A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers

Abstract

Purpose:

Gemcitabine and albumin-bound paclitaxel (ABP) exhibit synergistic anti-tumor efficacy, with ABP serving to increase the intratumoral gemcitabine concentration. Both drugs are active in squamous cell lung cancers (SQCLCs) and are conventional partners for carboplatin. We hypothesized that combining gemcitabine and ABP would enhance the anti-tumor activity in patients with advanced SQCLCs.

Experimental Design:

This was a Simon two-stage, open-label, single-arm, multicenter phase II study that enrolled patients between August 1, 2015 and June 1, 2018. We enrolled 37 patients with chemotherapy-naïve, PD-L1 low/unknown advanced stage IV SQCLC. Patients were administered weekly intravenous gemcitabine (1000 mg/m²) plus ABP (100 mg/m²) in a 3 week on, 1 week off schedule during Stage 1 and a 2 week on, 1 week off schedule in Stage 2. The primary endpoint was best objective response rate (ORR). Next-generation sequencing by MSK-IMPACT was used to calculate tumor mutation burden and genome doubling and assess somatic variants for correlations with efficacy.

Results:

Thirty-two patients were evaluable for response assessment. The study satisfied its primary endpoint, with confirmed partial responses in 18 of 32 patients and a complete response in 1 patient (ORR 59%, 95% CI 42% to 74%). Median progression-free survival (PFS), a secondary endpoint, was 7.5 (95% CI 6.7 to 10.5) months. There were no unexpected toxicities.

Conclusions:

Gemcitabine plus ABP was a safe, tolerable, and effective first-line therapy for patients with chemotherapy-naïve SQCLCs, with an ORR and median PFS substantially higher than carboplatin doublet regimens and efficacy comparable to carboplatin plus taxane plus pembrolizumab.

INTRODUCTION

Lung cancer remains the leading cause of cancer death in the United States despite modest improvements in overall mortality since the mid-2000s. While progress has been greatest for patients with non-small cell lung cancers (NSCLC), many of the improvements have come from gains in the detection and effective targeting of oncogene-defined subsets of patients with adenocarcinoma of the lung (ADCL). Indeed, the median overall survival (OS) for patients with the best prognosis stage IV ADCL now exceeds 3 years (1).

In contrast, patients with stage IV squamous cell lung cancers (SQCLCs) have seen few therapeutic advances over the past two decades. While the addition of pembrolizumab to carboplatin plus a taxane (KEYNOTE 407) recently cemented chemotherapy plus immunotherapy as a new first-line standard for many stage IV SQCLC patients, the study was of interest for another reason—the relatively poor, though historically consistent, performance of the platinum doublet control arm.

Platinum therapy began development in the late 1970s, with much of the early work focused on dose intensity studies that yielded average response rates of about 19% and little in the way of significant gains with increasing drug exposure (2). Contemporaneous pre-clinical studies using both cisplatin and carboplatin focused on platinum-resistant cell lines showed that several agents exhibited non-cross-resistant cytotoxic effects without synergistic antitumor activity (3,4). In the absence of data demonstrating antitumor synergy with any specific partner, several randomized trials were conducted with rotating non-platinum partners that showed, by and large, additive effects (5,6). The epoch of platinum doublet studies in NSCLC came to a head with Schiller and colleagues’ (7) comparison of four cisplatin-containing doublet therapies which found that, across all partners, platinum-doublet therapy generated an overall response rate (ORR) of 19%, median progression-free survival (PFS) of 3.6 months, and median OS of 7.9 months with no clinically meaningful differences between regimens.

More recent studies suggested that SQCLC responds modestly better to gemcitabine and albumin-bound paclitaxel (ABP) (8,9). Our group has also presented data suggesting that carboplatin might contribute minimally to the antitumor efficacy of ABP. Results of a phase 1/2 study of ABP in untreated stage IV NSCLC (10) showed that ABP monotherapy was associated with an ORR of 30%, median PFS of 5 months, and median OS of 11 months, similar to the benchmarks established for platinum-doublet regimens.

