We are pleased to provide highlights of important and potentially practice-changing developments in immunotherapy of non–small-cell lung cancer (NSCLC) presented at the 2022 annual meetings of the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO). In this print supplement, we will summarize pivotal clinical data that were presented on immune checkpoint inhibitor therapy of NSCLC at both of these key meetings.
A total of 25 data presentations from AACR 2022 and ASCO 2022 are summarized in this resource. We hope that the information reviewed here can be applied to clinical practice and offers valuable insights into the important progress that is being made in the care of patients with NSCLC.
The CheckMate 9LA trial demonstrated that treatment of patients with metastatic non–small-cell lung cancer (NSCLC) with nivolumab plus ipilimumab combined with 2 cycles of chemotherapy improved survival benefits compared with treatment of 4 cycles of chemotherapy alone.1 In a late-breaking presentation at the 2022 American Society of Clinical Oncology Annual Meeting, Paz-Ares and colleagues reported updated 3-year efficacy and safety data, and the results of exploratory biomarker analyses.2
CheckMate 9LA enrolled patients with stage IV or recurrent NSCLC with no known sensitizing EGFR/ALK alterations and an Eastern Cooperative Oncology Group performance status of 0 or 1.2 The patients were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks plus 2 cycles of chemotherapy (n = 361) or 4 cycles of platinum-based chemotherapy alone (n = 358).2
Patients were stratified by tumor PD-L1 expression level, sex, and histology. Patients with nonsquamous NSCLC in the chemotherapy-alone arm could receive pemetrexed maintenance. The study assessed overall survival (OS), progression-free survival (PFS), and objective response rate.2 For all patients with nonsquamous NSCLC and with tissue evaluable for mutational analysis (n = 313), the FoundationOne CDx™ assay was used to identify mutant (mut) or wild-type (wt) KRAS and STK11 genes. Exploratory assessments included evaluation of OS and PFS with nivolumab plus ipilimumab in combination with chemotherapy versus chemotherapy by mutation status and safety.2
At a minimum follow-up of 36.1 months, patients continued to derive long-term, durable OS benefits with nivolumab plus ipilimumab combined with 2 cycles of chemotherapy versus chemotherapy alone (hazard ratio, 0.74; 95% confidence interval, 0.62-0.87); 3-year OS rates were 27% versus 19%, respectively. The clinical benefit of nivolumab plus ipilimumab combined with 2 cycles of chemotherapy versus chemotherapy alone was observed in all randomized patients and across most subgroups, including by PD-L1 expression level or histology.2 The 3-year OS rates for the nivolumab/ipilimumab/limited chemotherapy regimen versus chemotherapy alone among patients with PD-L1 <1%, PD-L1 ≥1%, PD-L1 1%-49%, and PD-L1 ≥50% were 25% versus 15%, 28% versus 19%, 26% versus 15%, and 33% versus 24%, respectively.
In an exploratory analysis based on KRAS and STK11 mutation status, nivolumab plus ipilimumab combined with 2 cycles of chemotherapy improved OS versus chemotherapy alone (median OS, 16.3 vs 13.1 months). Similar trends of prolonged OS were also observed in patients with or without KRAS mutation (median OS, mut, 19.2 vs 13.5 months; wt, 15.6 vs 12.7 months) or STK11 mutation (mut, 13.8 vs 10.7 months; wt, 17.8 vs 13.9 months), respectively. No new safety signals were observed.2
In conclusion, the 3-year follow-up of CheckMate 9LA demonstrated that first-line nivolumab plus ipilimumab combined with 2 cycles of chemotherapy provided long-term, durable OS benefit versus chemotherapy alone in patients with metastatic NSCLC.2 Survival benefit of the combination regimen was observed regardless of PD-L1 level and was effective even in PD-L1–negative patients.
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Clinical studies have revealed several factors related to potential response to immune checkpoint inhibitors (ICIs), such as PD-L1 expression, tumor mutational burden, initial tumor size, history of steroid or antibiotic use, microsatellite instability status, and gut microbiota; however, robust predictive, validated biomarkers are still lacking.1 The PIONeeR project, founded on a large biomarker program and a randomized umbrella clinical trial, aimed to understand, predict, and overcome resistance to ICIs.1
The PIONeeR trial included >300 patients with advanced non–small-cell lung cancer (NSCLC). The biomarker analysis was focused on the first 137 patients with Eastern Cooperative Oncology Group performance status of 0 or 1 who received ≥2 lines of therapy.2 Enrolled patients were treated with nivolumab, pembrolizumab, or atezolizumab monotherapy. Tumor tissue was collected at baseline and at 6 weeks of treatment, and blood samples were collected every cycle throughout the 24 weeks after the initiation of the first treatment cycle. Response to ICIs was assessed by RECIST version 1.1 every 6 weeks.2 Immune cells were characterized in tumor and blood samples of each patient using flow cytometry for circulating immune-cell subtype quantification and endothelial activation and levels of soluble factors. In addition, dual- and multiplex-immunohistochemistry and digital pathology were used to quantify immune cells infiltrating the tumor. Whole exome sequencing was used to assess tumor mutational burden. A total of 331 biomarkers were measured in addition to routine clinical parameters.2
Multivariable logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histologic type, and PD-L1–positive tumor cells) with the risk of early progression.2
A total of 137 patients were included with tumors that were mainly nonsquamous (79%). Tumor cytotoxic T-cell density, especially PD-1–positive, were lower in patients with early progression (multivariable odds ratio [OR], 0.45; P = .022). Higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in early progression (multivariable OR, 3.8; P <.001). Among other biomarkers, regulatory T-cells (multivariable OR, 0.44; P = .018), natural killer cell subsets (multivariable OR, ≤0.44; P <.05), albumin (multivariable OR, 0.4; P <.01), and PD-L1 tumor cells percentage (multivariable OR, 0.27; P <.01) were decreased, whereas alkaline phosphatase was increased (OR, 3; P = .018) in patients with early progression. Multimodal data integration through supervised machine learning revealed a 37-biomarker signature that identified patients who may be resistant to anti–PD-1/PD-L1 prior to treatment initiation.3
In conclusion, the PIONeeR trial is the first study of comprehensive biomarker analysis that aimed at defining comprehensive predictive models of resistance in patients with advanced NSCLC treated with PD-1/PD-L1 ICIs. A signature of 37 biomarkers was seen in patients resistant to PD-1/PD-L1 ICIs before treatment initiation. In addition, the study demonstrated the complementary value of tumor and circulating biomarkers in predicting ICI efficacy and potential resistance.2,3
In the phase 3 POSEIDON study of first-line treatment of metastatic non–small-cell lung cancer (mNSCLC), the addition of the anti–CTLA-4 inhibitor tremelimumab to durvalumab and chemotherapy showed statistically significant improvements in progression-free survival and overall survival compared with chemotherapy alone.1 In addition, no new safety signals were identified, and treatment discontinuations due to treatment-related adverse events (TRAEs) were similar for both arms: tremelimumab plus durvalumab and chemotherapy (arm A) and durvalumab plus chemotherapy (arm B). Recently, Cho and colleagues presented the adverse events (AEs) observed in the POSEIDON trial and discussed their management strategies.2
The POSEIDON study was a randomized trial that included 1013 patients with EGFR/ALK wild-type mNSCLC who were randomized 1:1:1 to receive first-line tremelimumab plus durvalumab and chemotherapy (arm A, 330 patients), durvalumab plus chemotherapy (arm B, 334 patients), or chemotherapy alone (arm C, 333 patients).2
Hematologic AEs were the most common grade 3/4 TRAEs, including anemia, which was observed in 17%, 15%, and 20%, and neutropenia, which was observed in 16%, 13%, and 12% of patients in arms A, B, and C, respectively. Standard management approaches were used, including administering colony-stimulating factors and blood transfusions.
All-grade immune-related AEs (irAEs) occurred in 34%, 19%, and 5% of patients in arm A, B, and C, respectively. The addition of tremelimumab to durvalumab resulted in a higher incidence of diarrhea/colitis, dermatitis/rash, and endocrinopathies. Grade 3/4 irAEs occurred in 10%, 7%, and 2% of patients in arm A, B, and C, respectively, and serious irAEs occurred in 10%, 6%, and 1%, respectively. The incidence of irAEs that led to discontinuation was higher in arm A than in arms B and C (6%, 4%, and 0.6%, respectively). Similarly, irAEs that led to death were higher in arm A (0.6%, 0.3%, and 0%). However, most irAEs were low-grade and manageable with systemic corticosteroids or endocrine therapy.
