Summary
KN046, a bispecific antibody targeting PD-L1 and CTLA-4, presents a promising therapeutic option for metastatic non-small cell lung cancer (NSCLC). In this multicenter phase 2 trial, patients with nonsquamous (non-sq) NSCLC receive pemetrexed, whereas those with sq-NSCLC receive paclitaxel, plus KN046 and carboplatin. Following four cycles, maintenance therapy includes KN046 with pemetrexed for non-sq-NSCLC and KN046 for sq-NSCLC. The objective response rate is 46.0%, and the median duration of response is 8.1 months. The median progression-free and overall survival are 5.8 and 26.6 months, respectively. The common adverse events include anemia (87.4%), loss of appetite (72.4%), and neutropenia (70.1%). The most prevalent immune-related adverse event is pruritus (28.7%). These findings indicate that first-line treatment with KN046 and chemotherapy is effective and tolerable in metastatic NSCLC patients, warranting further investigation in a larger phase 3 trial. The trial is registered at ClinicalTrials.gov (NCT04054531).
Keywords: KN046, bispecific antibody, programmed cell death-ligand 1, cytotoxic T lymphocyte-associated antigen-4, chemotherapy, first-line, non-small cell lung cancer
Graphical abstract
Highlights
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KN046 is a bispecific antibody targeting PD-L1 and CTLA-4
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First-line KN046 plus chemotherapy shows promise in metastatic NSCLC
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The treatment regimen is well tolerated, with manageable side effects
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A large-scale randomized phase 3 trial is ongoing to verify these findings
Zhao et al. reveal that KN046, targeting PD-L1 and CTLA-4, combined with chemotherapy, shows notable efficacy in first-line treatment of metastatic NSCLC with manageable side effects. A phase 3 trial is underway to confirm these results.
Introduction
Lung cancer is the second most commonly diagnosed malignancy, with the highest mortality rate worldwide,1 and non-small cell lung cancer (NSCLC) accounts for 80%–90%.2 Phase 3 trials have proven that programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors combined with chemotherapy can increase median overall survival (OS) by 4.7–11.9 months compared with platinum-based chemotherapy alone in advanced NSCLC patients3,4,5,6,7,8 and has become the standard first-line treatment for patients with metastatic NSCLC as recommended by the National Comprehensive Cancer Network guidelines.9 However, a certain proportion of patients shows poor response. It is necessary to explore new combination therapies in metastatic NSCLC.
Considering the potential synergism of PD-1/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors,10 dual immunotherapy is being investigated. The CheckMate 227 trial Part 1, CheckMate 9LA, and POSEIDON trials confirmed the superiority of PD-1 (PD-L1) inhibitor plus CTLA-4 inhibitor with or without chemotherapy over chemotherapy alone in patients with advanced NSCLC.11,12,13,14 However, such drug combinations are more expensive and associated with greater side effects compared with single-agent immunotherapies.
Bispecific antibodies (bsAbs) can block two inhibitory immune checkpoints by bridging T cells and tumor cells or binding two molecules on the surface of the same T cell. KN046 is a recombinant humanized bsAb, comprising two identical strands. Each strand of KN046 consists of one PD-L1 single domain antibody (dAb), one CTLA-4 dAb, and one Fc domain. These three domains are fused in tandem. The dAb is derived from a humanized camel heavy-chain Ab, and the Fc region belongs to the wild-type immunoglobulin G1 subclass. It simultaneously binds to PD-L1 and CTLA-4, blocking the binding of PD-L1 to PD-1 and CTLA-4 to CD80/CD86.15 KN046 binds PD-L1 stronger than CTLA-4 and exerts stronger inhibitory effects on tumors with high PD-L1 expression.16,17 KN046 blocks both the CD80/CD86 and PD-1 signaling pathways in a single molecular structure, potentially improving spatial correlation and therapeutic efficacy. Preclinical studies also demonstrated reduced CTLA-4 affinity, suggesting a favorable safety profile.15 Moreover, its innovative design, featuring a lower molecular weight derived from humanized camel heavy-chain Abs, may enhance penetration into the tumor microenvironment.15 This dual-target approach, evidenced by increased interleukin-2 production compared to separate or combined anti-PD-L1 and anti-CTLA4 therapies, positions KN046 as a promising candidate in cancer immunotherapy, potentially offering a superior alternative to conventional monoclonal Ab therapies. The first-in-human study and the phase 1 trial showed that KN046 was safe and effective in patients with advanced solid tumors.18,19
This study aimed to evaluate the antitumor activity, safety, and tolerability of first-line KN046 combined with chemotherapy in patients with metastatic NSCLC.
