8110 Background: Thymic carcinoma, a rare malignancy, presents treatment challenges due to its aggressiveness and poor response to standard chemotherapy. Angiogenic pathway activation is implicated ...in its pathogenesis. S1701 evaluated the efficacy and safety of ramucirumab, an anti-angiogenic monoclonal antibody, in combination with carboplatin-paclitaxel. Methods: We conducted a randomized phase II trial with patients having histologically confirmed, unresectable thymic carcinoma and no prior therapy for recurrent or metastatic disease. Patients were randomized to receive carboplatin-paclitaxel with or without ramucirumab for 6 cycles, followed by maintenance ramucirumab for patients without progression. The primary endpoint was progression-free survival (PFS), assessed by RECIST 1.1. Secondary endpoints included response rate, safety and toxicity. The primary analysis was done using a 1-sided 10% level log-rank test. Target sample size was 66 patients. Results: Between 2018-2022, 21 patients enrolled to ramucirumab plus carboplatin-paclitaxel (RCP, n = 8) and to the control arm (CP, n = 13). Three patients in the control arm were excluded from the efficacy analysis, as one was ineligible and 2 had non-measurable disease. No grade 4 or higher treatment-related adverse events occurred in the RCP arm, although 50% (4 out of 8) experienced grade 3 adverse events and 2 patients discontinued ramucirumab due to toxicity. There were no grade 3 or higher thromboembolic or bleeding events in the RCP arm. Among 9 evaluable patients for safety in the control arm (3 withdrew consent prior to initiating therapy), 11% encountered grade 4 neutropenia and 11% reported grade 3 thromboembolic events. Response rate favored the RCP arm, with an 88% 80% CI 59% - 99% partial response rate compared to 40% 80% CI 19%-65% in the control arm (Figure, p = 0.04). Disease control rate was higher in the RCP arm (100% vs 70%, p = 0.0897). At median follow-up time of 16.7 months, PFS was not different (hazard ratio 80% CI: 0.51 0.24 – 1.09; p = 0.13). Median PFS was 8 months for RCP and 7 months for the control arm. At this time, OS remains immature. Conclusions: The addition of ramucirumab to CP led to higher response rates than CP alone. At this early analysis, PFS was not significantly improved; OS is pending. High-grade adverse events necessitate careful patient selection. Insights from S1701 emphasize the potential of targeting the angiogenic pathway, although larger trials are needed to confirm these findings. Future research should consider exploring larger multicenter trials and other combinations to improve outcomes. Challenges in enrollment emphasize the need for innovative strategies and larger collaborations in rare malignancies like thymic carcinoma. Funding: NIH/NCI/NCTN grant awards U10CA180888 and U10CA180819 and in part by Eli Lilly. Clinical trial information: 03694002.
The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non-small cell lung cancer (NSCLC). Taminadenant ...(PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response.
In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80-640 mg, orally, twice a day) with or without spartalizumab (anti-programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination.
During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea n = 1 (4.0%) each; 640 mg, and in the combination group were pneumonitis n = 2 (8.0%); 160 and 240 mg and fatigue and alanine/aspartate aminotransferase increase n = 1 (4.0%) each; 320 mg; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively.
Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status.
Pulmonary sarcomatoid carcinoma (PSC) or pleomorphic carcinoma is a rare subtype of non-small cell lung cancer. Some reports have suggested the efficacy of checkpoint inhibitor immunotherapy for PSC. ...However, owing to the small number of patients in each report, it remains unclear whether programmed death receptor-ligand 1 (PD-L1) expression is predictive of tumor response or survival.
The English literature was systematically searched for articles published from 2015 to 2019 and reported on tumor response or progression-free survival (PFS) after immunotherapy for advanced PSC. In addition, our institutional electronic medical records were searched for eligible cases to be included. Pooled analyses were performed.
Analyses included 90 patients. Best tumor response was partial or complete response in 54.5%, stable disease 15.9%, and progressive disease in 29.6%. The median PFS was 7.0 months. Among 66 patients with reported PD-L1 expression, the level was <1% in 7 patients (10.6%), 1%-49% in 10 patients (15.2%), and ≥50% in 49 patients (74.2%). A positive relationship between PD-L1 level and tumor response was observed. Among 47 patients with a PD-L1 of ≥50%, 33 patients (70.2%) achieved response, compared with 5 of 10 patients (50%) with a PD-L1 of 1%-49% and 2 of 7 patients (28.6%) with a PD-L1 of <1% (P = .026). PFS was superior among patients with a PD-L1 of ≥1% compared with those with a PD-L1 of <1% (14.4 months vs. 2.7 months respectively; P = .04).
Among patients with advanced PSC, PD-L1 expression is significantly associated with increased tumor responses and improved PFS after checkpoint inhibitor immunotherapy.
We performed a pooled analysis of published literature and institutional experience to understand the predictive value of programmed death receptor-ligand 1 expression on tumor response after checkpoint immunotherapy for pulmonary sarcomatoid carcinoma, a rare subtype of non-small cell lung cancer. As the level of programmed death receptor-ligand 1 expression increased, both tumor response and progression-free survival also significantly increased.