In summary, the safety profile of all combination regimens was manageable and consistent with AEs of the individual therapies. The most common grade 3/4 TRAEs were those observed with chemotherapy treatments. More irAEs occurred with the tremelimumab plus durvalumab combination than with durvalumab alone.
Accumulating evidence has demonstrated that the addition of cytotoxic chemotherapy and antiangiogenic therapy to immune checkpoint inhibitors (ICIs) may result in improved clinical benefit.1 Platinum-containing dual-agent chemotherapy combined with ICIs is the standard first-line treatment for patients with non–small-cell lung cancer (NSCLC); however, the optimal combination regimen remains unclear.2 In addition, platinum-based chemotherapy is associated with a serious adverse events profile.2
The CAPAP-lung study was a single-arm, multicenter, phase 2 trial that aimed to evaluate the efficacy and safety of camrelizumab (a PD-1 inhibitor) in combination with apatinib (a vascular endothelial growth factor receptor-2 inhibitor), and albumin paclitaxel without platinum as first-line therapy for nonsquamous NSCLC.2
Patients diagnosed with EGFR- and ALK-negative advanced nonsquamous NSCLC were treated with camrelizumab (200 mg every 3 weeks) in combination with 4 to 6 cycles of albumin paclitaxel (135 mg/m2, day 1, day 8/every 3 weeks) and apatinib (250 mg once daily for 5 days, resting for 2 days every week).2
A total of 54 patients of the planned 63 were enrolled from August 2020 to February 2022. The primary end point was progression-free survival (PFS), and secondary end points were overall survival, duration of response, objective response rate (ORR), and disease control rate (DCR) assessed by RECIST version 1.1.2
Of 54 enrolled patients, 38 were eligible for evaluation. Median PFS was 10.97 months (95% confidence interval [CI], 7.1-not reached) and the ORR and DCR were 71.1% (27/38; 95% CI, 53.9-84.0) and 97.4% (37/38; 95% CI, 84.6-99.9), respectively. Grade 3 adverse events were observed in 25 (46.3%) patients and grade 4 events were seen in 3 (5.6%) patients. The most common grade 3 treatment-related adverse events were decreased neutrophil count (14.8%), liver function damage (16.7%), rash (5.6%), and decreased white blood cell count (5.6%).
In summary, camrelizumab combined with albumin paclitaxel and apatinib demonstrated promising anticancer activity with a manageable safety profile for the first-line treatment of advanced nonsquamous NSCLC.
MEDI5752 is a novel monovalent bispecific antibody designed to target PD-1 and CTLA-4.1,2 The unique bispecific structure allows for preferential inhibition of these 2 checkpoints on activated T-cells in tumors, where co-expression is usually abundant.1,2 This results in improved anticancer immune response and reduced peripheral toxicity that is common when targeting these checkpoints independently.2 The results of the dose-escalation study for MEDI5752 from a phase 1, open-label, multicenter study in advanced solid tumors (NCT03530397) were recently reported at the American Association for Cancer Research 2022 annual meeting.2
The study enrolled patients with an Eastern Cooperative Oncology Group performance status of 0 or 1.2 Patients were treated with MEDI5752 at 10 dose levels ranging from 2.25 mg to 2500 mg intravenously every 3 weeks until progression or unacceptable toxicity. The primary objectives were safety and identification of maximum tolerated dose. Secondary objectives included preliminary antitumor activity by RECIST version 1.1, pharmacokinetics, and immunogenicity. Exploratory objectives included the evaluation of pharmacodynamic biomarkers.2
By the cutoff date of September 30, 2021, 86 patients were enrolled. The most common tumor types were renal-cell carcinoma (22.1%), non–small-cell lung cancer (16.3%), and head and neck cancer (8.1%).2 Of these patients, 95.2% had received prior systemic therapy, and 90.7% were immunotherapy naïve.2
MEDI5752 showed dose-dependent pharmacokinetics and sustained peripheral PD-1 receptor occupancy (>90%) at doses >225 mg. Dose-dependent increases in peripheral T-cell proliferation (Ki67+) and activation (ICOS+) plateaued at doses ≥500 mg and demonstrated CTLA-4–specific blockade in the range that is achieved with tremelimumab 6 mg/kg to 10 mg/kg.2
At doses ≥500 mg, MEDI5752 resulted in a significant expansion of new and existing T-cell clones.2 Across all doses, objective responses were observed in 19.8% of patients (n = 17; 1 complete response and 16 partial responses).2 Median duration of response was 17.5 months. Molecular response (defined as ≥50% reduction in ctDNA) was observed in 36.5% of participants. Doses ≥1500 mg (n = 53) were poorly tolerated and were associated with grade 3/4 treatment-related adverse events (TRAEs) in 50.9% of patients. Discontinuation due to TRAEs occurred in 45.3% of patients, and death occurred in 1 patient (at 2000 mg). However, doses <1500 mg (n = 33) were better tolerated, with grade 3/4 TRAEs occurring in 18.2% of patients, and discontinuations due to TRAEs occurring in 9.1%. A maximum tolerated dose was not reached based on the protocol-defined dose-limiting toxicity criteria. Immune-related adverse events were also less common at doses <1500 mg than doses >1500 mg (grade 3/4 rates of 18.2% vs 49.1%, respectively).2
MEDI5752 showed promising antitumor activity with durable clinical benefit and was well-tolerated at doses <1500 mg. In addition, MEDI5752 resulted in robust dual checkpoint blockade, T-cell activation, and expansion of new and existing T-cell clones.
Despite the proven efficacy of immune checkpoint inhibitor (ICI) therapy in treating solid tumors, there is still a need to identify reliable response biomarkers.1 The S1400I study was a randomized phase 3 trial of nivolumab plus ipilimumab versus nivolumab alone that included ICI-naïve patients with previously treated stage IV or recurrent squamous-cell lung cancer. Gonzalez-Kozlova and colleagues presented an analysis of circulating serum proteins in serial blood specimens from enrolled patients to determine if changes in serum protein levels could serve as response biomarkers to ICI therapy.2
A total of 561 serial blood specimens (baseline, weeks 3, 7, 9, and progression) from 160 of 252 eligible patients enrolled in the study were analyzed for 92 immuno-oncology analytes with the Olink proximity extension assay. Protein levels were normalized using internal controls and quantified as log2 protein expression (denoted as NPX). Linear mixed models evaluated change in expression from baseline at each time point (weeks 3, 7, and 9 and progression) and NPX differences at baseline, week 3, and progression based on the best objective response. A Cox model was used to evaluate the association between baseline NPX and survival.2
The level of serum proteins, PCDC1, CXCL9, and CXCL10, were increased from baseline at weeks 3, 7, and 9 and at the time of progression. In addition, the CCL19 protein level was increased at weeks 3 and 7 but not at week 9 or at progression. IL-10 and IFNγ were increased at week 3 but subsequently returned to baseline. Interestingly, patients treated with nivolumab plus ipilimumab had larger changes in CXCL13 protein level from baseline to progression compared with those treated with nivolumab alone. In addition, baseline levels of CCL23, CSF-1, IL-6, and MUC-16 were correlated with shorter survival (hazard ratio [HR] >1). Joint modeling of survival with cytokines showed an increased risk of death (HR >1) with higher longitudinal serum levels of CXCL13, MMP12, CSF-1, and IL-8. Patients achieving an objective response had higher IL-4 and LAMP3 and lower IL-6 and IL-8 at baseline and week 3 than nonresponders.
In conclusion, analyzing blood circulating soluble proteins represents an easily accessible noninvasive approach to predict treatment outcomes, which warrants further investigation in prospective trials.