Results
Patients and treatment
Between September 2019 and October 2020, 119 patients were screened and 87 were enrolled, including 51 in the non-sq-NSCLC cohort and 36 in the sq-NSCLC cohort. As of March 15, 2022, 28 patients in the non-sq-NSCLC cohort and 17 in the sq-NSCLC cohort were still in this trial, including 8 patients with non-sq-NSCLC and 6 with sq-NSCLC still receiving KN046, respectively (Figure 1). Baseline characteristics are presented in Table 1. Of the 87 patients, the median age was 61.0 (range, 32–76) years and 75.9% were males. A total of 35 patients (40.2%) were never smokers, 14 patients (16.1%) were current smokers, and 38 patients (43.7%) were former smokers. Fifteen (17.2%) patients had brain metastases and 11 (12.6%) had liver metastases. Thirty-seven (42.5%) patients had PD-L1− tumors (<1%).
Figure 1.
Study flowchart
∗One patient with non-sq- NSCLC discontinued the study treatment and started new antitumor therapy voluntarily without documented disease progression. PD, progressive disease.
Table 1.
Baseline patient characteristics
| Characteristic, median (range)/n (%) | Non-sq-NSCLC (n = 51) | sq-NSCLC (n = 36) | All (n = 87) |
|---|---|---|---|
| Age, years | 59.0 (41–74) | 64.5 (32–76) | 61.0 (32–76) |
| Gender | |||
| Male | 34 (66.7) | 32 (88.9) | 66 (75.9) |
| Female | 17 (33.3) | 4 (11.1) | 21 (24.1) |
| ECOG performance status | |||
| 0 | 11 (21.6) | 4 (11.1) | 15 (17.2) |
| 1 | 40 (78.4) | 32 (88.9) | 72 (82.8) |
| Smoking | |||
| Never | 24 (47.1) | 11 (30.6) | 35 (40.2) |
| Current smoker | 12 (23.5) | 2 (5.6) | 14 (16.1) |
| Former smoker | 15 (29.4) | 23 (63.9) | 38 (43.7) |
| Brain metastases | 13 (25.5) | 2 (5.6) | 15 (17.2) |
| Liver metastases | 4 (7.8) | 7 (19.4) | 11 (12.6) |
| PD-L1 (TPS) | |||
| <1% | 18 (35.3) | 19 (52.8) | 37 (42.5) |
| 1%–49% | 22 (43.1) | 9 (25.0) | 31 (35.6) |
| ≥50% | 8 (15.7) | 7 (19.4) | 15 (17.2) |
| Missing | 3 (5.9) | 1 (2.8) | 4 (4.6) |
| No. of tumor lesions | |||
| 1 | 1 (2.0) | 1 (2.8) | 2 (2.3) |
| 2 | 2 (3.9) | 4 (11.1) | 6 (6.9) |
| ≥3 | 48 (94.1) | 31 (86.1) | 79 (90.8) |
| Prior antitumor therapy | |||
| Yes | 4 (7.8) | 6 (16.7) | 10 (11.5) |
| Surgery | 4 (7.8) | 2 (5.6) | 6 (6.9) |
| Radiotherapy | 1 (2.0) | 4 (11.1) | 5 (5.7) |
| Chemotherapy | 0 | 5 (13.9) | 5 (5.7) |
| None | 47 (92.2) | 30 (83.3) | 77 (88.5) |
ECOG, Eastern Cooperative Oncology Group.
Among 56 (64.4%) patients with disease progression, 45 (51.7%) received subsequent antitumor therapies, including chemotherapy (35 [40.2%]), targeted therapy (31 [35.6%]), immunotherapy (19 [21.8%]), and traditional Chinese medicine (4 [4.6%]).
Efficacy
As of March 15, 2022, the median follow-up time was 23.1 (range, 0.39–29.83) months. Investigator-assessed best changes in tumor volume from baseline are presented in Figure 2A and the spider plots of change in tumor burden from baseline are presented in Figure S1. The tumor responses of each patient are presented in Figure S2. In the overall population, the confirmed objective response rate (ORR), clinical benefit rate (CBR), and median duration of response (DOR) were 46.0% (95% confidence interval [CI]: 35.2%–57.0%), 56.3% (95% CI: 45.3%–66.9%), and 8.1 (95% CI: 4.14–13.90) months, respectively (Table 2). The median progression-free survival (PFS) was 5.8 (95% CI: 5.26–7.10) months, and the 6- and 12-month PFS rates were 48.0% (95% CI: 36.64%–58.42%) and 25.7% (95% CI: 16.41%–36.04%), respectively. Median OS was 26.6 (95% CI: 16.92-not reached [NR]) months, and the 12-month OS rate was 74.2% (95% CI: 63.46%–82.18%).
Figure 2.
