platinum-etoposide for patients with extensive-stage SCLC (ES-SCLC): Primary results from the Phase 3b LUMINANCE study
Niels Reinmuth (Asklepios Clinics Munich-Gauting, Gauting, Germany) presented primary analysis of LUMINANCE, phase IIIb study evaluating durvalumab with up to six cycles of platinum-etopiside (EP) for extensive-stage small cell lung cancer (ES-SCLC). The CASPIAN study of durvalumab with platinum-etoposide (D+EP) compared to EP alone for first-line treatment of ES-SCLC established D+EP as a global standard of care treatment option; however, some elements of the CASPIAN study design did not reflect real world clinical practice. The LUMINANCE study also included patients who received up to 6 cycles of EP and patients with a World Health Organization (WHO) performance status (PS) of 2. Among a total of 152 patients in LUMINANCE, 64.5% were male and only 5 had a WHO PS of 2. Grade 3 or higher adverse events of any cause occurred in 59.2% of patients, while immune-mediated events of any grade occurred in 13.8% of patients, with 3.3% of them being of grade 3 or 4. Adverse events of grade 3 or higher occurred in 66.7% of patients who received 1 to 4 cycles of EP, compared 52.9% of patients who received five or more cycles of EP, suggesting additional cycles of EP were reserved for patients who better tolerated earlier cycles. The confirmed overall response rate (ORR) was 65.8%, which included 4 of the 5 patients with WHO PS 2, and median duration of response (DoR) was 5.1 months. Median progression free survival (PFS) was 6.2 months, and median overall survival (OS) was 13.1 months. Patients who received 5 or 6 cycles of EP achieved slightly better outcomes than those receiving 4 cycles, but this may be due to the selection of a more fit population that was predicted to tolerate additional cycles. Although the small sample size of patients with WHO PS 2 prevents meaningful interpretation of those findings, the safety and efficacy data from LUMINANCE are consistent with those of the CASPIAN study, further supporting the use of durvalumab in combination with platinum-etoposide for first-line treatment of ES-SCLC.
Long term survival analyses from the POSEIDON study: durvalumab in combination with tremelimumab and chemotherapy for first-line treatment of metastatic non-small cell lung cancer
LBA3. Durvalumab (D) ± tremelimumab (T) + chemotherapy (CT) in first-line metastatic (m) NSCLC: 5-year overall survival (OS) update from the POSEIDON study
Solange Peters (University Hospital of Lausanne, Lausanne, Switzerland) presented long-term overall survival (OS) results from the POSEIDON study, which led to the approval of tremelimumab in combination with durvalumab and chemotherapy (T+D+CT) for first-line treatment of metastatic non-small cell lung cancer (mNSCLC). At a median follow-up of over five years, T+D+CT (n=338) showed sustained OS benefit, compared to CT alone (n=337; HR 0.76), with five-year OS rates of 15.7% and 6.8%, respectively. Benefits associated with T+D+CT compared to CT alone were mostly consistent in all patient subgroups, with the exception of never smokers. The OS benefit with T+D+CT compared to CT was more pronounced in patients with nonsquamous histology (NSQ) (HR 0.69) than in patients with squamous histology (SQ) (HR 0.85). 5-year OS rates in NSQ histology were 20.5% with D+T+CT vs 9.1% with CT, while 5-year OS rates in SQ histology were 7.3% with D+T+CT vs 2.9% with CT. The OS benefit with T+D+CT compared to CT was also observed regardless of the presence of mutations in STK11 (evaluated in patients with NSQ histology; HR 0.57) KEAP1 (evaluated in patients with NSQ and SQ histology; HR 0.43), or KRAS (evaluated in patients with NSQ histology; HR 0.55). No new safety signals were observed. These updated results support the approved regimen of T+D+CT for first-line treatment of mNSCLC. The upcoming phase III TRITON clinical trial will provide further analyses and insights regarding harder-to-treat mutational subgroups.