Indeed, pre-clinical data (11) suggested that abandoning a platinum partner could improve doublet therapy effectiveness, with Frese and colleagues reporting compelling evidence of antitumor synergy between gemcitabine and ABP in models of pancreatic cancer. ABP’s ability to downregulate intracellular cytidine deaminase, the primary enzyme that inactivates gemcitabine, increased the intratumoral concentration of gemcitabine.

Considering these data, we launched a phase 2 study of gemcitabine plus ABP in patients with treatment-naïve stage IV SQCLC, hypothesizing that this non-platinum doublet regimen would generate superior efficacy compared to historical platinum doublet regimens.

PATIENTS AND METHODS

Study Design and Participants

This was a single-arm, phase 2, Simon two-stage, trial of gemcitabine plus ABP in patients with treatment-naïve stage IV SQCLC ( NCT02525653). Patients were recruited and treated at Memorial Sloan Kettering Cancer Center (MSK), its regional sites (7 sites), and Miami Cancer Institute. The study opened to accrual in August 2015 and completed accrual in June 2018. The study was approved by the MSK institutional review board and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent prior to participation.

Eligible patients were age 18 years or older with histologically confirmed SQCLC, a new diagnosis of untreated stage IV disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, measurable disease by RECIST 1.1, and less than grade 2 pre-existing peripheral neuropathy. Programmed cell death ligand 1 (PD-L1) tumor proportion scores (TPSs) were less than 50% or unknown (insufficient tissue for testing). Patients had normal organ and marrow function. Prior treatment with ABP or gemcitabine was precluded as was any prior systemic anti-cancer therapy for metastatic SQCLC. Patients with untreated brain metastases were excluded; patients with prior treated brain metastases who were off steroids were eligible.

Procedures

All patients received intravenous gemcitabine 1000 mg/m² plus ABP 100 mg/m². Patients in the first stage of the study received doublet therapy on days 1, 8, and 15 out of a 28-day cycle for up to 6 consecutive cycles of therapy. Interim analysis of the first stage of the study showed an average dose density equivalent to a 2-weeks on, 1-week off frequency, therefore, the dosing regimen was amended to treat on days 1 and 8 of a 21-day cycle with an option to initiate maintenance ABP after the fourth cycle. Toxicity was graded according to the National Cancer Institute’s (NCI’s) Common Terminology Criteria for Adverse Events version 4.0. Patients underwent CT imaging of known sites of disease every 2 cycles. Available archived tumors underwent next-generation sequencing (NGS) by MSK-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) (12).

Statistical Analysis

The primary objective of the study was to determine the objective response rate (ORR, complete response plus partial response) by RECIST 1.1. Secondary objectives included assessment of safety and tolerability, estimation of median PFS and overall survival (OS), and correlations between response metrics and NGS results. Patients were evaluable for the primary objective if they completed at least 1 imaging assessment after starting therapy. Patients who received at least 1 dose of therapy were evaluable for adverse event (AE) assessment. The trial was designed using a Simon optimal two-stage design. A best overall response less than 25% was considered not promising (null hypothesis) and an ORR rate greater than 45% was considered promising (alternative hypothesis). The probabilities of a one-sided Type I error (falsely accepting a non-promising therapy) and Type II error (falsely rejecting a promising therapy) were set to 0.05 and 0.2, respectively. In the first stage of this design, 17 patients were to be treated. If six or more patients had a response, then up to 24 additional patients were to be accrued in the second stage. At study completion, the regimen was to be considered worthy of further investigation if 15 or more responses were observed among up to 41 patients treated. With this design, the probability of early termination under the null hypothesis was 77%.

Somatic alterations in key oncogenes and tumor suppressors were assessed using MSK-IMPACT, a custom hybridization-capture based assay which interrogates for variants in 403 genes from formalin-fixed paraffin-embedded tumor specimens (12). Total, allelic, and integer copy number alterations were estimated using the FACETS algorithm (13); samples were called whole genome duplicated if the fraction of major alleles greater than 1 was over 50% (14). Tumor mutation burden was calculated as the number of mutations per Mb over the MSK-IMPACT target regions. PD-L1 expression was assessed using a New York State-approved, Clinical Laboratory Improvement Amendments-certified laboratory-derived test based on the E1L3N antibody clone, which was cross-validated against the Dako 22C3 antibody clone.(15,16) Expression is reported as the percentage of tumor cells with membranous staining (range 0-100%).