Treatment outcomes for patients with resectable non–small-cell lung cancer (NSCLC) have been inconsistent. Approximately 20% to 25% of patients with NSCLC present with resectable disease, but 30% to 55% of patients experience disease recurrence following curative surgery.1 In addition, the benefit of neoadjuvant chemotherapy compared with surgery alone is modest.1
Nivolumab, a fully human anti–PD-1 antibody, has been shown to induce an anticancer immune response by activating antitumor T-cells.1 Furthermore, chemotherapy was shown to induce antitumor immunity through direct or indirect immune-system activation. Accordingly, it was hypothesized that the combination of immune checkpoint inhibitors and chemotherapy could improve efficacy.1
CheckMate 816 is a randomized phase 3 study that investigated the efficacy of neoadjuvant nivolumab plus platinum doublet chemotherapy for patients with resectable NSCLC. The study included patients with stage IB (≥4 cm) to IIIA (per AJCC Cancer Staging Manual, 7th ed) resectable NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no known EGFR/ALK alterations. Patients were randomly assigned to receive nivolumab (360 mg) plus chemotherapy every 3 weeks (n = 179) or chemotherapy every 3 weeks for 3 cycles (n = 179). The primary end points were event-free survival (EFS) and pathologic complete response (pCR), assessed by a blinded independent review.1,2
Patients treated with nivolumab plus chemotherapy achieved a statistically significant improvement in pCR rate compared with those treated with chemotherapy alone (24% vs 2%, respectively; odds ratio, 13.94; 99% confidence interval [CI], 3.49-55.75; P <.001).1 The observed pCR benefit was achieved among all key subgroups, including disease stages, histologies, and PD-L1 expression levels. It is important to note that neoadjuvant nivolumab plus chemotherapy had no impact on the feasibility of curative surgery and did not result in an increased incidence of surgical complications or adverse events (AEs) compared with chemotherapy alone.1
At a median follow-up of 29.5 months, neoadjuvant nivolumab plus chemotherapy significantly improved EFS compared with chemotherapy alone (31.6 months; 95% CI, 30.2-not reached [NR] vs 20.8 months; 95% CI, 14.0-26.7; hazard ratio [HR], 0.63; 97.38% CI, 0.43-0.91; P = .005).1 The 2-year EFS rates were 63.8% versus 45.3%.1 In the pooled patient population, EFS was improved in patients with pCR compared with those without (median, NR vs 21.1 months; HR, 0.11; 95% CI, 0.04-0.29).2
The incidence of grade 3 to 4 treatment-related AEs was similar for both arms (33.5% vs 36.9%), and surgery-related AEs were also similar (11.4% vs 14.8%).
The researchers concluded that neoadjuvant nivolumab plus chemotherapy resulted in clinically meaningful improvement in EFS and pCR compared with chemotherapy alone. These findings established nivolumab plus chemotherapy as a potential new neoadjuvant treatment option for patients with stage IB to IIIA resectable NSCLC.
In the neoadjuvant setting, immunotherapy could be an effective treatment option and could result in pathologic downstaging, which may improve surgical outcomes.1,2 NeoCOAST is a global, randomized, phase 2 study that investigated the efficacy of neoadjuvant durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab, the anti-NKG2A monoclonal antibody monalizumab, or the anti-STAT3 antisense oligonucleotide danvatirsen in patients with resectable early non–small-cell lung cancer (NSCLC).2
NeoCOAST included patients with previously untreated, cytologically/histologically documented, resectable, stage I (>2 cm) to IIIA NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1.2 Patients were randomly assigned 1:1:1:1 to receive durvalumab (1500 mg intravenously [IV]) alone every 4 weeks or durvalumab combined with oleclumab 3000 mg IV every 2 weeks, monalizumab 750 mg IV every 2 weeks, or danvatirsen 200 mg IV weekly for one 28-day cycle, followed by surgery. Danvatirsen monotherapy was also given on days 1, 3, and 5 of the week prior to combination treatment.2
The primary end point was investigator-assessed major pathologic response (MPR; defined as ≤10% residual viable tumor cells at the tumor site and nodes, at surgery).2 Secondary end points included pathologic complete response (pCR; defined as no viable tumor cells), safety and tolerability, the feasibility of surgery, pharmacokinetics, and immunogenicity.2 Exploratory end points included tumor and microbiome biomarkers and blood mRNA signatures.2
A total of 84 patients were randomly assigned to the treatment groups between March 2019 and September 2020, and 83 received treatment: 26 received durvalumab, 21 received durvalumab plus oleclumab, 20 received durvalumab plus monalizumab, and 16 received durvalumab plus danvatirsen.2
Investigators reported that MPR was observed in 11.1% (95% confidence interval [CI], 2.4-29.2) of patients receiving durvalumab, 19.0% (95% CI, 5.4-41.9) in those receiving durvalumab plus oleclumab, 30.0% (95% CI, 11.9-54.3) in those receiving durvalumab plus monalizumab, and 31.3% (95% CI, 11.0-58.7) in those receiving durvalumab plus danvatirsen.2 In addition, pCR was observed in 3.7% (95% CI, 0.1-19.0), 9.5% (95% CI, 1.2-30.4), 10.0% (95% CI, 1.2-31.7%), and 12.5% (95% CI, 1.6-38.3) of patients, respectively.2
The rates of treatment-related adverse events were 34.6% with durvalumab (grade ≥3, 0%), 57.1% with durvalumab plus oleclumab (grade ≥3, 4.8%), 50.0% with durvalumab plus monalizumab (grade ≥3, 0%), and 43.8% with durvalumab plus danvatirsen (grade ≥3, 6.3%).2 The majority (91.6%) of patients were able to undergo surgery without delay. Of the 7 patients who were unable to complete surgery, 5 experienced progressive or stage IV disease.2
Patients with baseline PD-L1 expression ≥1% had a better MPR rate compared with those with <1% across all treatment groups. In addition, CD73 expression was associated with greater residual viable tumor cells at surgery in patients in the durvalumab group; however, for patients treated with durvalumab plus oleclumab, high CD73 (≥10% tumor cells) was associated with reduced viable tumor cells.
The researchers concluded that 1 cycle of durvalumab combined with oleclumab, monalizumab, or danvatirsen improved MPR and pCR rates compared with durvalumab alone, with no new safety signals. It is interesting to note that the observed responses were associated with baseline tumor PD-L1 and CD73 expression levels. These findings warrant further investigation of these agents in patients with resectable NSCLC.
Studies have shown that pembrolizumab improves overall survival (OS) when added to platinum-based doublet chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).1,2 However, the improvement in progression-free survival (PFS) and OS remains modest for most patients and can vary depending on the expression status of PD-L1.1,2 This highlights the need for additional therapeutic options. Canakinumab is a monoclonal anti–interleukin-1β antibody that inhibits protumor inflammation and potentially enhances antitumor immune responses, with the potential to synergize with PD-1 inhibitors plus chemotherapy.
CANOPY-1 was a randomized, double-blind, phase 3 study that investigated the addition of canakinumab or placebo to pembrolizumab plus platinum-based doublet chemotherapy in the first-line setting. Patients with previously untreated stage IIIB/C or IV NSCLC of any histology and no known EGFR or ALK alterations were randomly assigned 1:1 and stratified based on PD-L1 status, geographic region, and histology to canakinumab 200 mg or placebo every 3 weeks, plus pembrolizumab and histology-guided platinum-based doublet chemotherapy for 4 cycles, followed by maintenance canakinumab or placebo, with pembrolizumab with or without pemetrexed. The primary end points were investigator-assessed PFS (RECIST version 1.1) and OS.2
A total of 643 patients were randomly assigned to canakinumab (n = 320) or placebo (n = 323) in combination with pembrolizumab plus platinum-based doublet chemotherapy; the baseline characteristics were well-balanced across treatment arms.2
The median PFS was 6.8 months for both treatment groups (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.67-1.09; 1-sided P = .102). Median OS was 20.8 months and 20.2 months for the canakinumab and placebo arms, respectively (HR, 0.87; 95% CI, 0.70-1.10; 1-sided P = .123).
Grade 3/4 adverse events (AEs) were observed in 205 (64.1%) patients in the canakinumab arm and 191 (59.3%) patients in the placebo arm. Fatal AEs were reported for 37 (11.6%) and 47 (14.6%) patients, respectively. AEs of any grade leading to discontinuation of any study drug were reported for 72 (22.5%) patients in the canakinumab arm and 61 (18.9%) patients in the placebo arm.2
The researchers concluded that the addition of canakinumab to pembrolizumab plus platinum-based doublet chemotherapy was not associated with any new safety signals; however, the combination did not result in statistically improved PFS or OS in the first-line setting.
Immune checkpoint inhibitor (ICI) monotherapy is currently a standard second-line treatment option for patients with non–small-cell lung cancer (NSCLC). However, studies demonstrated that adding cytotoxic chemotherapy to ICI therapy may improve the treatment outcomes.1
This multi-institutional, open-label, randomized phase 2/3 trial compared the efficacy of nivolumab monotherapy (arm A) with nivolumab plus docetaxel (arm B) in patients with previously treated ICI-naïve NSCLC. The enrolled patients were prestratified based on tumor histology, sex, and driver mutations.1
The primary end point was the superiority of nivolumab plus docetaxel over nivolumab monotherapy in improving overall survival (OS) in the phase 3 part of the trial. The study was started in November 2017; however, the patients’ accrual was discontinued due to the approval of ICIs in the first-line setting in late 2018.
