Background

Aldesleukin (IL-2), at high doses in repeat cycles, is approved as monotherapy for patients (pts) with metastatic melanoma. Its limited efficacy is mediated through endogenous T cell activation, which also contributes to considerable toxicity (Rosenberg NEJM 1988). Lifileucel, a one-time investigational TIL cell therapy, showed a 31% IRC-assessed objective response rate (ORR) in 153 pts with advanced melanoma who progressed after immune checkpoint inhibitors and targeted therapy (if BRAF mutation positive) in the Phase 2 C-144-01 trial (Sarnaik SITC 2022) using abbreviated high-dose IL-2 (≤6 doses) with 79% lower potential maximum cumulative exposure than monotherapy. Prior studies found no association between IL-2 dosing and TIL cell therapy efficacy (Goff JCO 2016, Seitter CCR 2021). This post hoc analysis explores the association between number of IL-2 doses and clinical outcomes of lifileucel.

Methods

Pts with advanced melanoma received cyclophosphamide and fludarabine (NMA-LD, Day –7 to –1), a single lifileucel infusion (Day 0), and ≤6 IL-2 doses (600,000 IU/kg) every 8–12 h (Day 0–4). Per protocol, IL-2 was discontinued based on physiologic tolerance. The association between number of IL-2 doses administered and ORR (RECIST v1.1 per IRC) and duration of response (DOR) was explored.

Results

In 153 pts who received lifileucel, median number of IL-2 doses was 6 (1–2 doses: n=16; 3–4 doses: n=26; 5–6 doses: n=109; 2 pts did not receive IL-2). All pts developed G3/4 lymphopenia (per lab values) after NMA-LD (Day 0–4). ORR to lifileucel was 38%, 31%, and 31% in pts receiving 1–2, 3–4, and 5–6 doses, respectively (p=0.87); 67%, 75%, and 47% of responders had DOR ≥12 mo (Cox regression p=0.39). ORR was 40% in 5 pts who progressed after prior high-dose IL-2 monotherapy.

Conclusions

Lifileucel ORR and DOR were not associated with number of IL-2 doses administered. Pts with disease refractory to prior IL-2 monotherapy derived benefit from lifileucel. Presence of G3/4 lymphopenia in all pts at time of IL-2 administration argues against a direct antineoplastic effect of abbreviated IL-2 dosing as part of the lifileucel regimen.

Clinical trial identification

Clinicaltrials.gov; NCT02360579

Editorial acknowledgement

Medical writing support was provided by Jayasri Srinivasan and Swati Ghatpande of Second City Science, a Vaniam Group Company.

Background

Development of novel treatment options is essential for patients with metastatic melanoma (MM), as about half derive no durable benefit upon first-line treatment. Adoptive cell therapy with TIL has shown encouraging results in a recently completed multicenter phase 3 trial evaluating TIL in MM patients (NCT02278887); 39 (49%) patients showed a response (complete or partial) and 2 (3%) patients were not evaluable for response. Resection of a melanoma lesion (≥2-3cm) was required for the ex vivo outgrowth and expansion of TIL. However, the impact of location and size of metastasectomy used for TIL production on response is yet unknown.

Methods

Location and size of metastasectomy used for TIL production in relation to clinical response were evaluated in patients with unresectable stage IIIC-IV MM treated with TIL in a recently completed phase 3 trial. Regression analyses and corresponding Likelihood Ratio- and F-tests were performed to test statistical significance.

Results

Manufacturing of TIL was successful in 82/83 (98.8%) patients for whom production was started. In total, 80 patients were treated with a median number of 40.9x10⁹ TIL (range 4.9 – 110.4), of which 36 (45%), 34 (42.5%) and 10 (12.5%) underwent resection of a lymph node, (sub)cutaneous or visceral metastasis for TIL manufacturing, respectively. Visceral metastases included lung (n=6), liver (n=1), adrenal gland (n=1), small intestine (n=1) and spleen (n=1). Median time from randomization to metastasectomy was 10.3 days (range -14.5 – 22.5). In 10 (12.5%) patients, a second metastasectomy was performed due to initial insufficient TIL outgrowth. Location of metastasectomy had no influence on clinical response (p=0.949) or on the number of cells produced (p=0.540). In 50 (62.5%) patients 1 lesion of ≥ 2-3cm and in 30 (37.5%) patients >1 lesion was resected to obtain the required ≥ 2-3cm, with no differences in resulting cell numbers (p=0.115).

Conclusions

A high success rate of TIL manufacturing was observed for MM patients treated with TIL in a recently completed multicenter phase 3 trial. Location and size of metastasectomy had no impact on clinical response or cell numbers, making TIL a robust treatment option.