RESULTS

All patients had histologically-confirmed stage IV SQCLC (Table 1). The median age of the study population was 70 (range, 43-84) years; 22 of 37 patients (59%) were 70 years or older. Most patients were men, and nearly all patients were heavy former or current smokers. PD-L1 IHC results were available on 19 of 37 patient samples (51%) at the time of diagnosis and treatment; 18 of 37 patient samples (49%) had insufficient material for testing.

Table 1.

Patient and tumor characteristics

	n=37
Age
Median (range), yr	70 (43-84)
Age ≥ 70, No. (%)	22 (59)
Sex
Female, No. (%)	11 (30)
Male, No. (%)	26 (70)
Smoking history
Former/current smokers, No. (%)	35 (95)
Median pack years (range), packs/yr	40 (0-111)
Karnofsky performance status
Median (range)	80 (70-90)
Histology
Squamous, No. (%)	37 (100)
PD-L1 IHC
TPS ≤ 50%, No. (%)	19 (51)
TPS range	0-20%
Insufficient for testing, No. (%)	18 (49)
MSK-IMPACT
Performed, No. (%)	24 (65)
Insufficient for testing, No. (%)	13 (35)

PD-L1, programmed cell death ligand 1; IHC, immunohistochemistry; TPS, tumor proportion score

Overall, the most common clinical AEs were fatigue in 11 (30%) of 37 patients, peripheral edema in 4 (11%) patients, and dysgeusia, nail changes, lung infection, rash, and peripheral neuropathy (3 each [8%]) (supplementary Table 1). Nine (24%) of 37 patients experienced a grade 3 or higher clinical AE. The most common grade 3 or worse clinical AE was fatigue (in 4 patients [11%]). No patient experienced grade 2 or higher peripheral neuropathy. The most common laboratory toxicities were hematologic in nature, including anemia (29 [78%] of 37 patients), lymphopenia (18 [49%]), thrombocytopenia (21 [57%]), decreased neutrophil count (13 [35%]), and AST/ALT increases (16 [43%]/18 [49%] respectively) (supplementary Table 1). Twenty (54%) of 37 patients experienced a grade 3 or worse treatment-related laboratory AE, primarily lymphopenia (16 [43%] of 37 patients). Other grade 3 or higher AEs included anemia (in 6 [16%]), decreased neutrophil count (in 6 [16%]), thrombocytopenia (in 2 [5%]), and increased AST/ALT (in 2 [5% each]).

Seven patients (19% of 37 patients) experienced a treatment-related severe adverse event (SAE) (supplementary Table S2). There were no treatment-related deaths. No patient experienced an AE attributable to pneumonitis; however, 3% (1 of 37) of patients reported dyspnea and 8% (3 of 37 patients) were diagnosed with lung infections that resolved with supportive care.

Interim analysis at stage 1 suggested that most patients would benefit from a modest decrease in dose exposure based on AE and dose density data. Of the patients treated in stage 1, 24% (4 patients) experienced grade 3 anemia and 24% (4 patients) experienced neutropenia (grade 3 or worse neutrophil decrease). Four (23%) of 17 patients had a chemotherapy dose reduction and 9 (53%) of 17 patients had a dose held in their treatment course, most often on day 15 (supplementary Table S3). Overall, 86% of the planned doses of ABP and gemcitabine were delivered. Based on these data, the protocol was amended to provide treatment on day 1 and 8 of a 21-day cycle (12% decreased dose exposure) and to allow maintenance ABP to begin after the 4^th cycle of therapy. The median cycles of therapy delivered was 8 (range, 2.3-30). Key AE frequencies in the stage 2 cohort were commensurately lower, with grade 3 anemia in 2 (10%) of 20 patients and grade 3 or worse neutropenia in 3 (15%) of 20 patients (supplementary Table S4). Average dose delivered was also higher for both drugs in stage 2 (92-93%) (supplementary Table S5).