Of the enrolled patients, 128 were eligible for analysis. Patients’ demographics were well-balanced in both arms. The median OS was 14.7 months (95% confidence interval [CI], 11.4-18.7) in arm A and 23.1 months (95% CI, 16.7-not reached) in arm B. The hazard ratio (HR) of OS was 0.63 favoring nivolumab plus docetaxel (90% CI, 0.42-0.95; P = .0310). In arms A and B, the median PFS was 3.1 months (95% CI, 2.0-3.9) and 6.7 months (95% CI, 3.8-9.4), respectively. The HR for PFS was 0.58 favoring nivolumab plus docetaxel (95% CI, 0.39-0.88; P = .0095). The overall response rate (ORR) was 14.0% (95% CI, 6.3-25.8) in arm A and 41.8% (95% CI, 28.7-55.9) in arm B (P = .0014). Subgroup analyses of OS showed that the HRs also favored arm B over arm A across subgroups treated with the combination regimen, including all PD-L1 expression levels, smoking status, pathological type, metastasis site, tumor mutational burden, and prior therapy. Patients in arm B with EGFR-mutant tumors had higher median OS compared with arm A (11.0 months in arm A; 95% CI, 3.5-14.0; vs 20.6 months in arm B; 95% CI, 5.8-not reached; HR, 0.45; 95% CI, 0.17-1.17).
Patients in arm B experienced more hematologic toxicity and gastrointestinal adverse events compared with those in arm A. In addition, adverse events leading to treatment discontinuation were more common among patients in arm B compared with arm A (39.1% vs 9.4%). Moreover, 2 treatment-related deaths were reported: 1 from pneumonitis in arm A and 1 from myocarditis in arm B.
The investigators concluded that the combination of nivolumab plus docetaxel in the second-line treatment of patients with NSCLC improved OS, PFS, and ORR compared with nivolumab monotherapy, despite a slightly higher risk of toxicity. Importantly, this is the first randomized clinical trial to demonstrate the significant survival benefit of combining chemotherapy and ICI compared with ICI monotherapy in any cancer type.
Toripalimab, a novel anti–PD-1 humanized IgG4 monoclonal antibody, has shown manageable safety and antitumor activity in patients with advanced non–small-cell lung cancer (NSCLC).1 In combination with chemotherapy, toripalimab showed significant improvement in progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced NSCLC regardless of tumor PD-L1 expression. In this study, whole-exome sequencing (WES) was performed to identify correlative biomarkers for survival.2
The study enrolled 465 patients with treatment-naïve, advanced NSCLC without EGFR/ALK mutations. Patients were randomized 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) in combination with chemotherapy (pemetrexed plus platinum for nonsquamous and nab-paclitaxel plus carboplatin for squamous) for 4 to 6 cycles, followed by maintenance of toripalimab or placebo plus standard of care until disease progression, toxicity, or 2 years of treatment. The results were stratified based on PD-L1 expression status, histology, and smoking status.2
The primary end point was PFS determined by the investigator per RECIST version 1.1. Secondary end points included PFS by a blinded independent review committee (BIRC), OS, and safety.2
At the prespecified final PFS analysis (cutoff date October 31, 2021), a significant improvement in PFS was observed for patients in the toripalimab arm compared with the placebo arm: median PFS 8.4 months versus 5.6 months (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.39-0.61; 2-sided P <.0001). The 1-year PFS rates were 36.7% versus 17.2%, respectively, in the toripalimab plus chemotherapy and placebo plus chemotherapy arms. As assessed by BIRC, PFS was also significantly longer in the toripalimab arm. The improvements in PFS were observed among all key subgroups, including histology and PD-L1 expression. At the interim OS analysis, patients in the toripalimab group had a significantly longer OS than the placebo arm: median OS not reached versus 17.1 months (HR, 0.69; 95% CI, 0.52-0.92; 2-sided P = .0099). The observed benefits in OS in the toripalimab group were independent of PD-L1 expression level, but were not observed in PD-L1–negative patients. However, WES sequencing revealed that patients with high tumor mutational burden (TMB ≥10 muts/Mbp) in the toripalimab group achieved better PFS.
The incidence of grade ≥3 adverse events (AEs) (78.6% vs 82.1%) was similar between the 2 groups. AEs leading to discontinuation of toripalimab/chemo compared with placebo/chemo (14.3% vs 3.2%) and fatal AEs (5.5% vs 2.6%) were more frequent in the toripalimab group.2
WES results from 394 available patients showed that high TMB (≥10 muts/Mbp) was associated with significantly better PFS in the toripalimab arm over the placebo arm (median PFS, 13.1 vs 5.5 months) (interaction P = .026). In addition, patients with mutations in the FAK-PI3K-Akt or IL-7 signaling pathways demonstrated greater PFS and OS in the toripalimab plus chemotherapy regimen (P ≤.01).2
The investigators concluded that the combination of toripalimab plus chemotherapy in patients with advanced NSCLC resulted in superior PFS and OS compared with chemotherapy alone and had a manageable safety profile. These findings establish toripalimab with chemotherapy as a first-line treatment option for patients with advanced NSCLC without EGFR/ALK mutations.
Sugemalimab (formerly CS1001) is a fully human immunoglobulin G4 (IgG4, s228p) monoclonal antibody that targets PD-L1.1 GEMSTONE-302, a randomized, double-blind, phase 3 study, met its primary end point and demonstrated statistically significant and clinically meaningful improvement of progression-free survival (PFS) with sugemalimab plus chemotherapy compared with placebo plus platinum-based chemotherapy as a first-line option in patients with metastatic non–small-cell lung cancer (NSCLC). In addition, the combination regimen improved PFS in both squamous and nonsquamous NSCLC, regardless of PD-L1 expression levels.2
Zhou and colleagues reported the interim overall survival (OS) analysis results that were prespecified by the study protocol.2 The trial included patients with systemic treatment-naïve stage IV NSCLC, measurable disease per RECIST version 1.1, Eastern Cooperative Oncology Group performance status of 0-1, and no known EGFR, ALK, ROS1, and RET alterations. Patients were randomized 2:1 to receive sugemalimab (1200 mg, intravenous) or placebo plus platinum-based chemotherapy every 3 weeks for up to 4 cycles, followed by up to 35 cycles of maintenance therapy, which included sugemalimab or placebo for patients with squamous histology and sugemalimab or placebo plus pemetrexed for patients with nonsquamous histology.2
The primary end point was investigator-assessed PFS, and key secondary end points included OS, PFS in patients with tumor PD-L1 expression ≥1%, and overall response rate (ORR). In addition, patients in the placebo group could cross over to receive sugemalimab monotherapy upon disease progression.2
As of November 22, 2021, among all 479 enrolled patients, 51 (15.9%) and 7 (4.4%), respectively, remained on treatment with sugemalimab plus chemotherapy or placebo plus chemotherapy. The median follow-up was 25.4 months and 24.9 months, respectively. Following treatment discontinuation, 17.8% and 43.4% of the patients, respectively, received crossover sugemalimab or other nonstudy anti–PD-(L)1-containing therapies.2
In the intent-to-treat population, median PFS was 9.0 months with sugemalimab plus chemotherapy compared with 4.9 months with placebo plus chemotherapy (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.40-0.61), and the 2-year PFS rate was 20.8% versus 7.3%, respectively. In patients with PD-L1 ≥1%, the median PFS was 10.9 versus 4.9 months (HR, 0.48; 95% CI, 0.36-0.63; P <.0001). ORR was 63.4% versus 40.3% (P <.0001). In addition, sugemalimab plus chemotherapy resulted in clinical benefit in patients with baseline brain metastases and improved their OS (HR, 0.45) and intracranial PFS (post-hoc analysis, HR, 0.33) compared with placebo plus chemotherapy. No new safety signals were observed.2
Median OS was 25.4 months in the sugemalimab plus chemotherapy group compared with 16.9 months in the placebo plus chemotherapy group (HR, 0.65; 95% CI, 0.50-0.84; P = .0008), and the 2-year OS rate was 51.7% versus 35.6%, respectively. All subgroups treated with the sugemalimab-based regimen achieved OS benefit, including different tumor histologies (squamous: HR, 0.56; nonsquamous: HR, 0.72) and with varying PD-L1 expression levels (≥1%: HR, 0.64; <1%: HR, 0.66).
The researchers concluded that sugemalimab plus chemotherapy demonstrated statistically significant and clinically meaningful PFS and OS improvement compared with placebo plus chemotherapy, irrespective of tumor histology or PD-L1 expression levels, in patients with newly diagnosed metastatic NSCLC, thus offering a new first-line treatment option in this setting.