9102
Background: Nintedanib (NT) is an oral triple kinase inhibitor that is active against NSCLC and inhibits the activity of the immunosuppressive cancer associated fibroblasts in the tumor ...microenvironment (TME). Targeting the TME with NT may represent an important synergistic approach in improving immunotherapy (IO) outcomes for NSCLC. We initiated a phase Ib/II trial to evaluate the combination of NT, nivolumab (N) and ipilimumab (I) in advanced (a)NSCLC. Based on the phase IB (dose escalation) results, the combination of N (3mg/kg/2w), I (1mg/kg/6w) and NT (150mg once daily) was declared as the recommended phase 2 dose (RP2D). Here we present the final analysis of the regimen in treatment naïve (TN), and IO pretreated (IP) aNSCLC. Methods: This is a single institution, non- randomized, parallel assignment phase I/II clinical trial of aNSCLC pts. Eligible pts were TN (Arm A) or with disease progression following IO (Arm B) with planned sample size of 40/arm. Enrollment into phase II was by the Bayesian two-stage design method with the primary objective of determining the overall response rate (ORR) in the intent to treat population. Key secondary objectives were overall survival (OS) and progression-free survival (PFS). Descriptive statistics were used to summarize demographic and safety data. The Kaplan- Meier method with log-rank test (5% level of significance, 95% CI and 2-sided test) was used for survival analysis. Results: 22 and 29 pts received the N+I+NT at the RP2D in Arm A and B, respectively. The median age was 67 42;92 with 53% (27/51) females, 84% (42/51) Caucasian, ECOG 1 in 88% (45/51), and a current/prior history of tobacco use in 88% (45/51) pts. Adenocarcinoma histology was common (64%, 33/51) with PD-L1 ≥1% in 52% (22/42) pts. As of Oct 24, 2022, 18 and 26 pts were evaluable for response in Arm A and B, respectively. Clinical efficacy was observed in the TN and IP cohorts (Table). The most common treatment-related adverse events (TRAEs) were similar in both cohorts. TRAE of any grade in Arm A were nausea (8, 36%), diarrhea (8, 36%), fatigue (7, 32%), and in Arm B were nausea (10, 34%), fatigue (9, 31%), anorexia (8,27%). Conclusions: The combination of nivolumab, ipilimumab and nintedanib had a manageable toxicity profile and demonstrated promising antitumor activity in both TN and IP aNSCLC patients. Clinical trial information: NCT03377023 . Table: see text
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Background: Histone deacetylase inhibitors enhance tumor immunogenicity through various mechanisms including induced expression of MHC and T cell chemokines. A previous phase I trial ...demonstrated the combination of pembrolizumab (P) with vorinostat (V) in advanced/metastatic (m)NSCLC was well tolerated with signals of activity in ICI-pretreated pts. To further investigate the combination, we conducted a first-line, phase II trial. Methods: Pts with treatment-naïve mNSCLC and tumor PD-L1 expression ≥ 1% were eligible. Pts were randomized, open-label, 1:1 to receive P 200 mg IV q3 wk as monotherapy Arm A vs P 200 mg IV q3 wk plus V 400 mg PO daily Arm B. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for exploratory correlative analysis including gene expression and changes in the tumor microenvironment. Results: Between 7/2017 – 2/2022, 86 pts were enrolled, with 83 pts evaluable for response (40 in Arm A and 43 in Arm B). Median age was 69 (range 44 - 87), 47% female, and ECOG PS 0/1 in 9%/91%. PD-L1 TPS was ≥50% in 20/40 (50%) of pts in Arm A, and in 23/46 (50%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (15%) and fatigue (10%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included fatigue (41%), nausea (44%), diarrhea (35%) and increased creatinine (33%). 3 pts in Arm B experienced grade ≥ 3 irAE (2 grade 3 pneumonitis and 1 grade 4 myopericarditis). In Arm B, 22/45 (49%) of pts had a dose-reduction in vorinostat, most commonly due to grade 2-3 fatigue or nausea. Efficacy results by intention-to-treat are summarized in the Table below. For evaluable patients only, ORR was 44% in Arm B (19/43) and 28% in Arm A (11/40) (p=0.18). RNA-sequencing of a subset of patients showed a significant increase in interferon-γ pathway activity in both Arms. However, between the two Arms, interferon-γ pathway activity was enhanced to greater extent in Arm B, which may have contributed the higher overall response rate. Conclusions: To our knowledge, this is the first randomized trial investigating the combination of HDAC inhibition and anti-PD1 therapy in NSCLC. Although the combination arm had a numerically higher ORR compared to P monotherapy, the result did not meet the primary endpoint for significance. While there were no new safety signals with the combination therapy, reduction or interruption in V dose occurred frequently, which may have contributed to lack of survival differences between arms. Clinical trial information: NCT02638090 . Table: see text
To investigate the potential value of postoperative concurrent chemoradiation among patients with high-risk salivary gland carcinomas.
Case control study based on retrospective medical record review.