Clinical trial identification

NCT02278887

Background

Penpulimab is a novel humanized IgG1 mAb that blocks PD-1 binding to PD-L1, engineered to eliminate FcγR binding and ADCC/ADCP completely.

Methods

AK105-302 is a 1:1 randomized, double-blind, placebo-controlled, multicenter, phase III trial to compare penpulimab or placebo plus carboplatin and paclitaxel as first-line treatment for locally advanced or metastatic squamous NSCLC. The stratification factors included PD-L1 and gender. Eligible pts were randomized 1:1 to receive penpulimab 200 mg or placebo plus chemotherapy every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy until disease progression or 24 months, subjects in placebo group may choose to cross over to open-label penpulimab monotherapy for up to 24 months. The primary endpoints were PFS in the ITT population and in the PD-L1 positive population (TPS of PD-L1≥1%), assessed by an IRRC. The secondary endpoints were OS, ORR, DoR, DCR and TTR.

Results

175 pts were assigned to penpulimab plus chemotherapy (P+C) and 175 to placebo plus chemotherapy (C). At data cutoff (Jun 1, 2022), the median follow-up was 23.56m. The mPFS by IRRC was significantly longer with P+C than with C (7.6m vs. 4.2m; HR 0.44, 95%CI: 0.34-0.56; p < 0.0001), 12m-PFS rate (37.1% vs. 9.2%) and 24m-PFS rate (23.8% vs. 5.9%) were significantly higher in P+C than C. In the PD-L1 positive population, the mPFS by IRRC was also significantly longer with P+C than with C (8.1m vs. 4.2m; HR 0.37, 95%CI: 0.27-0.51; p < 0.0001). The mOS of P+C was not reached, but the benefit trend was obvious (NR vs. 19.8m; HR 0.55, 95%CI: 0.40-0.75; p = 0.0002), 24m-OS rate (61.1% vs. 41.6%) were significantly higher in P+C than C. ORR by IRRC was 71.4% in P+C and 44.0% in C. Treatment with P+C was associated with more durable response (mDoR by IRRC: 8.25m vs 2.96m) than C. Grade ≥3 TRAEs occurred in 63.6% (P+C) vs. 62.9% (C). Serious TRAEs occurred in 28.3% (P+C) vs. 26.9% (C). TRAEs led to treatment discontinuation were 5.2% in P+C and 3.4% in C.

Conclusions

These positive data will support penpulimab plus chemotherapy may be a promising and safe first-line treatment for locally advanced or metastatic squamous NSCLC.

Clinical trial identification

NCT03866993

Background

Cemi (anti-PD-1) used as monotherapy has been shown to improve overall survival (OS) vs chemo in patients (pts) with advanced NSCLC, no EGFR, ALK or ROS1 aberrations, and PD-L1 expression in ≥50% of tumor cells. Since the benefit of PD-(L)1 blockade decreases with decreased PD-L1 expression, combination therapies are required for tumors with low PD-L1. Both chemotherapy and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have been shown to augment the effects of anti–PD-1 in pts with advanced NSCLC. The addition of a reduced course of chemo and CTLA-4 to anti-PD1 could provide an additional benefit in pts with PD-L1 expression <50%.

Methods

In EMPOWER-Lung 3 part 1, 323 pts with PD-L1 expression of <50% were randomized (1:1:1) to: standard platinum-based doublet chemo for 4 cycles (StC), cemi 350 mg once every 3 weeks (Q3W) for up to 108 weeks + standard chemo, or cemi 350 mg Q3W for up to 108 weeks + reduced chemo for 2 cycles + ipi 50 mg Q6W for up to 4 cycles (CIC). The primary endpoint was OS. Secondary endpoints included progression free survival (PFS), objective response rate (ORR), patient-reported outcomes, and safety. Part 1 was stopped early due to reprioritization to standard chemo+cemi for NSCLC pts regardless of PD-L1 expression and only descriptive statistical analyses were done.

Results

49% of pts in each group had <1% expression of PD-L1. At a median (med) follow-up of 35.5 months (m), med OS was 20.1m (13.7, 28.3) for CIC pts (N=109) vs 13.9 (10.0, 17.7) for StC pts (N=106), with a hazard ratio (HR) of 0.615 (95% confidence interval, 0.441, 0.857). Med PFS was 6.4m vs 6.3m with HR of 0.813 (0.596, 1.108). ORR was 35.8% and 28.3% for CIC and StC, respectively. Med duration of response was 15.9m vs 6.3m. Safety profile was generally consistent with the known safety profile for cemi, chemo, and ipi. Grade ≥3 treatment emergent adverse events (TEAEs) were observed in 43.1% of CIC pts and 42.7% of StC pts, TEAEs resulting in discontinuation of study treatment or death observed in 4.6% vs 0%, and in 4.6% vs 4.9%, of CIC and StC pts respectively.