Tumor response assessment and Kaplan-Meier plots of PFS and OS based on PD-L1 expression
(A) Best changes in tumor volume from baseline as assessed by the investigators according to RECIST 1.1. (The dashed line represents the optimal percentage of tumor change from baseline was 30%.)
(B) ORR based on PD-L1 expression. （CI, confidence interval.）
(C) PFS based on PD-L1 expression. (Kaplan-Meier analysis was used for PFS, and COX regression model was used for HR, HR confidence interval, and p value, with TC < 1% as reference.) (The dashed line represents the median PFS time.)
(D) OS based on PD-L1 expression. TC, PD-L1 expression in tumor cells, assessed through immunohistochemistry. The tumor proportion score (TPS), representing the percentage of PD-L1+ tumor cells out of total viable tumor cells, categorizes samples as TC<1% (TPS less than 1%) and TC≥1% (TPS 1% or higher). (Kaplan-Meier analysis was used for OS, and COX regression model was used for HR, HR confidence interval, and p value, with TC < 1% as reference.) (The dashed line represents the median OS time.)
Table 2.
Efficacy endpoints
| Endpoint | Non-sq-NSCLC (n = 51) | sq-NSCLC (n = 36) | All (n = 87) |
|---|---|---|---|
| Best overall response, n (%) | |||
| CR | 0 | 0 | 0 |
| PR | 22 (43.1) | 18 (50.0) | 40 (46.0) |
| SD | 21 (41.2) | 11 (30.6) | 32 (36.8) |
| PD | 5 (9.8) | 5 (13.9) | 10 (11.5) |
| Unknown | 3 (5.9) | 2 (5.6) | 5 (5.7) |
| ORR, % (95% CI) | 43.1 (29.3–57.8) | 50.0 (32.9–67.1) | 46.0 (35.2–57.0) |
| CBR, % (95% CI) | 52.9 (38.5–67.1) | 61.1 (43.5–76.9) | 56.3 (45.3–66.9) |
| DOR, median (95% CI), mo | 9.7 (4.01–20.73) | 7.3 (3.52-NR) | 8.1 (4.14–13.90) |
| PFS, median (95% CI), mo | 5.8 (4.80–7.16) | 5.7 (4.17–8.71) | 5.8 (5.26–7.10) |
| OS, median (95% CI), mo | 27.2 (15.18-NR) | 26.6 (12.19-NR) | 26.6 (16.92-NR) |
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
The confirmed ORR and CBR were 43.1% and 52.9% in the non-sq-NSCLC cohort, and 50.0% and 61.1% in the sq-NSCLC cohort. The median DOR was 9.7 (95% CI: 4.01–20.73) months in the non-sq-NSCLC cohort and 7.3 (95% CI: 3.52-NR) months in the sq-NSCLC cohort (Table 2). The median PFS was 5.8 (95% CI: 4.80–7.16) months in the non-sq-NSCLC cohort and 5.7 (95% CI: 4.17–8.71) months in the sq-NSCLC cohort. There were 24 and 17 OS events in the non-sq-NSCLC and sq-NSCLC cohorts, respectively. The median OS was 27.2 (95% CI: 15.18-NR) months in the non-sq-NSCLC cohort and 26.6 (95% CI: 12.19-NR) months in the sq-NSCLC cohort (Table 2; Figure S3).
In the overall population, patients with positive PD-L1 expression (≥1%) had numerically higher ORR (50.0% [23/46] vs. 37.8% [14/37]), longer OS (median, NR vs. 15.2 months), and longer PFS (median 6.3 vs. 4.8 months) compared with those with negative PD-L1 expression (Figures 2B–2D). The benefit trend was more obvious in the sq-NSCLC cohort (Figures 2B and S4).
In general, patients without brain metastases at baseline (72; 38 with non-sq-NSCLC and 34 with sq-NSCLC) had better ORR (47.2% vs. 40.0%), median PFS (5.9 vs. 4.9 months), and OS (26.6 vs. 14.8 months) compared with those with brain metastases at baseline (15; 13 with non-sq-NSCLC and 2 with sq-NSCLC). Given the limited sample size, these data should be interpreted with caution.
Safety
The median duration of treatment was 23.0 (range, 1.7–129.7) weeks for KN046 and 23.71 (range, 3.0–129.7) weeks for pemetrexed (in the non-sq-NSCLC cohort). The safety data are summarized in Table 3. Treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) occurred in all 87 patients. Grade ≥3 TEAEs, serious TEAEs, and grade ≥3 serious TEAEs occurred in 63 (72.4%), 35 (40.2%), and 33 (37.9%) patients, respectively. Grade ≥3 TRAEs and serious TRAEs occurred in 58 (66.7%) and 27 (31.0%) patients, respectively. The most common TRAEs were anemia (76 [87.4%]), loss of appetite (63 [72.4%]), neutropenia (61 [70.1%]), leukopenia (59 [67.8%]), and thrombocytopenia (49 [56.3%]).