Addition of lenvatinib to first-line standard of care pembrolizumab and chemotherapy does not significantly improve survival in patients with metastatic nonsquamous non-small cell lung cancer
64O. Lenvatinib plus pembrolizumab, pemetrexed, and a platinum (len + pembro + chemo) as first-line therapy for metastatic nonsquamous non-small cell lung cancer (NSCLC): phase 3 LEAP-006 study
Roy S. Herbst (Yale School of Medicine, New Haven, CT, USA) reported results from LEAP-006, a phase III study comparing lenvatinib combined with pembrolizumab and chemotherapy of pemetrexed and carboplatin or cisplatin (len + pembro + CT) to placebo with pembrolizumab and chemotherapy of pemetrexed and carboplatin or cisplatin (pbo + pembro + CT) as first-line therapy for metastatic nonsquamous non-small cell lung cancer (NSCLC). The antiangiogenic tyrosine kinase inhibitor lenvatinib has been shown to shift the tumor microenvironment to an immune-stimulatory state and has exhibited anti-tumor activity in combination with CT or pembro. In the LEAP-006 trial, patients were randomized to len + pembro + CT (n=375) or to pbo + pembro + CT (n=373). At a median follow-up of 36.8 months, no overall survival (OS) benefit was observed with len + pembro + CT compared to pbo + pembro + CT (HR 1.05), with median OS 21.8 months and 22.1 months, respectively. No OS benefit was observed across patient subgroups. Median progression-free survival (PFS) was not significantly improved with len + pembro + CT: median PFS was 12.2 months with len + pembro + CT and 9.2 months with pbo + pembro + CT (HR 0.88). Overall response rate (ORR) and duration of response (DoR) were not significantly improved with len + pembro + CT compared to pbo + pembro + CT: ORR was 60.0% and 53.6% respectively, and median DoR was 15.8 months and 13.7 months. Treatment-related adverse events were grade 3 or higher in 69.7% of patients receiving len + pembro + CT and 55.6% of patients receiving pbo + pembro + CT. Adding lenvatinib to pembrolizumab and chemotherapy did not improve on the efficacy of pembrolizumab and chemotherapy alone as first-line therapy for stage IV nonsquamous NSCLC without targetable genetic alterations. The observed efficacy of pembrolizumab, pemetrexed and carboplatin/cisplatin was consistent with observed efficacy in the KEYNOTE-189 study, thus pembrolizumab combined with pemetrexed and carboplatin/cisplatin remains the standard of care for first-line treatment of patients with stage IV nonsquamous NSCLC without targetable genetic alterations. Trials of other kinase inhibitors in combination with immune checkpoint blockade and chemotherapy are ongoing.
The combination of lenvatinib and pembrolizumab compared to docetaxel does not significantly improve survival in patients with metastatic non-small cell lung cancer that progressed on a PD-(L)1 inhibitor and platinum-containing chemotherapy
65O. Phase 3 LEAP-008 study of lenvatinib plus pembrolizumab versus docetaxel for metastatic non-small cell lung cancer (NSCLC) that progressed on a PD-(L)1 inhibitor and platinum-containing chemotherapy
Natasha B. Leighl (Princess Margaret Cancer Centre, Toronto, Canada) presented final analysis of LEAP-008, a phase III study comparing lenvatinib with pembrolizumab (len + pembro), docetaxel (doce) alone, and lenvatinib (len) alone for metastatic non-small cell lung cancer (NSCLC) that progressed on a PD-(L)1 inhibitor and platinum-containing chemotherapy. Patients were randomized to len + pembro (n=185), doce (n=189) or len (n=48). At a median follow-up 31.8 months, len + pembro did not significantly improve overall survival (OS) compared to doce. Median OS was 11.3 and 12.0 months, respectively, and OS benefits associated with len + pembro were not observed in any patient subgroups. Progression-free survival (PFS) also was not significantly improved comparing len + pembro to doce (5.6 months vs. 4.2 months), and no significant PFS benefits with len + pembro were observed across patient subgroups. Overall response rates for len + pembro, doce, and len were 22.7%, 14.3%, and 12.5%, respectively. Median durations of response for len + pembro and doce were similar, at 6.9 months and 6.8 months respectively. 91.7% of patients receiving len + pembro experienced a treatment-related adverse event, with 59.7% of them being of grade 3-5, compared to a frequency of grade 3-5 treatment-related adverse events of 48.6% for doce and 57.4% for len. Lenvatinib in combination with pembrolizumab did not improve efficacy compared to docetaxel for stage IV NSCLC that progressed after prior anti-PD-(L)1 therapy and chemotherapy, and the observed safety profile aligned with previous studies of the combination in other advanced cancers. Results from this study underscore the high unmet need for more effective therapies for patients with stage IV NSCLC that progressed following prior anti-PD-(L)1 therapy and platinum-based chemotherapy.
