Maintenance Therapy In Stage Research Articles

A phase I/II multisite study of rucaparib and pembrolizumab maintenance therapy in stage IV non-squamous non–small cell lung cancer after initial therapy with carboplatin, pemetrexed, and pembrolizumab.

TPS9138 Background: Carboplatin, pemetrexed, and pembrolizumab (CPP) followed by pemetrexed and pembrolizumab maintenance is a standard of care (SOC) for non-squamous metastatic non-small cell lung cancer (NSCLC), based on results of the KEYNOTE-189 study. The progression free survival (PFS) on this study was 8.8 months. There is increasing data to support that certain sporadic tumors harbor somatic mutations in genes of the homologous recombinant repair (HRR) pathway resulting in a “BRCAness” phenotype rendering sensitivity to PARP inhibitors (PARPi). TCGA data suggest up to 38% of NSCLC have mutations in HRR pathway genes. Furthermore, treatment with PARPi is shown to upregulate PD-L1 expression, which is associated with pembrolizumab response in NSCLC. We therefore hypothesized that maintenance therapy with a PARPi and pembrolizumab will improve PFS compared to SOC pemetrexed and pembrolizumab. Methods: This is a single arm, multi-site, investigator-initiated phase I/II study that is enrolling treatment-naïve patients with stage IV nonsquamous metastatic NSCLC without any targetable driver mutations eligible for CPP. Patients without progression after 4 cycles of CPP then proceed to maintenance with rucaparib 600mg PO BID and pembrolizumab 200mg IV every 21 days. The primary objective is efficacy assessed by PFS and second objectives include overall survival, safety, tolerability, and objective response rate (ORR). Correlatives in this study include PD-L1 expression, tumor mutational burden (TMB), and measurements of HRR deficiency as assessed by homologous repair deficiency (HRD) and loss of heterozygosity (LOH) using established methods. Key exclusion criteria include untreated brain metastases and prior exposure to a PARPi or PD-1/PD-L1 inhibitor. The phase I cohort which consisted of 6 patients treated with the approved full doses of rucaparib and pembrolizumab was completed without dose limiting toxicity (DLT). Using a Bayesian decision-theoretic two-stage design, the first stage will enroll 38 patients. If predefined PFS parameters are met, an additional 17 patients, for a total of 55 patients, will be enrolled. To date, 21 patients have been enrolled. Clinical trial information: NCT03559049.

P2.01-18 ORION: Durvalumab+Olaparib Versus Durvalumab Alone as Maintenance Therapy in Stage IV Non-Small Cell Lung Cancer (NSCLC)

P2.01-18 ORION: Durvalumab+Olaparib Versus Durvalumab Alone as Maintenance Therapy in Stage IV Non-Small Cell Lung Cancer (NSCLC)

ORION: A Phase 2, randomized, multicenter, double-blind study to assess efficacy and safety of durvalumab+olaparib vs durvalumab alone as maintenance therapy in Stage IV non-small cell lung cancer (NSCLC).

TPS9126 Background: Systemic chemotherapy for first-line (1L) metastatic NSCLC shows mixed outcomes. Results from studies using immunotherapy alone or combined with chemotherapy as 1L treatment in patients (pts) with metastatic NSCLC represent a substantial advance, but further improvement is needed. Increased DNA damage triggered by polyadenosine 5’diphosphoribose polymerase inhibition may confer antitumor activity, modify tumor immunogenicity, and further sensitize tumors to immune checkpoint inhibition, thus promoting a more durable antitumor response. This Phase 2, randomized, multicenter, double-blind study (NCT03775486) is designed to assess the efficacy and safety of durvalumab + olaparib vs durvalumab alone as maintenance therapy in pts whose Stage IV NSCLC has not progressed following 1L platinum-based chemotherapy + durvalumab. Methods: Adult pts with Stage IV NSCLC with tumors lacking activating EGFR mutations and ALK fusions are eligible. In the initial therapy phase, all pts will receive durvalumab (1500 mg IV) concurrent with platinum-based doublet therapy. Durvalumab + chemotherapy will be administered for 4 cycles for both squamous NSCLC (nanoparticle albumin-bound [nab]-paclitaxel + carboplatin or gemcitabine + carboplatin/cisplatin) and nonsquamous NSCLC (nab-paclitaxel + carboplatin or pemetrexed + carboplatin/cisplatin). Pts whose disease does not progress (complete or partial response [CR/PR] or stable disease [SD]; investigator-assessed RECIST 1.1) will be randomized (1:1) to durvalumab (1500 mg IV, every 4 weeks) + either olaparib (300 mg, oral, BID) or its matching placebo until disease progression. Randomization will be stratified based on objective response to durvalumab + chemotherapy (CR/PR or SD) during the initial therapy phase and histology (squamous or nonsquamous). The primary endpoint is PFS (investigator-assessed, RECIST 1.1). Secondary endpoints are OS, PFS in pts with homologous recombination repair related gene mutation, ORR, duration of response, HRQoL, pharmacokinetics and immunogenicity of durvalumab, and safety. Pt enrollment is ongoing. Clinical trial information: NCT03775486.