Table 3.
Safety signals in the 87 patients
| Adverse event, n (%) | Any grade | Grade ≥3 |
|---|---|---|
| Overview of AEs | ||
| TEAEs | 87 (100) | 63 (72.4) |
| Serious TEAEs | 35 (40.2) | 33 (37.9) |
| TRAEs | 87 (100) | 58 (66.7) |
| Serious TRAEs | 27 (31.0) | 26 (29.9) |
| irAEs | 50 (57.5) | 11 (12.6) |
| Serious irAEs | 9 (10.3) | – |
| TEAEs leading to dose adjustment | 11 (12.6) | – |
| TEAEs leading to delayed dosing | 28 (32.2) | – |
| TEAEs leading to temporary discontinuation | 51 (58.6) | – |
| TEAEs leading to permanent discontinuation | 17 (19.5) | – |
| TEAEs leading to death | 6 (6.9) | 6 (6.9) |
| TRAEs leading to death | 4 (4.6) | 4 (4.6) |
| TRAEs occurring in >20% of patients | ||
| Anemia | 76 (87.4) | 17 (19.5) |
| Loss of appetite | 63 (72.4) | 1 (1.1) |
| Neutropenia | 61 (70.1) | 31 (35.6) |
| Leukopenia | 59 (67.8) | 22 (25.3) |
| Thrombocytopenia | 49 (56.3) | 17 (19.5) |
| Infusion-related reactions | 48 (55.2) | 3 (3.4) |
| Pruritus | 48 (55.2) | 0 |
| Nausea | 47 (54.0) | 1 (1.1) |
| Elevated ALT | 46 (52.9) | 5 (5.7) |
| Elevated AST | 45 (51.7) | 2 (2.3) |
| Hypoalbuminemia | 45 (51.7) | 1 (1.1) |
| Hypoesthesia | 38 (43.7) | 0 |
| Rash | 34 (39.1) | 3 (3.4) |
| Diarrhea | 32 (36.8) | 8 (9.2) |
| Constipation | 31 (35.6) | 0 |
| Hypocalcemia | 28 (32.2) | 2 (2.3) |
| Hyponatremia | 26 (29.9) | 0 |
| Oral mucositis | 26 (29.9) | 0 |
| Peripheral edema | 23 (26.4) | 1 (1.1) |
| Weakness | 22 (25.3) | 0 |
| Fever | 21 (24.1) | 1 (1.1) |
| Hypothyroidism | 21 (24.1) | 0 |
| Hypochloremia | 20 (23.0) | 0 |
| Hypokalemia | 19 (21.8) | 2 (2.3) |
| Alopecia | 19 (21.8) | 0 |
KN046-related AEs were detected in 83 (95.4%) patients, including grade ≥3 KN046-related AEs in 30 (34.5%) cases. The most common (>10%) KN046-related AEs were infusion-related reactions (IRRs) (46 [52.9%]), pruritus (39 [44.8%]), rash (33 [37.9%]), elevated aspartate aminotransferase (AST; 30 [34.5%]), elevated ALT (25 [28.7%]), fever (17 [19.5%]), loss of appetite (14 [16.1%]), diarrhea (12 [13.8%]), hypothyroidism (10 [11.5%]), and hypoalbuminemia (9 [10.3%]). KN046-related serious AEs occurred in 19 (21.8%) patients, mostly including diarrhea (4 [4.6%]), immune-mediated lung diseases (3 [3.4%]), fever (3 [3.4%]), and elevated ALT (3 [3.4%]).
In this study, immune-related AEs (irAEs), grade ≥3 irAEs, and serious irAEs were reported in 50 (57.5%), 11 (12.6%), and 9 (10.3%) patients, respectively. The most common (>10%) irAEs were pruritus (25 [28.7%]), elevated AST (21 [24.1%]), rash (19 [21.8%]), elevated ALT (13 [14.9%]), and hypothyroidism (9 [10.3%]). The most common grade ≥3 irAEs were diarrhea (3 [3.4%]), allergic dermatitis (2 [2.3%]), rash (2 [2.3%]), and immune-mediated lung diseases (2 [2.3%]).
Seventeen (19.5%) patients permanently discontinued the treatment owing to TEAEs. Treatment-related deaths occurred in 4 (4.6%) patients. Among them, one case of immune-related pneumonia was considered KN046 related.
Pharmacokinetics immunogenicity
Serum concentrations of KN046 in both the non-sq- and sq-NSCLC cohorts plateaued at approximately 10,000 ng/mL after the first 5 doses (Figure S5A). A total of 84 patients were tested for anti-drug Ab (ADA) at baseline and during follow-up. Treatment-emergent ADA (TE-ADA) was detected in 67.9% of patients (57/84) (Table S1). TE− patients had higher serum KN046 concentrations compared with TE+ patients in the first four cycles (Figure S5B).