...A tertiary care comprehensive cancer center.
A total of 24 patients, 12 with major salivary gland carcinoma who were treated with postoperative concurrent chemoradiotherapy from 1998 to 2007 (chemoradiation group), and a control group of 12 patients treated with postoperative radiation alone.
Overall survival, progression-free survival, toxic effects.
All but 1 patient had stage III or IV disease; close or positive surgical margins were identified in 20 patients (83%). The median radiation dose was 63 Gy. In the chemoradiation group, platinum-based regimens were used in all. Treatment was well tolerated, but toxic effects, predominantly hematologic, were increased in the chemoradiation group. To date, 8 patients have died; the median overall survival was 53 months. The overall survival in the chemoradiation group was significantly better than in the radiation-alone group: 3-year survival rates were 83% and 44%, respectively (P = .05).
Locally advanced or high-grade salivary gland carcinomas follow an aggressive clinical course. Based on our limited experience, postoperative chemoradiation with a platinum-based regimen seems to be effective in selected patients and warrants further investigation.
Lung cancer screening with low-dose computed tomography (LDCT) can reduce mortality from lung cancer. Individuals with previous malignancy are at an increased risk of lung cancer but are often ...underrepresented in clinical trials. This study compares the outcomes of LDCT screening among individuals with and without cancer history.
The study cohort included consecutive participants undergoing LDCT screening at a tertiary care cancer institution. Abnormal screening result was defined as having Lung-RADS 3 or 4 at baseline (T0). Participant information was prospectively collected and predicted risk of lung cancer was calculated per the PLCOm2012 model.
A total of 454 participants underwent LDCT screening. Abnormal screening result occurred in 57 (13.2%) participants at T0, and lung cancer was diagnosed in 11 (2.4%) participants. Among 153 individuals with cancer history, abnormal result occurred in 9.8%, compared with 15.4% among those without cancer history (P = .11). Lung cancer was diagnosed in 1.3%, compared with 3.5% (P = .22). The predicted risk of lung cancer at 6 years was higher among individuals with cancer history than those without: 4.8% versus 2.2% (P < .001). In a multivariable analysis, cancer history significantly reduced the likelihood of abnormal screening (odds ratio, 0.49; 95% confidence interval, 0.26-0.94; P = .03). We observed a higher proportion of participants who had a previous CT scan available for comparison at T0 among individuals with cancer history than those without: 43.1% versus 9.1% (P < .001).
In this single-institutional study, individuals with cancer history were significantly less likely to have abnormal screening results than those without cancer history.
Epidemiologic studies indicate that smokers with cancer history have a higher risk of developing lung cancer than smokers without cancer history. We analyzed prospectively collected data from our institutional lung cancer screening program. Comparing between the 2 groups, those with cancer history actually had a significantly lower rate of abnormal screening results than their counterparts.
Small-cell lung carcinoma (SCLC) is usually a wide-spread, highly-lethal malignancy but occasionally presents as localized, limited stage cancer amenable to local treatment. We reviewed our ...experience using surgery or stereotactic body radiotherapy (SBRT) to assess safety, survival rates and treatment toxicity in clinical stage I SCLC patients.
Electronic medical records of patients with clinical stage I lymph node-negative SCLC who underwent surgical resection or SBRT between 1996 and 2021 were retrospectively reviewed. A multivariable Cox Proportional Hazards model was constructed.
Of 96 patients meeting inclusion criteria, 77 underwent resection and 19 underwent SBRT. Surgical patients were younger (mean 68.4 ± 9.2 years surgery versus 74.3 ± 6.6 years SBRT, P = .005) and had better pulmonary function (81.5 ± 19.6 FEV1% of predicted surgery versus 44.0 ± 20.9% SBRT, P < .001). SBRT patients had significantly more comorbidities. For both cohorts, 59 tumors were pure SCLC and 37 were mixed SCLC/NSCLC histology. Median survivals were 21 months versus 31 months for SBRT and surgery patients respectively (P = .07). There were no treatment-related mortalities. Mean length of hospital stay for surgical patients was 5.4 ± 5.7 days. Survival was longer in lymph node-negative surgery patients (median 48 months node-negative versus 19 months node-positive, P = .04). For node-negative-surgery patients, the estimated 2- and 5-year survival rates are 60% and 48%.
Our single-institutional experience over 25 years demonstrates that local treatment with surgery or SBRT for clinical stage I SCLC is safe and effective, with survivals lower than similar stage non–small-cell carcinoma patients. However, our results compare favorably with prior small-cell surgical series and far better than reported results of chemoradiotherapy for similar stage patients, thereby validating current recommendations for employing surgery or SBRT for stage I SCLC.
Although SCLC is usually a wide-spread, highly-lethal disease, occasionally presents as localized, limited stage cancer amenable to local treatment. Our 25-year experience treating 96 patients with clinical Stage I SCLC with either surgery or SBRT (for medically inoperable patients) demonstrated safety and effectiveness, especially when followed by adjuvant chemotherapy, and has results superior to chemoradiotherapy alone.
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