Concurrent Radiotherapy with Erlotinib Followed by Maintenance Erlotinib in Patients with EGFR Mutation- Positive Adenocarcinoma Lung

To assess the efficacy and tolerability of erlotinib in combination with radiation therapy followed by maintenance therapy in Stage III and IV, epidermal growth factor receptor mutationpositive adenocarcinoma lung patients.The single-arm, quasi-experimental study was conducted at the Mayo Hospital, Lahore, Pakistan, from September 2013 to December 2014, and comprised patients with lung adenocarcinoma who were followed up till December 2017. The patients received concurrent radiation therapy (60- 70 Gy in 30-35 fractions) along with erlotinib 150mg/day, followed by erlotinib 150mg/day as maintenance therapy till disease progression. Primary endpoint was overall response rate according to Response Evaluation Criteria in Solid Tumours guideline version 1.0, while secondary endpoint was progression-free survival, overall survival and toxicity assessment with Common Terminology Criteria for Adverse Eventsversion 3.0. Before starting erlotinib, all patients received four cycles of standard chemotherapy with platinum doublets (Pemetrexed, Docetaxel, Paclitaxel, Gemcitabine). Data was analysed using SPSS 16..of the 62 patients initially enrolled, 49(79%) completed the study. Of them, 37(75.5%) patients were smokers. Mean age of the patients was 57.0±8.51 years (range: 31-73 years) and 40 (81.6%) were male subjects. Objective response rate was 71.4% (n=35). Median progression-free survival for stage III disease was 7.4 months and for stage IV disease 2.8 months. Corresponding median overall survival rates were 12.9 months and 5.5 months. Common adverse events observed were rash n=30(61.2%), fatigue n=21(42.9%) and diarrhoea n=18(36.7%).Concurrent radiotherapy with erlotinib was effective and well-tolerated in patients with locally advanced adenocarcinoma lung harbouring epidermal growth factor receptor mutation.

Maintenance Sunitinib following Initial Platinum-Based Combination Chemotherapy in Advanced-Stage IIIB/IV Non–Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study—CALGB 30607 (Alliance)

IntroductionThe aim of this study was to evaluate efficacy of maintenance sunitinib after first-line chemotherapy for stage IIIB/IV NSCLC. MethodsCancer and Leukemia Group B 30607 trial was a randomized, double-blind, placebo-controlled, phase III study that enrolled patients without progression after four cycles of first-line platinum-based doublet chemotherapy with or without bevacizumab. Bevacizumab was allowed only during the four cycles of chemotherapy. Patients were randomized to receive sunitinib, 37.5 mg/d, or placebo and were treated until unacceptable adverse event(s), progression, or death. The primary end point was progression-free survival (PFS). ResultsA total of 210 patients were enrolled, randomized, and included in the intent-to-treat analysis. Ten patients did not receive maintenance therapy (four who received placebo and six who received sunitinib). Grade 3/4 adverse events affecting more than 5% of the patients were fatigue (25%), thrombocytopenia (12%), hypertension (12%), rash (11%), mucositis (11%), neutropenia (7%), and anemia (6%) for sunitinib and none for placebo. There were three grade 5 events in patients receiving sunitinib (one pulmonary hemorrhage, one other pulmonary event, and one death not associated with a Common Terminology Criteria for Adverse Events term) and two grade 5 events in patients receiving placebo (one other pulmonary event and one thromboembolism). Median PFS was 4.3 months for sunitinib and 2.6 months for placebo (hazard ratio = 0.62, 95% confidence interval: 0.47–0.82, p = 0.0006). Median overall survival was 11.7 months for sunitinib versus 12.1 months for placebo (hazard ratio = 0.98, 95% confidence interval: 0.73–1.31, p = 0.89). ConclusionsMaintenance sunitinib was safe and improved PFS as maintenance therapy in stage IIIB/IV NSCLC but had no impact on overall survival. There is no room for future investigations of sunitinib in this setting.