The CheckMate 227 part 1 trial (NCT02477826) demonstrated that first-line nivolumab plus ipilimumab is more effective than platinum-doublet chemotherapy in patients with metastatic non–small-cell lung cancer (NSCLC) regardless of tumor PD-L1 expression level.1 The combination treatment resulted in long-term, durable survival benefits. In a late-breaking presentation at the 2022 American Society of Clinical Oncology Annual Meeting, Brahmer and colleagues reported the results of the 5-year follow-up of CheckMate 227.2
CheckMate 227 enrolled patients with previously untreated stage IV or recurrent NSCLC, with no known EGFR/ALK mutations and an Eastern Cooperative Oncology Group performance status of 0 or 1.2 Patients with a PD-L1 expression level of ≥1% were randomized in a 1:1:1 ratio to receive nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), nivolumab (240 mg every 2 weeks), or platinum-doublet chemotherapy. Patients with tumor PD-L1 <1% were randomized 1:1:1 to receive nivolumab plus ipilimumab, nivolumab (360 mg every 3 weeks) plus chemotherapy, or chemotherapy alone.2
Patients were treated until progression, toxicity, or ≤2 years with immunotherapy. The investigators assessed overall survival (OS), progression-free survival, objective response rate, duration of response, and a novel efficacy end point, treatment-free interval.2 The treatment-free interval was evaluated in patients who discontinued study therapy for any reason, including treatment completion. It was defined as the time from the last study dose to the start of subsequent systemic treatment or death, whichever occurred first.2
At a minimum follow-up of 61.3 months, patients with tumor PD-L1 ≥1% (n = 1189) continued to derive long-term OS benefits with nivolumab plus ipilimumab compared with chemotherapy (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.66-0.91). The 5-year OS rates were 24% for patients in the nivolumab plus ipilimumab arm versus 17% for the nivolumab arm and 14% for the chemotherapy group.2 Patients in the nivolumab plus ipilimumab group had a median OS of 17.1 months compared with 15.7 months and 14.9 months for the nivolumab and chemotherapy arms, respectively.2
Similarly, patients with tumor PD-L1 <1% (n = 550) continued to derive OS benefit from nivolumab plus ipilimumab treatment compared with chemotherapy (HR, 0.65; 95% CI, 0.52-0.81). The 5-year OS rates were 19% for nivolumab plus ipilimumab, 10% for nivolumab plus chemotherapy, and 7% for chemotherapy alone. Patients in the nivolumab plus ipilimumab arm had a median OS of 17.4 months compared with 15.2 months and 12.2 months for the nivolumab and chemotherapy arms, respectively.2
Moreover, the median duration of response among patients treated with nivolumab plus ipilimumab was 24.5 months compared with 6.7 months for the chemotherapy group (PD-L1 ≥1%) and 19.4 months for the nivolumab plus ipilimumab group compared with 4.8 months for the chemotherapy group (PD-L1 <1%).2 Nivolumab plus ipilimumab increased the 5-year survivorship regardless of PD-L1 expression level, and the responses lasted ≥5 years in more than 40% of patients who responded. Furthermore, most responders remained treatment-free for ≥3 years after discontinuation of treatment.2
In summary, the 5-year follow-up of CheckMate 227 demonstrated that nivolumab plus ipilimumab is an effective and durable treatment regimen for patients with metastatic NSCLC, regardless of PD-L1 expression and is effective even in PD-L1–negative patients.
Intact DNA damage repair machinery is critical for maintaining normal cell-cycle function and preventing the development of cancer. Dysregulation of these pathways results in the accumulation of mutations, which increases malignancy potential. In addition, the continued disruption of the DNA repair machinery drives further progression of metastatic disease. Lung cancer is among the most genomically unstable cancers.1
In non–small-cell lung cancer (NSCLC), ATM is mutated in approximately 10% of patients and thus is the most mutated DNA damage and repair gene. A recent study by Ricciuti and colleagues characterized the clinicopathologic, genomic, and immunophenotypic correlates of ATM mutations in NSCLC and the effect of these mutations on the clinical outcomes with PD-(L)1 inhibition.2
Clinicopathologic and genomic data were collected from 3592 patients with NSCLC at the Dana-Farber Cancer Institute. Genomic profiling of tumor samples was performed using OncoPanel.2 Multiplexed immunofluorescence for CD8, PD-1, PD-L1, FOXP3, and CK AE1/AE3 was performed on 416 NSCLC samples to examine tumor-infiltrating immune cells. ATM immunohistochemistry was also performed on 184 ATM mutated (ATMMUT) NSCLC samples with available tissue. ATMMUT tumors were defined as harboring loss-of-function mutations (nonsense, frameshift, splice site, known deleterious missense mutations). Tumors lacking ATM mutations or harboring benign ATM alterations were defined as ATM wild-type (ATMWT).2
The researchers identified 399 deleterious ATM mutations in 10.2% (365/3592) of samples. Of these mutations, 138 (34.6%) were truncating, such as nonsense, frameshift, and splice site mutations. The remaining 261 (65.4%) were missense mutations. They further found that ATMMUT NSCLC samples were significantly enriched with KRAS, STK11, RBM10, and KDM5C co-mutations (P <.01), whereas co-mutations in EGFR, CDKN2A, and TP53 were nearly mutually exclusive (P <.01).2
Among ATMMUT NSCLC, those with ATM loss by immunohistochemistry were significantly enriched with KRAS and STK11 co-mutations, whereas those with retained ATM expression were enriched with TP53 co-mutations (P <.01).2
Patients with ATMMUT NSCLC had similar outcomes with PD-(L)1 inhibition with or without chemotherapy compared with ATMWT patients and similar immune cell subsets infiltration (P >.05). Patients with deleterious mutations in ATM and TP53 (ATMMUT/TP53MUT) had increased response rates to chemoimmunotherapy compared with those with ATMMUT/TP53WT, ATMWT/TP53MUT, or ATMWT/TP53WT genotypes (70% vs 56.2% vs 35.7% vs 27.4%, respectively; P = .01). These patients also had increased tumor–stroma interface CD8+ T-cells (P <.01) and higher PD-L1 expression on tumor (P <.01) and immune (P <.01) cells.2
The investigators concluded that deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features, which could guide treatment selection in the future. In addition, response rates to chemoimmunotherapy were correlated with the presence of deleterious mutations in ATM and TP53 (ATMMUT/TP53MUT).
Targeting PD-1 or its ligand (PD-L1) has been shown to induce an anticancer immune response in a proportion of patients with non–small-cell lung cancer (NSCLC).1 However, the efficacy of immune checkpoint inhibitors varies among patients. Studies have demonstrated that immune-related adverse events (irAEs) correlate with survival for single-agent anti–PD-1/PD-L1 therapy in NSCLC.2 Similarly, combined pharmacologic blockade of a second checkpoint, such as CTLA-4, with PD-1 allows heightened immune activation, resulting in both improved cancer outcomes but more irAEs.2
Studies have demonstrated that inherited heterozygosity for single-nucleotide polymorphisms (SNPs) within and surrounding CTLA-4 is associated with autoimmune diseases, such as autoimmune thyroid disease and rheumatoid arthritis, and type 1 diabetes.2,3 Based on these findings, Allen and colleagues hypothesized that SNPs impacting CTLA-4 function could be enriched in patients with NSCLC with exceptional response to single-agent anti–PD-1. In this study, exceptional response was defined as progression-free survival of ≥2 years and ≥1 irAEs of Common Terminology Criteria for Adverse Events grade ≥2.2
The researchers performed whole-genome sequencing on germline DNA from 35 prospectively recruited patients meeting these criteria from a treatment pool of >700 patients. The frequency of a curated list of SNPs located within a 200-kilobase region encompassing CTLA-4 was analyzed and compared with patients with lung cancer within the Pan-Cancer Analysis of Whole Genomes (PCAWG) and with cancer- and dementia-free elderly individuals in the Medical Genome Reference Bank (MGRB).2
Several noncoding SNPs enriched within the exceptional responders compared with control populations were identified using linear regression analysis. It is interesting to note that one of these SNPs was found in 15.7% of exceptional responders, which was twice the frequency of comparable cases within PCAWG and almost 4 times more than MGRB and remained statistically significant following rigorous adjustment. This noncoding SNP is reported to exhibit differential enhancer activity and has been associated with rheumatoid arthritis and type 1 diabetes. Its enrichment within the exceptional responders suggests that the altered CTLA-4 function may cooperate with the blockade of PD-1 to confer a higher immune response.2
The investigators concluded that this common variant might serve as a response biomarker for single-agent anti–PD-1 treatment or may comprise a potential therapeutic target. Preclinical analyses and validation within an independent cohort are underway.