Efficacy and safety based on TE-ADA
Among 84 patients with immunogenicity data, TE− patients (28) had numerically higher ORR (60.7% vs. 39.3%) and CBR (71.4% vs. 50.0%) compared to TE+ patients (56). The median DOR (7.5 vs. 6.1 months), PFS (7.1 vs. 5.5 months), and OS (NR vs. 20.6 months) were also longer in TE− patients (Table S2).
The safety profile was similar between TE+ and TE− patients, except that TE− patients had fewer treatment-related IRRs (35.7% vs. 67.9%) (Table S3).
Discussion
This phase 2 trial evaluated the efficacy and safety of a bsAb targeting PD-L1 and CTLA-4 in combination with chemotherapy as a first-line treatment in metastatic NSCLC. First-line KN046 plus chemotherapy showed satisfactory responses and promising OS in these patients.
In our study, the confirmed ORRs were 43.1% for non-sq-NSCLC and 50.0% for sq-NSCLC. For context, previous clinical trials have reported ORRs ranging from 48.3% to 57.4% for non-sq-NSCLC5,20 and from 44.7% to 74.8% for sq-NSCLC4,21,22,23 when using anti-PD-1/PD-L1 Abs plus chemotherapy. Although indirect comparisons are challenging with varying patient selection criteria and treatment settings, our results appear consistent with the efficacy observed in these studies. The median OS observed with KN046 plus chemotherapy in our study was 26.6 months, a duration that aligns with the upper range of median OS reported in similar trials.4,5,6,8,14,24,25 In the CameL-Sq study, camrelizumab plus chemotherapy as a first-line treatment in patients with advanced sq-NSCLC achieved a median OS of 27.4 months.22
Regarding dual immunotherapies combining anti-CTLA-4 and anti-PD-1/L-1 Abs, the CheckMate 227 trial with nivolumab plus ipilimumab reported an ORR of 33.4% and a median OS of 17.1 months,11 and the CheckMate 9LA trial combining nivolumab, ipilimumab, and chemotherapy reported an ORR of 38.2% and a median OS of 15.6 months.26 Similarly, the POSEIDON trial, with durvalumab, tremelimumab, and chemotherapy, reported an ORR of 38.8% and a median OS of 14.0 months.14 Given the different baseline characteristics and clinical settings across studies, all of these indirect comparisons should be interpreted with caution. In this study, all of the cases had stage IV disease, whereas some studies also enrolled patients with stage III disease.20,21,22,23,27 In addition, the proportion of patients with PD-L1 ≥50% was 17.2% in this study, lower than the 19%–40.2% reported by the above-mentioned trials.4,5,8,11,13,22 Despite the unfavorable baseline characteristics that may lead to poor prognosis, the median OS reached 26.6 months in the overall population in the present study, indicating a remarkable efficacy of KN046 plus chemotherapy in NSCLC. Our results preliminarily showed that bsAbs targeting PD-L1 and CTLA-4 in combination with chemotherapy mainly conferred benefits in long-term survival, which needed to be verified in further large-scale studies. Recently, a preliminary study on MEDI5752, a PD-1/CTLA-4 bsAb, in combination with carboplatin/pemetrexed, has shown superior therapeutic effect compared to pembrolizumab plus carboplatin/pemetrexed in the treatment-naive non-sq-NSCLC population.28 This emerging evidence, alongside our findings, contributes to the expanding knowledge based on the potential of bispecific Abs in NSCLC treatment. The study drug KN046 not only has the potential to enhance the immune response against cancer cells but also introduces a therapeutic approach that may lessen the frequency of AEs that are typically associated with the use of dual-Ab treatments. The evolving research and development of bispecific Abs such as KN046 and MEDI5752 are paving the way for more effective and potentially safer treatment options in the management of NSCLC.
In our study, the incidence of grade ≥3 TRAEs was observed to be 66.7%, which is slightly higher compared to the incidences reported with pembrolizumab (56.5%)4 and atezolizumab (58.4%)25 when combined with chemotherapy. However, it is important to consider the variations in study protocols and patient demographics when interpreting these figures. The proportion of patients experiencing serious TRAEs in our study was 31.0%, aligning with the 24.5%–30% range observed in trials such as CheckMate 227, CheckMate 9LA, and POSEIDON.11,13,14 The most common TRAEs identified were anemia, loss of appetite, neutropenia, leukopenia, and thrombocytopenia, which are consistent with those reported in prior studies involving immunotherapy and chemotherapy combinations.6,13,14,24,29,30 Notably, no new safety signals emerged during long-term follow-up. The incidence of grade ≥3 irAEs was 12.6%, and the rate of treatment discontinuation due to TEAEs was 19.5%, comparable to the rates reported with durvalumab plus tremelimumab and chemotherapy in the POSEIDON trial (10% and 22.1%, respectively).14 Treatment-related deaths occurred in 4 (4.6%) patients, with one case of immune-related pneumonia attributed to KN046. Overall, our findings indicate that KN046 combined with platinum-based chemotherapy is generally safe and well tolerated. In addition, the use of KN046 offers a more convenient administration option compared to combinations of two immune checkpoint inhibitors because it involves the administration of a single drug.