Strategy of using herbal extract preparations for stage IV cancer in palliative care: An enhanced and maintenance therapy.

89 Background: Palliative care is focused and seems as rationally anti-cancer way that have low systemic toxicity and acceptable effectiveness for stage IV cancer, especially herbal extracted medicines, which can regulate tumor microenviroment and body immune system. Our previous lab studies have indicated that TGF-beta, EGF, VEGF, IL-10 cytokines expression and mico-vessel density can be downgraded in tumor microenviroment by herbal extract preparation from Ginseng, Herba Agrimonia, Hairyvein and Arginine etc. Methods: 13 patients with unresectable pancreatic cancer, 31 patients with liver cancer, and 168 patients with stage IV lung cancer were studied. Herbal extract preparation, which was approved by the China Food and Drug Administration; hyperthermia; and psychological rehabilitation were initiated as alternative therapies. Survival time, quality of life and toxicity were evaluated during treatment. Results: The average ECOG score decreased from 3 to 2, and appetite and sleep improved in all three groups. According to CTCAE criteria, no severe hematology and digestion side-effect above grade 2 were observed. In pancreatic cancer group, the median and the average survival time were 5.1 and 6.5 months. The longest survival time was 16.7 months and patient still alive. The 3-, 6-, and 10-month survival rates were 92.3%, 46.2% and 30.8%, respectively. In liver cancer group, the average and median survival time were 12.48 and 5.03 months, respectively; the longest survival time was 84.17 months. The 3-, 6-, and 12-month survival time rates were 77.42%, 38.71%, and 29.03%, respectively. In lung cancer group, 31.58% patients suffered from pleural effusion. The 6 month, 1-, 2- and 5-year survival time rates were 33.93%, 19.05%, 14.29% and 4.17%, respectively. Furthermore, once the survival time was beyond 6 months, the average and median survival time reached 29.98 and 14.80 months; and the 1-, 2- and 5-year survival time rates were up to 56.14%, 42.11% and 12.28%, respectively. Conclusions: Herbal extract preparations, which are a part of palliative care, show acceptable effectiveness and toxicity. Thus, it may prove to be a considerable strategy and optional maintenance therapy for stage IV patients.

START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer.

7500 Background: L-BLP25 is a MUC1 antigen specific cancer immunotherapy. We report results from the phase III START study of L-BLP25 in patients (pts) not progressing after primary chemoradiotherapy (CRT) for stage III NSCLC. Methods: From Jan 2007 to Nov 2011, 1513 pts with unresectable stage III NSCLC that did not progress after CRT (platinum based chemo and ≥50 Gy) were randomized (2:1; double-blind) to L-BLP25 (806 µg lipopeptide) or placebo (PBO) SC weekly x 8 then Q6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 x 1 or saline was given 3 days prior to first L-BLP25/PBO dose. Primary endpoint was overall survival (OS). Results: The primary analysis population (n=1239) was defined prospectively to try to account for a clinical hold by excluding pts randomized 6 months (m) before the hold. Arms were balanced for baseline characteristics. Median age was 61 y; 38.2% had stage IIIA and 61.3% IIIB; 65% had concurrent and 35% sequential CRT. Median OS was 25.6 m with L-BLP25 vs. 22.3 m with PBO (adjusted HR 0.88, 95% CI 0.75-1.03, p=0.123). Secondary endpoints time-to-progression and time-to-symptom-progression support consistency of results: HR 0.87 (95% CI 0.75-1.00, p=0.053) and 0.85 (95% CI 0.73-0.98, p=0.023). In predefined subgroup analyses, pts with concurrent CRT (n=806) had median OS of 30.8 m (L-BLP25) vs. 20.6 m (PBO; HR 0.78, 95% CI 0.64-0.95, p=0.016), while median OS with sequential CRT was 19.4 m (L-BLP25) vs. 24.6 m (PBO; HR 1.12, 95% CI 0.87-1.44, p=0.38; interaction p=0.032, Cox PH model). Sensitivity analyses revealed that there was no OS benefit in pts randomized 6 m before the hold (HR 1.09, CI 0.75-1.56, p=0.663). LEBLP25 was well tolerated with no safety concerns identified and no emergent evidence of immune related adverse events. Conclusions: L-BLP25 maintenance therapy in stage III NSCLC was well tolerated, but did not significantly prolong OS. Sensitivity analyses showed a smaller treatment effect due to the clinical hold, suggesting that longer uninterrupted treatment with L-BLP25 is required. Clinically meaningful prolongation of OS was observed in the predefined subgroup of pts with primary concurrent CRT. Clinical trial information: NCT00409188.