Conclusions

In this descriptive analysis, the addition of cemi and ipi to a reduced course of chemo led to a meaningful OS benefit in pts with PD-L1 <50%.

Clinical trial identification

NCT03409614

Editorial acknowledgement

Medical writing support was provided by Osnat Ben-Shahar PhD of Regeneron Pharmaceuticals, Inc.

Background

This study evaluated the real-world outcomes among patients (pts) with squamous (SQ) or non-squamous cell (NSQ) advanced non-small cell lung cancer (aNSCLC) receiving either first-line (1L) immuno-oncology (IO) monotherapy or IO in combination with chemotherapy (IO+CT).

Methods

Eligible pts (age ≥18 years) were identified from the Flatiron Health database (January 2011 - March 2022) with confirmed aNSCLC (Stage III−IV) who received either 1L IO monotherapy or IO+CT on or after January 1, 2016. Pts with EGFR/ALK tumor mutations and pts with unknown histology were excluded. Overall survival (OS) and real-world progression-free survival (rwPFS) were estimated using Kaplan-Meier methods for the IO monotherapy and IO+CT cohorts. Analyses were also conducted by histology and tumor programmed death ligand 1 (PD-L1) subgroups.

Results

A total of 11,445 pts were identified, among which 4,354 (38%) received IO monotherapy and 7,091 (62%) received IO+CT. Among pts receiving IO monotherapy, median OS was 14.2 and 11.1 months for NSQ and SQ aNSCLC, respectively. Among pts receiving IO+CT, median OS was 12.1 months (NSQ) and 10.5 months (SQ). Median rwPFS was 4.7 months for pts receiving IO monotherapy, and was 5.6 months for pts receiving IO+CT. Table 1 reports the OS and rwPFS results by histology and PD-L1 subgroups. Median OS and rwPFS were lowest in the tumor PD-L1 <1% subgroup among pts treated with IO+CT regardless of histology as well as among SQ pts receiving IO monotherapy.

Table 1. Survival outcomes for patients with SQ and NSQ aNSCLC receiving IO or IO+CT

Conclusions

The real-world survival estimates were generally lower than those reported in pivotal trials and it further affirms the unmet need among patients with aNSCLC, especially among those with low PD-L1 expression levels.

Background

Atezo (anti–PD-L1) IV is approved in NSCLC, SCLC, triple-negative breast cancer, hepatocellular carcinoma, urothelial carcinoma and unresectable/metastatic melanoma. To reduce treatment burden and improve convenience and efficiencies in healthcare, a novel fixed-dose atezo SC co-formulated with recombinant human hyaluronidase is being developed. We report Part 2 (Phase III) of the open-label, randomized, multicentre IMscin001 study (NCT03735121) to investigate non-inferiority of drug exposure at Cycle 1 after atezo SC vs IV administration in NSCLC.

Methods

Adults with previously treated locally advanced/metastatic NSCLC (no prior cancer immunotherapy) and ECOG PS 0 or 1 were randomised 2:1 to receive 2L atezo SC (1875 mg) or IV (1200 mg) every 3 weeks. Primary endpoints: non-inferiority for Cycle 1 observed serum C_trough and model-predicted AUC_{0-21 days}; secondary endpoints: steady-state PK, safety, efficacy (PFS, ORR), patient-reported outcomes, immunogenicity.

Results

There were 247 and 124 patients in the atezo SC and IV arms, respectively (median follow-up: 4.6 mo; data cut-off: 26 Apr 2022). Median age was 64.0 years (range 27–85), 69% were male and 74% had ECOG PS 1. The lower bounds of the 90% CI of the geometric mean ratios (GMRs) for C_trough (GMR 1.05 [90% CI: 0.88, 1.24]) and AUC (GMR 0.87 [90% CI: 0.83, 0.92]) were above the predefined non-inferiority margin of 0.8. Efficacy, immunogenicity and safety were similar between arms (table).

Conclusions

Atezo SC demonstrated non-inferior exposure vs IV for both co-primary PK endpoints. Efficacy and safety were similar between arms and consistent with the known atezo IV profile; atezo immunogenicity was comparable between arms and within the historical range for atezo IV across indications. These results support atezo SC as an alternative to IV.

Clinical trial identification

NCT03735121

Editorial acknowledgement

Research support for third-party writing assistance for this abstract, furnished by Marcia Gamboa, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.