Thirty-two patients were evaluable for response; five patients withdrew before their first scan for treatment-unrelated reasons (supplementary Table S6). The ORR was 59% (18 partial responses, 1 complete response, 95% CI 42% to 74%) (Figure 1). The ORR in stage 1 patients was 54% (7/13 responses) and the ORR in stage 2 patients was 63% (12/19 responses) (OR 1.47, 95% CI 0.28 to 7.7; P = 0.72). The overall disease control rate (DCR) was 100% (18 partial responses, 1 complete response, 12 stable disease). Median PFS in the N=37 patients who received at least one dose of study treatment was 7.5 (95% CI 6.7 to 10.5) months (Figure 2 and supplementary Figure S1A). Median OS was 14.2 (95% CI 12.2 to 24.5) months (supplementary Figure 1B). One patient discontinued study therapy to manage radiation necrosis in a brain metastasis (resected, no evidence of tumor) but has had no evidence of progression to date off trial.

Figure 1.

Waterfall plot of radiographic responses. Light blue indicates patients treated during stage 1. Dark blue indicates patients treated during stage 2. Partial responses were defined as a 30% or larger reduction in tumor size (green line).

Figure 2.

Swimmer plot of responses. Light blue indicates patients treated during stage 1. Dark blue indicates patients treated during stage 2.

Figures 3 and S2 overlay the correlative molecular data collected from these patients with objective response data. MSK-IMPACT was performed in 24 (65%) of 37 patients, either on material available at the time of diagnosis or upon subsequent biopsy and PD-L1 IHC on 19 (51%) of 37 patients (all with a TPS of less than 50%). Somatic alterations in the upstream PI3K-RTK-RAS pathway are shown for clarity; complete NGS data are shown in supplementary Figure 2. As anticipated, a substantial amount of genomic variability was seen in these patients. There were no significant correlations between molecular alterations and treatment efficacy, with responses seen across the range of somatic variants, tumor mutation burden, genome doubling, and PD-L1 expression.

Figure 3.

Integrated plot of radiographic response and correlates, including smoking history, PD-L1 tumor proportion score determined via immunohistochemistry (IHC), tumor mutation burden, a consolidated oncoprint of somatic alterations in key PI3K-RTK-RAS members, and genome doubling.

CONCLUSIONS

Treatment options for patients with SQCLC remain limited, both in terms of available lines of therapies and their respective efficacies. The KEYNOTE 407 trial, which added pembrolizumab to carboplatin plus taxane, is the most recent study to have led to an FDA approval indication in the first-line setting (17). Despite this, outcomes for patients with SQCLC are poorer than they are for patients with ADCL. As an example, the median PFS for carboplatin plus pemetrexed plus pembrolizumab (KEYNOTE 189; enrolling non-squamous NSCLC) (18) is 8.8 (95% CI 7.6 to 9.2) months, exceeding the median PFS for carboplatin plus taxane plus pembrolizumab (KEYNOTE 407; enrolling SQCLC) of 6.4 (95% CI 6.2 to 8.3) months. As second-line pembrolizumab is associated with a median PFS of 3.9-5.0 months (depending on PD-L1 TPS) (19), it is possible that the PFS benefit seen in KEYNOTE 407 results from an early switch to pembrolizumab in the maintenance setting rather than combinatorial efficacy with chemotherapy.

It is against this first-line platinum-doublet backdrop that our data are framed. Gemcitabine plus ABP was associated with an ORR of 59% (95% CI 42% to 74%) and median PFS of 7.5 (95% CI 6.1 to 10.5) months. This substantially exceeds the historical efficacy of carboplatin doublet regimens, including the control arm of KEYNOTE 407 (median PFS 4.8 [95% CI 4.3 to 5.7] months, ORR 38.4% [95% CI 32.7% to 44.4%]). The regimen was generally well-tolerated, with no unexpected side effects. Gemcitabine plus ABP compares well to carboplatin plus taxane plus pembrolizumab as well, with similar ORRs and favorable median PFS, taking into consideration the limits of cross-trial comparisons. It is important to note that because the efficacy of the regimen was greater than what we had hypothesized, the study completed accrual early with 32 evaluable patients. The 95% CI for the ORR of 59% seen at this sample size, 42% to 74%, squarely rejects the null hypothesis and provides assurance, vis-a-vis the lower bound of the 95% CI, that the activity of gemcitabine + ABP is at least as promising as the alternative hypothesis response rate, with a true ORR closer to what was observed in this study.