The formation of ADAs is known to alter a drug’s bioavailability, pharmacokinetic, and pharmacodynamic properties, often influencing drug efficacy.31 In our study, TE-ADAs were positive in 67.9% of patients, a rate that appears high but is within the observed range in a recent systematic review of 141 trials across 15 checkpoint inhibitors.32 This review highlighted considerable variability in ADA reporting, with incidences ranging from 0% to 74%. The heterogeneity in ADA incidence across trials suggests that multiple factors, including the molecular structure of the drug, patient-specific variables, and methodological differences in ADA detection, may influence these rates. In our cohort, TE-ADA was seemingly associated with treatment efficacy and IRRs. TE− patients exhibited numerically higher ORR and CBR, along with longer median DOR, PFS, and OS compared to TE+ patients. In addition, the incidence of IRRs was notably lower in TE− patients. However, considering the relatively small sample size of our study, larger studies are needed to confirm these correlations between TE-ADA and both efficacy and safety outcomes. Our future research will focus on investigating potential factors contributing to the elevated ADA rates, such as the Fc segment glycosylation, drug preparation stability, and impurity presence, to better understand and address this phenomenon in the context of KN046 therapy.
Our study findings have laid the groundwork for further investigation into the combination of KN046 with chemotherapy. A large-scale randomized phase 3 trial (ENREACH-LUNG-01; the trial is registered at ClinicalTrials.gov [NCT04474119]) is under way. This trial aims to rigorously verify the efficacy and safety of KN046 in combination with platinum-containing chemotherapy in first-line treatment for advanced sq-NSCLC patients. The comparison of KN046 plus carboplatin and paclitaxel against placebo plus the same chemotherapy regimen in this trial will provide more definitive evidence and potentially establish KN046 as a valuable addition to the therapeutic options for sq-NSCLC.
In conclusion, the encouraging results from this phase 2 study show that first-line KN046 combined with platinum-based chemotherapy is effective and tolerable in patients with metastatic NSCLC, representing a valuable potential treatment option for this patient population.
Limitations of the study
Since this was a single-arm phase 2 trial, it was impossible to draw a firm conclusion. Nevertheless, KN046 demonstrated favorable survival as well as patient tolerability and safety based on a median follow-up of 23.1 months. This trial is ongoing and follow-up will be extended to explore long-term efficacy and safety. In addition, although our findings provide valuable insights into the efficacy and safety of KN046 in Chinese patients with metastatic NSCLC, further studies involving diverse populations are warranted to assess the generalizability of these results across different ethnicities. Our study detailed the association of TE-ADAs with pharmacokinetics and clinical outcomes, but we did not investigate the specific mechanisms. Further research is required to elucidate these mechanisms comprehensively. In addition, this study did not investigate tumor immune infiltrates and immunologic memory, aspects that could provide deeper insights into the immunological mechanisms and treatment responses in NSCLC patients treated with KN046. Future research incorporating these parameters would enhance our understanding of the impact of the treatment on the tumor microenvironment and immunologic landscape.
STAR★Methods
Key resources table
| REAGENT or RESOURCE | SOURCE | IDENTIFIER |
|---|---|---|
| Antibodies | ||
| PD-L1(SP263)-N-Assay | Ventana | Cat# 743–7066; Cat# 790-4905;RRID:AB_2819099 |
| Anti-KN046 Polyclonal Antibody | Wuxi AppTec | Cat# SA170518BB;RRID:AB_3094759 |
| Chemicals, peptides, and recombinant proteins | ||
| KN046 | Jiangsu Alphamab Biopharmaceuticals Co., Ltd. | N/A |
| pemetrexed | Qilu Pharmaceutcal Co., Ltd. | N/A |
| paclitaxel | Hospira Australia Pty Ltd | N/A |
| carboplatin | Qilu Pharmaceutcal Co., Ltd. | N/A |
| Biotin KN046 | Phamaron | Cat# B0606201901 |
| Sulfo-Tag KN046 | Phamaron | Cat# S0606201901 |
| Critical commercial assays | ||
| OptiView DAB IHC tDetection Kit | Ventana | Cat# 760-700 |
| Software and algorithms | ||
| SAS, version 9.4 | SAS Institute Inc. | https://support.sas.com/downloads/browse.htm?fil=&cat=49 |
Resource availability
Lead contact
Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Li Zhang (zhangli@sysucc.org.cn).