Early metabolic response after TIL therapy may indicate prognosis of patients with advanced melanoma
66MO. Early complete metabolic response predicts long-term efficacy after adoptive cell therapy using tumor-infiltrating lymphocytes
Troels H. Borch (Copenhagen University Hospital, Herlev, Denmark) presented a study investigating whether early metabolic response to tumor-infiltrating lymphocyte (TIL) therapy, as assessed by FDG-PET scans, added prognostic information to conventional tumor response assessment by computed tomography scans. Although TIL therapy is associated with durable survival benefits for patients with advanced melanoma, it can be difficult to distinguish patients that will achieve temporary tumor control from those that will achieve long-term benefit. The study included 44 patients who received lymphodepletion followed by TIL therapy for advanced melanoma in phase I/II trials. Radiologic responses were assessed by RECIST criteria, and metabolic responses were assessed by PERCIST criteria. At the time of the second follow-up PET/CT scan, which was performed 12-16 weeks after TIL infusion, 1 patient achieved a complete response (CR) by RECIST criteria, but 7 patients achieved a complete metabolic response (CMR) by PERCIST criteria. At a median follow-up of 108 months, 6 of the 7 patients with a CMR were still alive, and CMR was associated with prolonged progression-free survival (PFS). Partial responses (PR) were observed in 14 patients, compared to 6 partial metabolic responses (PMR). Among the 14 patients who achieved a PR by RECIST criteria, the 6 patients who also had a CMR by PERCIST criteria had not reached a median PFS (mPFS) vs. 7.7 months among the 8 patients who did not achieve a CMR (non-CMR) (p = 0.0003). Median OS (mOS) was not reached among the 6 patients with a PR and CMR vs. 35.7 months in patients with a PR and non-CMR (p=0.034). Findings from this study indicate that early complete metabolic response is a strong predictor of long-term survival after TIL therapy for melanoma, and PERCIST may provide more accurate early prognostic information than RECIST. Although larger follow-up studies are needed to validate these findings, the data indicate that monitoring patient metabolic response after TIL therapy has the potential to inform patient-specific management and follow-up strategies.
Tumor-infiltrating lymphocytes as indicators of response to immune checkpoint blockade in patients with early triple negative breast cancer
163MO. Single-cell T cell dynamics induced by neoadjuvant nivolumab +/- ipilimumab in early triple negative breast cancer with tumor-infiltrating lymphocytes (BELLINI trial)
Olga I. Isaeva (The Netherlands Cancer Institute, Amsterdam, Netherlands) presented single-cell analyses from the BELLINI trial comparing preoperative nivolumab monotherapy with nivolumab in combination with ipilimumab for early-stage triple negative breast cancer (TNBC). Patients received a short course of preoperative nivolumab (n=16) or nivolumab in combination with ipilimumab (n=15). Each cohort included 5 patients with low levels of TILs (5-10%), 5 patients with intermediate levels of TILs (11-49%), and 5 patients with high levels of TILs (50% or higher). T cell populations within the patient tumors were characterized by single-cell RNA sequencing. The aim of this analysis was to investigate the differences in the tumor microenvironment (TME) and T cell receptor repertoire of responders and non-responders to anti-PD-1 therapy with or without anti-CTLA4 therapy in early TNBC. Analysis of patient pre-treatment tumor samples indicated that, compared to non-responders, tumors of responders contained significantly higher baseline levels of follicular helper T cells and tumor-specific CD8 T cells. After treatment, the TME of responders contained significantly higher levels of effector CD8 T cells and lower levels of regulatory T cells, compared to non-responders. When comparing the two treatment arms, tumors from patients treated with nivolumab contained significantly higher levels follicular helper T cells and regulatory T cells and significantly lower levels of naïve CD4 T cells compared to patients treated with nivolumab and ipilimumab. These data indicate that high levels of pre-existing TILs may be predictive of response to neoadjuvant immune checkpoint blockade for TNBC, while increased levels of regulatory T cells after treatment is associated with lack of response.