Our study is one of the few SQCLC trials to report comprehensive molecular data for all patients who had available tissue. The purpose of these biomarker data was hypothesis generation; there were no a priori hypotheses that have yet been developed surrounding chemotherapy response and squamous cell lung cancer genomics, largely because few genotype to phenotype studies have been conducted in this disease. It is important to note that while we had hypothesized an ORR of 45%, allowing us to divide the study population in half between responders and non-responders for the purposes of the biomarker analysis, we saw substantially greater efficacy than expected which limited the potential impact of any correlative-response analysis. This said, in contrast to prior analyses of immunotherapy, there was no correlation between tumor mutation burden and response (20). There were also no correlations between patterns of somatic variants and efficacy. Whole genome doubling (WGD), or tetraploidization, has emerged as a newly characterized poor prognostic genomic factor, providing cancer cells with a competitive advantage over their diploid counterparts. It is often associated with TP53 mutations and occurs in roughly 30% of NSCLC tumors.(21) Thirty-five percent of our samples exhibited WGD, though there was no significant association between WGD and ORR, PFS, or OS. All patients had tumors that exhibited low or unknown PD-L1 expression; with the limitation of small sample size, no intra-class tumoral PD-L1 expression correlations with efficacy were evident. Insufficient material was available to assess for SPARC (secreted protein acidic and rich in cysteine) and CAV-1 (Caveolin-1), both of which have been associated with increased response to ABP, albeit in settings where the overall efficacy was lower relative to our study (22-24).

While we found no significant positive or negative correlations between response/survival and our biomarker data, the results are nevertheless valuable as a safeguard for and indicator of a heterogeneous cross-section of SQCLC patients not marked by a disproportionate representation of tumors that bear, for example, 3q amplification, G1/S checkpoint aberrations, upstream PI3K alterations, or recurrent NFE2L2 or KEAP1 mutations. This is important, as while the relatively high ORR found in our study makes it unlikely that common genotype to phenotype correlations would be found (vis a vis outlier analyses in lower ORR studies), it does raise as a possibility the presence of unintended genomic selection biases (i.e. all tumors negative for WGD). Imbalances compared to other datasets were not evident across any of the biomarker analyses we performed.(25,26)

In conclusion, gemcitabine plus ABP is a safe, tolerable, and effective first-line chemotherapy regimen for patients with advanced SQCLC and exhibits efficacy characteristics that are favorable in comparison to standard platinum-doublet chemotherapy and similar to triplet therapy with chemotherapy plus pembrolizumab. Gemcitabine plus ABP is a reasonable alternative in patients for whom immune checkpoint inhibitor or platinum therapy is contraindicated and a promising chemotherapy backbone for future chemo-immune checkpoint inhibitor combinations.

Translational relevance: Despite recent advances in first-line therapy that incorporate immune checkpoint inhibition as standard of care, median overall survival in patients diagnosed with stage IV squamous cell lung cancers (SQCLCs) has only modestly improved from ~12 months to 15.9 months. This lags the improvement in overall survival in lung adenocarcinoma patients treated with chemotherapy and immune checkpoint inhibition. We hypothesized that part of the reason for this limitation is an anachronistic reliance on platinum doublet chemotherapy, which has seen no practical improvements in efficacy in over two decades. We report that gemcitabine plus albumin-bound paclitaxel, which exhibits synergistic anti-tumor activity pre-clinically, is an effective therapy for patients with newly diagnosed SQCLC. The regimen improves upon the historical efficacy of platinum doublet regimens and approaches the benefit seen with platinum plus taxane plus pembrolizumab. Gemcitabine plus albumin-bound paclitaxel is thus a promising chemotherapy backbone for future chemo-immune checkpoint inhibitor combinations.