1210 - Long-Term Efficacy and Safety of L-BLP25 Vaccine in a Multi-Centre Open-Label Study of Patients with Unresectable Stage III NSCLC

ABSTRACT Introduction L-BLP25 (Stimuvax®) is an antigen-specific cancer immunotherapeutic agent targeting the mucin 1 tumour-associated antigen. Phase IIb data suggest prolonged overall survival with L-BLP25 when administered after completion of chemoradiotherapy for locally advanced non-small-cell lung cancer (NSCLC; non-significant). This study was initiated in April 2005 to obtain safety data when modifications of the adjuvant component of the immunotherapeutic were performed. Here we report an updated analysis of long-term data based on the cut-off date 18 May 2011. Methods The primary objective of this open-label phase II study was to evaluate the safety of the new formulation of L-BLP25 in patients with unresectable stage IIIA/B NSCLC, with a secondary objective of assessment of survival time. Following completion of initial chemoradiotherapy, patients with stage III NSCLC received treatment with L-BLP25 starting with weekly injections over 8 weeks, followed by injections given every 6 weeks from week 13 onwards until disease progression. A single low dose of intravenous cyclophosphamide 300 mg/m2 (maximum 600 mg) was given 3 days before first vaccination. Results Twenty-two patients were enrolled. After a median follow-up of 70.3 months (median treatment duration 9.9 months [range, 1–73]), median survival time was 51.9 months (95%CI, 17.5, not estimable [NE]) and median progression-free survival was 31.4 months (95%CI, 5.7, NE). Five-year survival was 50% (95%CI, 29–71%); previously reported 1- and 2-year survival rates, 82% (95%CI, 66–98%) and 64% (95%CI, 44–84%), respectively. Four patients survived more than 72 months. Safety findings were consistent with previous reports; adverse events (AEs) consisted mainly of fatigue (59%), injection-site reactions (55%) and mild-to-moderate influenza-like illness. Two serious treatment-emergent AEs were assessed as being treatment-related: cholecystitis and pneumonia. Conclusions Long-term follow-up of this small patient population provides encouraging survival data for L-BLP25 maintenance therapy in stage III NSCLC. Long-term safety data were consistent with previous reports and did not reveal any new safety issues. Disclosure C. Butts: Charles Butts has provided consultancy and served on Speakers' Bureaux for Merck Serono. A. Maksymiuk: Andrew Maksymiuk has some stock shares in Merck Canada ( M. Falk: Martin Falk is a Merck Serono employee. A.H. Loos: Dr Loos is a Merck employee. All other authors have declared no conflicts of interest.

Sequential Local Injection of Low-Dose Interferon-Beta for Maintenance Therapy in Stage II and III Melanoma: A Single-Institution Matched Case-Control Study

Objective: To determine the beneficial effect of maintenance therapy in stage II and III melanoma by sequential local injection of low-dose interferon-β. Methods: We reviewed 46 patients with stage II and III primary melanoma at our institution from 2004 through 2009. Twenty-one patients were treated with interferon-β maintenance therapy consisting of subcutaneous injection of natural interferon-β at a dose of 3 × 10⁶ IU/day for 10 consecutive days, and 25 patients underwent observation alone. Results: Compared with all patients, overall survival and relapse-free survival were significantly worse in the observation group than in the interferon-β group (p = 0.024 and 0.029, respectively). In stage II, a significant difference in overall survival, but not in relapse-free survival, was seen between the two groups (p = 0.041). When the interferon-β group was stratified by subgroup, there was a statistical difference only between dosage and duration (p = 0.027 and p < 0.001, respectively). Conclusions: This study demonstrates that maintenance therapy by interferon-β is beneficial in the outcome of the disease without substantial toxic effects, especially in patients with stage II melanoma. Extension of the duration of treatment beyond 2 years could further improve the therapeutic efficacy of interferon-β.