Despite advances in the use of immune checkpoint inhibitors (ICIs) to treat patients with non–small-cell lung cancer (NSCLC), only a subset of patients achieves the desired clinical benefit.1 Thus, there is an increasing interest in combining ICIs with other therapeutic modalities, including chemotherapy.1 However, the benefit in real-world practice of combining ICIs with chemotherapy compared with ICI monotherapy in patients with NSCLC is not well-established.2
This retrospective study included patients with metastatic NSCLC from a single-institution database treated with an ICI alone (pembrolizumab, nivolumab, or atezolizumab) or combined with platinum-based chemotherapy between January 2014 and February 2020. The study’s primary outcomes were clinical progression-free survival (PFS) and overall survival. First-line treatment outcomes were analyzed using propensity score adjustment for clinical and sociodemographic characteristics.2
A total of 1139 patients (54% male; median age, 64.9 years) were included in the study. Adenocarcinoma histology, smoking history, higher PD-L1 expression, and lower metastatic stage were associated with improved PFS. PD-L1 expression and smoking were associated with improved PFS only in patients with adenocarcinoma. Conversely, patients with squamous histology had shorter PFS independent of PD-L1 and smoking history.
In first-line–treated patients (n = 680), ICI combined with chemotherapy resulted in higher progression-free rates at 3 and 6 months compared with ICI monotherapy (3-month PFS, 85.2% vs 68.8%; P = .001 and 6-month PFS, 66.4% vs 52.6%; P = .008). The presentation provided overall results for ICI therapy and did not distinguish data among the 3 ICIs used. There was no difference overall in PFS or overall survival in either the full cohort or propensity matched cohort that took into account covariates. Treatment with ICI and chemotherapy concurrently compared with sequentially was associated with similar PFS (log-rank P = .12).
The investigators concluded that the addition of chemotherapy to ICIs may protect against early progression in real-world practice but does not affect long-term outcomes. Furthermore, treatment with sequential compared with concurrent ICI and chemotherapy regimens led to similar outcomes. These findings suggest that combination therapy may benefit patients at risk of early progression.
Anti–PD-(L)-1 monotherapy and in combination with chemotherapy are both standard first-line regimens for patients with PD-L1–high (≥50%) metastatic non–small-cell lung cancer (NSCLC).1 The efficacy of these treatment options has not been assessed prospectively.1 In addition, molecular tumor characteristics that are differentially associated with response to anti–PD-(L)-1 monotherapy compared with combination treatment with chemotherapy are not well-defined.1
This study included patients with EGFR- and ALK-negative metastatic NSCLC treated with anti–PD-(L)-1 monotherapy or in combination with chemotherapy at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute. The study excluded patients with PD-L1 expression <50%, and those treated with immune checkpoint inhibitors (ICIs) or chemoimmunotherapy in the first-line or higher setting. The goals of the study were to compare overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) and investigate potential clinical, pathologic, and molecular response correlates. Tumor mutational burden (TMB) values were harmonized using a z-score conversion.1
Of the 639 patients with stage IV EGFR/ALK wild-type NSCLC and PD-L1 ≥50% treated in the first-line setting, 504 received pembrolizumab and 135 received pembrolizumab plus chemotherapy. Patient baseline characteristics, including Eastern Cooperative Oncology Group performance status, median PD-L1 expression, and TMB were balanced between both treatment groups. Moreover, there was no difference between the groups in PD-L1 expression, TMB, or mutational (KRAS, STK11, or KEAP1) profile. Never-smokers with durable responses (>6 months) were less common in the monotherapy group (6% vs 18%; P <.001).
There was no significant difference in OS among patients treated with pembrolizumab monotherapy or in combination with chemotherapy (hazard ratio [HR], 0.8; 95% confidence interval [CI], 0.6-1.08; P = .2). However, patients in the ICI monotherapy group had a shorter median PFS (HR, 0.7; 95% CI, 0.6-0.9; P = .004) and lower ORR compared with the chemoimmunotherapy group (40% vs 55%; P = .002).
The investigators concluded that the addition of chemotherapy to ICI in patients with PD-L1–high NSCLC did not improve OS compared with ICI monotherapy. Furthermore, there were no apparent differences in PD-L1 expression or molecular features associated with durable response to ICI monotherapy compared with the chemotherapy combination.
Advances in cancer immunotherapy have led to the development and approval of innovative immune checkpoint inhibitors (ICIs) that stimulate an anticancer immune response. ICIs that target PD-L1 demonstrated efficacy in patients with advanced non–small-cell lung cancer (NSCLC) as monotherapy and in combination with other therapeutic modalities.1 The US Food and Drug Administration (FDA) has approved ICIs with or without chemotherapy to treat patients with PD-L1–high advanced NSCLC in the first-line setting; however, the clinical benefit of these regimens has not been well-established in this population.2
This study analyzed pooled data from 12 randomized controlled trials that investigated anti–PD-(L)1 regimens with or without chemotherapy to treat patients with advanced NSCLC in the first-line setting. PD-L1 score was measured based on the proportion of tumor cells stained by the assay, and analysis was conducted for patients with tumor PD-L1 scores ≥50%.2 Using a pooled analysis, the study compared overall survival (OS), progression-free survival (PFS), and overall response rate between chemoimmunotherapy and immunotherapy alone. Median survival times were estimated using Kaplan-Meier methods, and hazard ratios (HRs) using Cox proportional hazards models stratified by trial. In addition, odds ratios were calculated using a logistic regression model with trial as a covariate. All analyses were adjusted for age, sex, race, Eastern Cooperative Oncology Group (ECOG) performance status, histology, and smoking status.2
The study included 3189 patients with NSCLC and PD-L1 scores ≥50%. Of the enrolled patients, 38% were aged 65 to 74 years, with ECOG scores of ≥1. In addition, 89% were former or current smokers. The median OS in the pooled chemoimmunotherapy (chemo-IO; n = 455) and immunotherapy-only (I-O; n = 1298) arms was 25.0 months compared with 20.9 months (HR, 0.82; 95% confidence interval [CI], 0.62-1.08); median PFS was 9.6 months versus 7.1 months, respectively (HR, 0.69; 95% CI, 0.55-0.87). The overall response rate was higher with chemo-IO than with I-O (61% vs 43%; odds ratio, 1.2; 95% CI, 1.1-1.3).2
The researchers concluded that most patients with PD-L1 scores ≥50% treated with FDA-approved chemoimmunotherapy regimens had OS and PFS outcomes comparable to or better than patients treated with ICI monotherapy. Importantly, elderly patients aged ≥75 years did not achieve improved outcomes with chemoimmunotherapy compared with ICI monotherapy. These findings highlight the importance of shared decision-making and consideration of patient factors that affect tolerability.
Immune checkpoint inhibitors (ICIs) have emerged as effective treatment options for patients with advanced non–small-cell lung cancer (NSCLC) due to their durable clinical benefit and manageable toxicity. However, resistance and early progression have been reported, even in patients with tumors that express biomarkers associated with ICI response.1 Resistance to ICIs has led to an interest in combining ICIs with chemotherapy to improve patient outcomes.2 This study investigated the hypothesis that a circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients at risk of early progression following treatment with ICIs, which may guide treatment with regimens that combine ICIs and chemotherapy in the first-line setting.2 TF is a measure of the proportion of ctDNA that is derived from tumor cells in blood samples and has been shown to correlate with tumor growth and metastasis.3
This study used the nationwide (US-based) deidentified Flatiron Health-Foundation Medicine NSCLC clinico-genomic database. The deidentified data were obtained from approximately 280 US cancer clinics. Real-world overall survival (rwOS) and real-world progression-free survival (rwPFS) were estimated using Kaplan-Meier analysis. Hazard ratios (HRs) were calculated using multivariate Cox proportional hazard models adjusting for relevant covariates. TF, which reflects the proportion of ctDNA that is derived from tumor cells,3 was measured using an aneuploidy-based assay plus variant-based estimate and was categorized as follows: ≥10%: elevated; 1%-10%: intermediate; <1%: low. Early progression was defined as real-world progression within 8 weeks of starting therapy.2
The trial included 426 patients with advanced NSCLC who initiated first- or second-line ICI therapy (128 ICI, 298 ICI plus chemotherapy) within 60 days of testing with a liquid biopsy. Of these patients, 88 (21%) had elevated TF, 193 (45%) had intermediate TF, and 145 (34%) had low TF. Patients with elevated TF had a higher frequency of liver involvement (elevated: 27%; intermediate: 12%; low: 8%) and had worse Eastern Cooperative Oncology Group performance status scores of >2 at baseline (elevated: 33%; intermediate 22%; low: 17%). Among the 100 patients with elevated TF, 44% had an unknown PD-L1 status, 23% had high PD-L1 expression, 19% had low PD-L1 expression, and 14% were negative for PD-L1. In addition, early progression was more frequent among patients with elevated TF (elevated: 26%; intermediate: 22%; low: 15%).