Material availability
This study did not generate new unique reagents.
Data and code availability
Data from this study can be made available upon request and approval by the study management committee and subject to appropriate data transfer agreements. Requests should be directed to L.Z. This paper does not report original code. Any additional information required to reanalyze the data reported in this work paper is available from the lead contact upon request.
Experimental model and subject details
Ethics statement
This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and approved by the ethics committees of all participating centers. The trial protocol for our study was also approved by the National Medical Products Administration (NMPA). Written informed consent was obtained from each patient before enrollment.
Human subjects
Chinese adults, both male and female, with histologically or cytologically confirmed treatment-naïve stage IV NSCLC, no epidermal growth factor receptor (EGFR) sensitizing mutations or anaplastic lymphoma kinase (ALK) rearrangements for non-squamous (non-sq)-NSCLC were enrolled in the study. Baseline patient characteristics was provided in Table 1.
Sample size estimation
Due to the exploratory nature of the phase II trial, no formal statistical testing was planned. The sample size was based on estimation without a statistical hypothesis to explore the efficacy and toxicity of KN046 when combined with chemotherapy. Approximately 40 participants with non-sq-NSCLC and 40 participants with sq-NSCLC were planned to be enrolled in this study.
Subject allocation
The current phase II clinical trial was a one-arm study, with no control group, and thus all the patients were enrolled in one group.
Method details
Study design and participants
This multicenter, phase 2 trial was conducted in 6 centers in China. Eligible patients were 18–75 years of age with histologically or cytologically confirmed treatment-naïve stage IV NSCLC, no epidermal growth factor receptor (EGFR) sensitizing mutations or anaplastic lymphoma kinase (ALK) rearrangements for non-squamous (non-sq)-NSCLC, ≥1 measurable lesion(s) according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1,21 and an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0–1. For patients with prior neoadjuvant/adjuvant chemotherapy, the time elapsed from chemotherapy completion to the first diagnosis of metastatic disease should be >6 months. Patients were excluded with symptomatic brain metastases, radical radiotherapy within 3 months, prior immunotherapy, systemic corticosteroids or immunosuppressive therapy within 14 days, interstitial pneumonia/pulmonary diseases, autoimmune diseases, or other malignant tumors within 5 years. Detailed eligibility criteria are listed in the trial protocol (supplementary appendix).
Procedures
The dosage of KN046 was based on the safety and preliminary efficacy data garnered from the KN046-AUS-001 (first-in-human study) and KN046-CHN-001 (first-in-China study) trials.19,20 Patients were administered KN046 (5 mg/kg), carboplatin (area under the curve [AUC] = 5), and pemetrexed (500 mg/m2) for non-sq-NSCLC or paclitaxel (175 mg/m2) for squamous (sq)-NSCLC intravenously on day 1 of each 3-week cycle. Chemotherapy was given for 4 cycles, while KN046 was administered once every 3 weeks (Q3W) until confirmed disease progression, unacceptable toxic effects, or completion of the 2-year treatment, whichever occurred first. Pemetrexed (500 mg/m2 on day 1) could also be continued in the non-sq-NSCLC cohort at the discretion of the investigators.
In case of grade ≥3 KN046-related hematological or non-hematological toxicity, KN046 was interrupted and resumed after the toxicity recovered to grade ≤1. If the same KN046-related toxicity re-occurred, the drug was permanently discontinued. The specific criteria for interruption or permanent discontinuation of KN046 are listed in the protocol. Dose reduction was not allowed for KN046. Prophylaxis of infusion-related reactions (IRRs) was recommended in the protocol (diphenhydramine 25–50 mg intramuscularly or orally, cimetidine 400 mg intravenously, and acetaminophen 500–1000 mg orally). Symptomatic treatment was provided based on the investigators’ clinical experience in case of IRRs.
Tumor imaging was scheduled every 6 (±1) weeks in the first year and every 12 (±1) weeks thereafter. Objective response was assessed by the investigators according to RECIST 1.1.21 Patients with disease progression who were clinically stable and benefiting from the treatment in the opinion of the investigators could continue to receive the study treatment until confirmed progression at least 4 weeks later. During follow-up, patients were contacted every 12 weeks to assess survival.
Adverse events were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Treatment-emergent adverse event (TEAE), treatment-related adverse event (TRAE), and immune-related adverse event (irAEs) were recorded during the treatment period and until 30 days after the last drug administration. Serious TEAEs were recorded until 90 days after the last KN046 dose. Serious TEAEs suspected to be related to KN046 were recorded regardless of the occurrence time from KN046 discontinuation.