Stereotactic body radiotherapy prior to neoadjuvant immune checkpoint blockade for resectable hepatocellular carcinoma
LBA4. Low-dose stereotactic body radiotherapy prior to pre-operative cemiplimab for patients with resectable hepatocellular carcinoma
Thomas U. Marron (Icahn School of Medicine at Mount Sinai, New York, NY, United States of America) presented results from a single-arm phase II trial investigating the efficacy of low-dose stereotactic body radiotherapy (SBRT) prior to immune checkpoint inhibition with cemiplimab in patients with resectable hepatocellular carcinoma (HCC). This trial builds upon prior studies showing that the administration of immune checkpoint inhibitors (ICI) after concurrent chemoradiation is associated with survival benefits for patients with lung cancer as well as on small trials in locally advanced HCC showing that SBRT can induce immunogenic cell death and improve ICI activity. Furthermore, while surgery is the current standard of care for early resectable HCC, ICIs are the standard of care for advanced HCC, and a previous study of perioperative ICIs for resectable HCC showed over 50% necrosis in 35% of patients after two doses of cemiplimab. In this trial, 20 patients received SBRT (8 Gy x 3 fractions) followed by 2 cycles of neoadjuvant cemiplimab every three weeks before surgical resection followed by 8 cycles of adjuvant cemiplimab. No treatment-related adverse events (AE) of grade 3 or higher occurred during neoadjuvant therapy, no treatment-emergent or treatment-related AEs resulted in death, and there were no treatment-related adverse events that changed the surgical plan. Four patients completed neoadjuvant therapy but were removed from the trial prior to surgery, not due to toxicity. Of the 16 patients who underwent surgery, 2 patients achieved complete tumor necrosis (100%), 3 achieved significant tumor necrosis over 70%, and 6 achieved tumor necrosis of 50% or higher. Pathologic response rates were similar to those observed with cemiplimab alone. This was the first clinical trial to report clinical efficacy of SBRT in combination with immune checkpoint blockade in patients with resectable HCC, and tissue and blood analyses to characterize the effects of SBRT on anti-tumor immunity are ongoing.
Disease-free survival results for PEARLS/KEYNOTE-091: adjuvant pembrolizumab after complete resection and optional chemotherapy for early-stage non-small cell lung cancer
120MO. Adjuvant pembrolizumab versus placebo for early-stage NSCLC after resection and optional chemotherapy: Updated results from PEARLS/KEYNOTE-091
Benjamin Besse (Gustave Roussy, Villejuif, France) presented final disease-free survival (DFS) analysis of PEARLS/KEYNOTE-091, a phase III trial of adjuvant pembrolizumab for completely resected stage IB – IIIA non-small cell lung cancer (NSCLC) according to the AJCC 7th edition. Patients were randomized to receive adjuvant pembrolizumab (pembro, n=590) or placebo (pbo, n=587) after complete surgical resection and optional adjuvant chemotherapy. Previously reported results from the second interim analysis of PEARLS/KEYNOTE-091 indicated that pembro significantly improved disease-free survival (DFS) compared to placebo in the intent-to-treat (ITT) population, although no improvement was observed in the subpopulation of patients with PD-L1 TPS of 50% of more (PD-L1-high). These results led to the approval of pembrolizumab in the adjuvant setting following resection and platinum-based chemotherapy for stage IB – IIIA NSCLC. Median follow-up for this final DFS analysis was 51.7 months. DFS was significantly improved with pembro compared to pbo in the ITT population (HR 0.81, 95% CI, 0.68-0.96); however, the DFS was still not significantly improved in the PD-L1-high subpopulation (HR 0.83, 95% CI, 0.59-1.16; P=0.13). Four-year DFS rates with pembro and pbo were 52.4% and 45.7%, respectively, in the ITT population and 57.0% and 49.1%, respectively, in the PD-L1-high population. Among patients who received adjuvant chemotherapy, 4-year DFS rates were 52.5% with pembro and 44.7% with pbo (HR 0.80, 95% CI, 0.67-0.96). DFS benefits with pembro were also observed among patients with intermediate (TPS 1% - 49%) or low (TPS less than 1%) PD-L1 expression (HR 0.74 and 0.84, respectively), although the statistical significance was achieved only in the subgroup with PD-L1 1-49%. No new safety signals were observed. Grade 3-5 adverse events occurred in 34.1% of patients treated with pembro vs 25.8% of those who received pbo. 7.9% of patients in the pembro arm presented with immune-mediated adverse events of grade 3-5, compared to 1.9% of patients in the pbo arm. These results confirm the efficacy of adjuvant pembrolizumab in prolonging the disease-free survival patients with stage IB – IIIA (AJCC 7th edition) NSCLC following complete resection and adjuvant platinum-based chemotherapy.