Patients with low TF treated with either an ICI with or without chemotherapy had better median rwPFS (low: 6.7 months; intermediate: 5.1 months, HR: 1.39 [1.11-1.74]; elevated: 3.4 months, HR: 1.74 [1.31-2.31]). In addition, patients with low TF had better median rwOS (low: 14.2 months; intermediate: 8.4 months, HR: 1.52 [1.10-2.09]; elevated: 4.6 months, HR: 2.17 [1.47-3.21]). Combining chemotherapy to ICI in patients with elevated TF improved rwPFS and rwOS compared with patients who received an ICI alone.2 Among patients with elevated TF, those treated with the combination regimen had rwPFS and rwOS of 4.3 months and 7.2 months, respectively, compared with rwPFS and rwOS of 1.9 months for those treated with ICI monotherapy.
In summary, evaluation of ctDNA may identify patients with advanced NSCLC who are at high risk for early progression following initiation of ICI therapy and who may benefit from the combination of ICI plus chemotherapy in the first-line setting.
Limited non–small-cell lung cancer (NSCLC) tissue sections pose challenges for biomarker testing to guide therapeutic decisions.1 Genetic sequencing helps guide targeted therapy, but recent proteogenomic studies demonstrated the importance of protein expression in classifying tumor subtypes. Precision cancer treatment is primarily based on genetic sequencing rather than proteomic testing due to the lack of robust proteomic assays.2 To complement existing approaches for treatment and trial matching of lung cancer patients, a multiplexed proteomic assay was developed and evaluated in this study.2
Candidate biomarkers were selected based on known biology and clinical relevance. Using a matrix prepared from 25 NSCLC cell lines, reverse calibration curves were used to evaluate assay sensitivity, linearity, and performance. When needed, samples were reviewed by a pathologist and processed with filter-aided sample preparation.2
The multiplexed liquid chromatography-multiple reaction monitoring (LC-MRM) assay was successfully applied to NSCLC cell lines (n = 25), formalin-fixed paraffin-embedded (FFPE) specimens (n = 30), and frozen tissues (n = 108).2 The results differentiated subtypes of 25 NSCLC cell lines and frozen lung squamous-cell carcinomas (LSCC) based on the expression levels of proteins to assess tumor phenotype, cancer signaling, and immune status.2
The samples prepared from FFPE specimens with limited sizes demonstrated compatibility with biopsies. The LC-MRM data from tumor specimens were consistent with pathology evaluations. The 108 tumors from LSCC patients could be grouped into subtypes, including immune hot and immune cold tumors based on B- and T-cell markers. Quantitation of cancer antigens can also assist with the direction of immunotherapy.2
The investigators demonstrated that a highly multiplexed targeted proteomics assay can be used to quantify biomarkers in lung cancer cell lines, FFPE specimens, and frozen tumor tissues. Furthermore, the LC-MRM assay can be implemented with tumor biopsies to enable therapy selection and trial matching. A future study is planned to allow the researchers to examine the MRM assay results of 108 LSCC tissues by comparing them to previous proteogenomic results to further understand tumor biology.2
Despite the proven efficacy of immune checkpoint inhibitors (ICIs) in treating patients with non–small-cell lung cancer (NSCLC), only a subset of patients achieves the desired treatment goals.1 To date, identifying reliable and robust biomarkers to predict the benefit of ICI treatment remains challenging.2 The objectives of this study were to evaluate the ability to predict response to ICI therapy by integrating medical imaging, histopathologic, and genomic characteristics to develop a multimodal biomarker for immunotherapy response.
The investigators used baseline data from a diagnostic clinical workup at a single center.2 The multimodal data set included DNA alterations from next-generation sequencing, computed tomography scan images, and digitized PD-L1 immunohistochemistry (IHC). A workflow was designed to extract data for each patient and used an attention-gated machine learning approach to integrate the features into a risk prediction model.
The study included 247 patients with advanced NSCLC who received immunotherapy and completed radiology, pathology, genomics, and clinical evaluations. The patient cohort was 54% female with a median age of 68 years (range, 38-93 years), and 88% of patients had a smoking history.
A radiomics approach was used, and the average individual lesion predictions were aggregated to construct patient-level response predictions, which resulted in an overall AUC (area under the curve) = 0.65 (95% confidence interval [CI], 0.57-0.73), where AUC = 0.0 is 100% wrong and AUC = 1.0 is 100% correct. In addition, formalin-fixed, paraffin-embedded tissue slides of pretreatment PD-L1 IHC staining of tumor specimens were digitized. Overall, 52% of slides showed a PD-L1 tumor proportion score (TPS) ≥1% and were used to extract IHC-texture, a novel spatial characterization of PD-L1 staining. Logistic regression modeling on IHC-texture resulted in prediction accuracy of AUC = 0.62 (95% CI, 0.51-0.73), which was inferior to the pathologist-assessed PD-L1 TPS (AUC = 0.73; 95% CI, 0.65-0.81).
A dynamic, deep attention-based, multiple-instance learning model was implemented with masking to evaluate the impact of combining features from all modalities. The multimodal model (AUC = 0.80; 95% CI, 0.74-0.86) was superior to unimodal measures, including tumor mutational burden (AUC = 0.61; 95% CI, 0.52-0.70) and PD-L1 TPS (AUC = 0.73; 95% CI, 0.65-0.81).
In conclusion, this proof-of-concept study demonstrated that multimodal approaches using expert-guided machine learning are superior to conventional unimodal strategies in predicting response to immunotherapy in patients with NSCLC.
Although immune checkpoint inhibitors (ICIs) have advanced the treatment of patients with non–small-cell lung cancer (NSCLC), most patients develop resistance to ICIs following an initial response. The mechanisms of resistance remain largely unknown.1
This retrospective study included patients with advanced NSCLC treated with ICIs at the Dana-Farber Cancer Institute and whose tumors underwent genomic analysis before and after treatment. Mutations, tumor mutational burden (TMB), copy number variations, and PD-L1 tumor proportion scores (TPS) were analyzed in pre- and post-ICI samples. Acquired resistance was defined as the development of disease progression after an initial objective response or stable disease ≥3 months with PD-(L)1 blockade.2
A total of 45 patients with advanced NSCLC who received ICI had matched pre- and post-ICI tissue samples available for genomic profiling. Several putative resistance mechanisms were identified in 55% of cases (n = 25), including an acquired STK11 mutation (20%), an acquired KEAP1 mutation (4%), and development of concurrent KEAP1 and SMARCA4 mutations (4%). In addition, 1 (4%) patient with KRAS G12C–mutant NSCLC developed concurrent STK11 and KEAP1 mutations that led to resistance to ICI therapy. In 3 (12%) cases with preexisting STK11 or KEAP1 mutations before ICI administration, acquired copy losses of STK1 and KEAP1, respectively, were identified, resulting in bi-allelic inactivation of these genes. In addition, acquired beta-2-microglobulin (B2M) mutations were detected in 3 (12%) patients, 1 of whom developed concurrent B2M copy loss, indicating bi-allelic inactivation. Eight (32%) additional patients developed B2M gene deletions.2
Other acquired alterations that were implicated in ICI resistance included CDKN2A/B loss (n = 10; 40%), including 5 with bi-allelic deletion, acquired PTEN deletions (n = 5; 20%), and MDM2 amplification (n = 2; 8%).
Furthermore, alterations in immune checkpoint genes were identified, including acquired CD274 (PD-L1) and PDCD1LG2 (PD-L2) loss in 8% of cases (n = 2), and bi-allelic deletion in 1 case (4%). ICI treatment did not affect TMB (median TMB: 8.7 [pre-ICI] vs 9.1 [post-ICI] mut/Mb; P = .6), PD-L1 expression (median PD-L1 TPS: 3% [pre-ICI] vs 5% [post-ICI] mut/Mb; P = .5), or aneuploidy levels (as fraction of the genome altered [FGA]) (median FGA: 18.4% [pre-ICI] vs 21.1% [post-ICI]; P = .2). These findings suggest that acquired gene level copy number variations were not a reflection of increased cancer aneuploidy.2
In a control cohort of 30 patients with pre- and post-chemotherapy matched samples that underwent genomic analysis, no acquired mutations in STK11, KEAP1, SMARCA4, or B2M were detected.2
The investigators concluded that mechanisms of acquired resistance to PD-(L)1 blockade are heterogeneous, and novel therapeutic approaches are required to delay and overcome ICI resistance in patients with NSCLC.