Tumor tissue samples without radiotherapy within 1 year were suitable for PD-L1 testing. PD-L1 expression was assessed by immunohistochemistry at the central laboratory (MEDx Translational Medicine Co., Ltd.). Staining was assessed for the tumor proportion score (TPS), which was calculated as the proportion of positive tumor cells in total viable tumor cells.
Samples for pharmacokinetics were collected according to the protocol. Immunogenicity was assessed with treatment-emergent anti-drug antibody (TE-ADA) for KN046 by the central laboratory. TE-ADA positivity was defined as any post-treatment ADA detection with negative baseline ADA or post-treatment ADA titer increased by ≥ 4-fold versus baseline ADA levels.
Outcomes
The primary endpoints were confirmed objective response rate (ORR, defined as the proportion of patients achieving a complete [CR] or partial response [PR] per RECIST 1.1) and duration of response (DOR, defined as time from documentation of tumor response to disease progression or death without documented progression) as assessed by the investigators. CR and PR required a confirmatory computed tomography (CT) or magnetic resonance imaging (MRI) repeat assessment at least 4 weeks after the first detection of response.
Secondary endpoints included clinical benefit rate (CBR, defined as the proportion of patients with complete response, partial response, or stable disease [SD] ≥24 weeks), 6-month and 12-month progression-free survival (PFS) rates, and 12-month OS rate. PFS was defined as time from the initiation of the study treatment to confirmed disease progression or death. OS was defined as time from the initiation of the study treatment to death.
In exploratory analysis, ORR, PFS, OS, and safety data were analyzed across three subgroups: PD-L1 expression (<1% vs. ≥ 1%), baseline brain metastases (with vs. without), and TE-ADA (TE-positive vs. TE-negative).
Quantification and statistical analysis
The safety set (SS) included all patients administered ≥1 dose of the study drug (KN046 and/or chemotherapy). Efficacy-related endpoints were evaluated in patients administered ≥1 dose of the study drug with ≥1 measurable lesion at baseline.
Age was expressed as median (range), and categorical variables were expressed as frequency and percentage. The reverse Kaplan-Meier method was used to calculate the median follow-up time. The 95% confidence intervals (CIs) of ORR and CBR were calculated by the Clopper-Pearson method. Kaplan-Meier curves were plotted to estimate DOR, PFS, OS, and the corresponding 95% CIs. Time-to-event endpoints were summarized with Kaplan-Meier estimates and 95% CIs at 6 and 12 months. All statistical analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC, USA).
Additional resources
This trial is registered with ClinicalTrials.gov, NCT04054531.
Acknowledgments
This study was funded by Jiangsu Alphamab Biopharmaceuticals Co., Ltd. We are grateful to all of the patients and their families, as well as all of the members of the collaborative group in this trial. Medical writing assistance was funded by Jiangsu Alphamab Biopharmaceuticals Co., Ltd.
Author contributions
Conceptualization, Y.Z., G.C., Y.H., and L.Z. Methodology, Y.Z. and T.X. Investigation, Y.Z., G.C., X.L., J.W., B.C., S.H., S.Y., Y.H., T.X., and Y.L. Formal analysis, Y.Z., Y.L., and N.W. Data curation, Y.Z., G.C., X.L., J.W., B.C., S.H., S.Y., Y.H., T.X., and N.W. Resources, Y.Z., G.C., X.L., J.W., B.C., S.H., S.Y., Y.H., and L.Z. Writing – original draft, Y.Z. Writing – review and editing, Y.Z., G.C., X.L., J.W., B.C., S.H., S.Y., Y.H., T.X., Y.L., N.W., and L.Z. Validation, Y.L. and N.W. Visualization, Y.Z., G.C., Y.L., and N.W. Software, N.W. Supervision, Y.Z., T.X., Y.H., and L.Z. Project administration, Y.Z. and T.X. Funding acquisition, Y.H. and L.Z.
Declaration of interests
L.Z. received financial support from Hengrui, BeiGene, Xiansheng Pharma, Eli Lilly, MSD, Novartis, Roche, Hansoh, and Bristol-Myers Squibb Pharma. T.X., Y.L., and N.W. were employees of Jiangsu Alphamab Biopharmaceuticals.
Published: March 19, 2024
Footnotes
Supplemental information can be found online at https://doi.org/10.1016/j.xcrm.2024.101470.
Contributor Information
Li Zhang, Email: zhangli@sysucc.org.cn.
Yan Huang, Email: huangyan@sysucc.org.cn.
Supplemental information
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data from this study can be made available upon request and approval by the study management committee and subject to appropriate data transfer agreements. Requests should be directed to L.Z. This paper does not report original code. Any additional information required to reanalyze the data reported in this work paper is available from the lead contact upon request.