Four-year analysis of C-144-01: Long-term efficacy of tumor-infiltrating lymphocyte cellular therapy for advanced melanoma
119O. Long-term efficacy and patterns of response of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: A 4-year analysis of the C-144-01 study
Martin Wermke (TU Dresden, Dresden, Germany) presented the 4-year analysis of C-144-01, a phase II study of lifleucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cellular therapy for advanced unresectable or metastatic melanoma who progressed on or after immune checkpoint inhibitors. Data from cohorts 2 and 4 were presented, representing 153 patients with malignant melanoma. Patients received nonmyeloablative lymphodepletion followed by a single lifleucel infusion and up to six doses of high-dose interleukin- (IL-) 2. The overall response rate, which had previously been reported, was 31.4% (N=48) in this heavily pretreated population. Mediation duration of response was not reached, and the longest patient response was ongoing at 55.8 months. Responders were more likely to have lower disease burden and less likely to have LDH levels above the limit of normal than non-responders, suggesting that lifleucel treatment at earlier disease stages may increase the likelihood of achieving clinical benefit. In addition, some responders had a late deeping of response, as three patients achieved a complete response after 18 months. The four-year estimated overall survival (OS) was 21.9%, and median OS was 13.9 months. Treatment-emergent adverse events (TEAEs) were consistent with known safety profiles of lymphodepletion and IL-2. Almost all TEAEs occurred within two to three weeks after infusion, and no long-term safety signals were observed. Data indicate that lifleucel is associated with favorable long-term survival outcomes, durable responses, and no long-term safety concerns, supporting the use of lifleucel as a potential treatment option for patients with advanced melanoma.
Combination of oncolytic adenovirus with tumor infiltration lymphocyte (TIL) therapy for metastatic melanoma
48O. Safety and efficacy of combined treatment with tumor infiltrating lymphocytes (TILs) and oncolytic adenovirus TILT-123 for patients with metastatic melanoma - Results from a phase I trial
Tine J. Monberg (Copenhagen University Hospital, Herlev, Denmark) reported the first results from a phase I 3+3 dose-escalation trial of TILT-123 (igrelimogene litadenorepvec), an oncolytic adenovirus armed with tumor necrosis factor-alpha and interleukin- (IL-) 2 in combination with tumor infiltrating lymphocyte (TIL) therapy. The rationale behind this combined treatment was that TILT-123 cytokine production would enhance T cell recruitment and cytotoxicity at the tumor, thus increasing TIL therapy efficacy, while eliminating the need for toxic pre- and post-conditioning. The safety of TILT-123 represented the primary endpoint of the study. The efficacy of TILT-123 was evaluated by both RECIST 1.1 and PET criteria, and represented a secondary endpoint. Patients with checkpoint inhibitor-refractory or recurrent unresectable stage III-IV melanoma received the first dose of TILT-123 intravenously and then five additional intratumoral doses over a period of 64 days. TIL therapy was administered during TILT-123 therapy as a one- or two-time treatment. Data from 16 patients with progressive cutaneous (n=7), mucosal (n=5), or uveal (n=4) metastatic melanoma were reported. No dose-limiting toxicities were observed; one patient experienced a grade 3-4 adverse event (AE) related to TILT-123, and 3 patients experienced grade 3-4 AEs related to TIL therapy. Disease control rate was 38% (n=6). Four patients achieved stable disease (SD), with one patient with uveal melanoma and one patient with cutaneous melanoma achieving long-lasting stable disease for over 10 months. One patient with mucosal melanoma has a durable complete response still ongoing after two years from treatment initiation, and one patient with cutaneous melanoma has a partial response ongoing for 7 months. Higher disease control was observed when using PET evaluations, with 7 of 14 (50%) evaluable patients exhibiting disease control 78 days after the first dose of TILT-123. The data suggest that the combination of oncolytic virus TILT-123 and TIL therapy is safe and feasible for patients with metastatic melanoma and that this combined treatment has potential to treat hard-to-treat melanoma subtypes.