Accumulating evidence has demonstrated that the functional activity and trafficking of T (CD8) lymphocytes, the primary target cells of nivolumab, and other immune cells are regulated over the 24-hour cycle by the molecular circadian timing system.1 Based on these studies, it was hypothesized that the pharmacologic effects of nivolumab, which targets PD-1 receptors expressed on T-cells, could be affected by circadian clocks.2
In this study, researchers investigated whether increasing the proportion of morning nivolumab infusions could improve efficacy in patients with metastatic non–small-cell lung cancer (NSCLC). Patients received nivolumab (240 mg intravenously every 2 weeks) at a time of day that was randomly allocated for each course by the day-hospital coordinators.2
The median time of actual nivolumab infusions was adjusted for each patient. The study population was split into 3 timing cohorts based on a 24-hour cycle: a “morning” group, in which patients received ≥2/3 of nivolumab infusions before 12:54; an intermediate group, where the patients received ≥1/3 of nivolumab infusions before and 1/3 after 12:54; and an “evening” group, where patients received ≥2/3 of nivolumab infusions after 12:54. Toxicity rates, tumor responses, progression-free survival (PFS), and overall survival (OS) were assessed based on the nivolumab timing group.2
A total of 95 previously treated patients with stage IV NSCLC were retrospectively assigned to a “morning” group (36 patients), an intermediate group (24 patients), and an “evening” group (35 patients). Of the included patients, 76% received nivolumab as second-line therapy.2
Tumor PD-L1 status was positive for 39 of 72 patients (54%). Patient characteristics were similar among the 3 groups, except for liver metastases (41.7%, 8.3%, and 25.7% for “morning,” intermediate, and “evening” groups, respectively; P = .010).
Grade 2-4 fatigue was observed least in the “morning” group (28%) compared with 62% (intermediate) and 40% (“evening”) (P = .027). Median PFS was 11.1 months for the “morning” group, 5.9 months for the intermediate group, and 3.1 months for the “evening” group (P = .002). Median OS was 34.2 months for the “morning” group, 15.3 months (95% confidence interval [CI], 8.0-22.7) for the intermediate group, and 12.4 months (95% CI, 4.0-20.7) for the “evening” group (P = .023). Respective 2-year survival rates were 52.6%, 26.2%, and 15.0%, respectively (P = .002). Multivariable analysis confirmed that the administration of >2/3 nivolumab in the morning was associated with longer PFS (hazard ratio [HR], 0.26, 0.14-0.51; P <.001) and OS (HR, 0.22, 0.10-0.51; P <.001).
The investigators concluded that nivolumab was more effective in the “morning” than in the intermediate or “evening” groups. These findings highlight the importance of randomized and translational circadian timing studies to understand the mechanisms of the chronopharmacology of ICIs to maximize their therapeutic benefits while minimizing the risk of therapeutic resistance.
Immune checkpoint inhibitors (ICIs) have advanced the treatment of patients with non–small-cell lung cancer (NSCLC). However, pivotal clinical trials have excluded patients with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS ≥2) despite their prevalence in the real-world setting.1 The main objective of this study was to evaluate the impact of ECOG PS on clinical outcomes and healthcare utilization in a large cohort of patients with NSCLC treated with ICIs in a real-world setting.
The study used the Alberta Immunotherapy Database to identify patients with advanced NSCLC who received ≥1 doses of pembrolizumab or nivolumab between January 1, 2010, and December 30, 2019. The data cutoff was October 1, 2020. In addition, baseline clinical, pathologic, and laboratory-based data were collected retrospectively.
The primary outcome of the study was median overall survival stratified by ECOG PS, and the secondary outcomes were median time-to-treatment failure (mTTF) and healthcare utilization measures, including emergency department visits, hospitalizations, and death in hospital. Kaplan-Meier survival curves were used to assess survival outcomes and compared with the log-rank test. In addition, the association between ECOG PS and healthcare utilization was represented with risk ratios and evaluated using chi-square tests.
The study included 790 patients with a median follow-up time of 20.6 months. Of these patients, 29.2% (n = 231) had PS ≥2 at the time of ICI initiation. Patients with PS ≥2 had significantly lower median overall survival (3.3 months; 95% confidence interval [CI], 2.5-4.0) than those with favorable PS (PS <2) (13.4 months; 95% CI, 11.7-16.0) (hazard ratio [HR], 3.0; 95% CI, 2.5-3.6; P <.0001), and lower mTTF of 1.4 months (95% CI, 0.9-1.8) compared with 4.9 months (95% CI, 4.4-5.6) (HR, 2.2; 95% CI, 1.9-2.6; P <.0001). In addition, the 3- and 12-month survival rates were also significantly lower in the PS ≥2 group than in the PS <2 group (52.8% vs 86.4% and 13.4% vs 41.0%; P <.0001 for both comparisons).
In addition, patients with PS ≥2 were significantly more likely to utilize the emergency department (relative risk [RR], 1.6; 95% CI, 1.3-2.0; P <.001) and be admitted to the hospital (RR, 2.3; 95% CI, 1.7-3.0; P <.0001) within the first month after treatment initiation. These patients were also significantly more likely to die in the hospital during their first admission (RR, 2.7; 95% CI, 1.8-4.1; P <.0001) and at any point during treatment (RR, 2.2; 95% CI, 1.6-3.0; P <.0001).
The researchers concluded that patients with NSCLC in the real-world setting who have poor ECOG PS at the time of ICI initiation had significantly worse survival outcomes and were significantly more likely to utilize healthcare services than those with favorable ECOG PS. These findings highlight the need for randomized trials to evaluate the efficacy of ICI in this high-risk population.
Intratumoral injection of toll-like receptor agonists induces an interferon response signature and antitumor CD8+ T-cells, improving responses to anti–PD-1 therapy. In addition, toll-like receptor 9 (TLR9)-mediated T-cell activation can induce PD-1 expression. Thus, combining TLR9 agonists with approved PD-1 blockade therapies is a rational approach to target cancer immune evasion.1
Vidutolimod is a cytidine phosphate guanosine (CpG-A) oligodeoxynucleotide packaged in a virus-like particle. It acts as a TLR9 agonist leading to the activation of plasmacytoid dendritic cells (pDC). Studies have shown that intratumoral vidutolimod alone or in combination with intravenous anti–PD-L1 has promising anticancer activity in patients with anti–PD-L1-refractory melanoma or non–small-cell lung cancer (NSCLC). The response, however, was not correlated with anti–PD-L1-related biomarkers. The aim of this study was to identify novel transcriptional signatures as potential response biomarkers to vidutolimod-based therapy.2
In this study, RNA sequencing was performed on baseline biopsies from patients with anti–PD-L1-refractory NSCLC (n = 11) treated with vidutolimod alone or in combination with anti–PD-L1 therapy. Deconvolution of immune cells was performed using TIMER2.0. Prediction models were generated using QLattice. Signatures were characterized using both publicly available bulk and single-cell RNA-Seq data sets of pDC subsets or PD-1/CTLA-4 blockade response data sets.2
The investigators identified 2 gene signatures, COPII vesicle and Golgi targeting, that were strongly correlated with response to vidutolimod.2 Leading-edge analysis of these signatures identified 35 common core genes that strongly differentiated RECIST version 1.1 responders compared with patients with progressive disease. Common core enrichment was also significantly associated with tumor shrinkage in patients with NSCLC (P = .027).2 Common core genes were significantly correlated with response to vidutolimod single-agent or combination treatment but not with clinical baseline prognostic factors or interferon-γ18.
A model based on common core genes and transcription factor ELF2 predicted response in melanoma (area under the curve, 0.93; 95% confidence interval, 0.82-1.00). In public data sets, common core genes were not associated with response to PD-1/CTLA-4 blockade but were highly expressed in the type I interferon-secreting subset of pDCs and some myeloid cells.
The investigators concluded that COPII vesicle and Golgi targeting transcriptional signatures were associated with antitumor activity of intratumoral vidutolimod in combination with anti–PD-L1 in patients with anti–PD-1-refractory melanoma or NSCLC.