An open label non-randomized phase II trial of erlotinib following concurrent chemo-radiotherapy as maintenance therapy in patients (p) with stage III non-small cell lung cancer (NSCLC): A Galician Lung Cancer Group study

18501 Background: Based on recent studies, concurrent chemo-radiotherapy could be considered the standard treatment of stage III NSCLC pts without malignant effusions. Erlotinib is an oral EGFR TKI that has shown activity in recurrent and metastatic NSCLC. This phase II study aims to assess the activity and toxicity of the addition of erlotinib as a maintenance therapy in stage III NSCLC pts after a standard concurrent chemo-radiotherapy regimen. Methods: Pts with stage IIIA-IIIB (without malignant effusions) medically inoperable or unresectable NSCLC who had received concurrent chemo-radiotherapy and had no sign of progression disease after that treatment, performance status (PS) 0–2, adequate bone marrow, hepatic and renal function, measurable disease by RECIST criteria, and written informed consent were enrolled into this prospective open label one arm phase II study. Pts were treated with erlotinib 150 mg/day po for 6 months as maintenance therapy after standard concurrent chemo-radiotherapy. Primary endpoint of the study is the percentage of pts without evidence of disease progression after 6 months of erlotinib therapy. Results: A total of 28 pts have been recruited from March 2006 to the moment of this analysis. Data from 21 pts is available. All pts were caucasian, men 90%, median age 64 years (range 41–76), current/ever smokers 95,2%, PS 0–1 100%, histology adenocarcinoma 14.3%, squamous cell carcinoma 81%, other histologies 4.7% and stage IIIB 76,2%. 18 pts have been evaluable for response, 16,7% reached complete response, 11.1% partial response, 61,1% stable disease and 11,1% progression disease. 16 pts have ended treatment with erlotinib, of which 8 pts were treated during the 6 expected months, 3 stopped erlotinib due to adverse events (1 grade 3 rash, 1 grade 2 asthenia + grade 2 diarrhea and 1 grade 2 dyspnea + respiratory infection), 2 presented progression disease and 1 retired the informed consent. Conclusions: Erlotinib as maintenance therapy after standard concurrent chemo-radiotherapy treatment in stage III NSCLC p seems to be efficient and does not appear to increase toxicities. Data on survival will be presented. No significant financial relationships to disclose.

Phase I trial of neoadjuvant and postoperative paclitaxel (P), carboplatin (C) and erlotinib with concurrent accelerated hyperfractionation radiation (AHFR) followed by erlotinib maintenance therapy in stage III non-small cell lung cancer (NSCLC)

2091 Background: Erlotinib (E), a potent reversible Her1/EGFR tyrosine kinase inhibitor is a radiosensitizer in preclinical studies. Our study was conducted to determine the recommended dose of E when given with P, C and AHFR before/after surgery in patients (pts) with potentially resectable stage III NSCLC. Methods: Pts had biopsy-proven Stage III NSCLC, and ECOG performance status of 0/1. Treatment Plan was: 1) Induction AHFR (30 Gy/1.5 Gy BID), with concurrent P [50 mg/m2] C (AUC 2), weekly x 3, and E at 3 dose levels (DL); I: 50, II: 100, and III: 150 mg, orally once daily (qd) for 4 weeks (wks); 2) Surgery after 4 wks; 3) a second identical course of chemoradiotherapy (CRT) 4–6 wks postoperatively; 4) 2-year maintenance of a fixed dose of E (150 mg qd). 3 to 6 pts were treated at each DL of E. A dose level was deemed intolerable if greater than or equal to 2 of 6 pts develop a dose-limiting toxicity (DLT). Results: Between 8/03 and 11/04, 6 male and 3 female pts were enrolled, 4 at DL I, 3 at DL II, 2 at DL III. Median age was: 61(range 33–68) years. All pts completed induction treatment. 7 pts had surgery (3 lobectomy; 4 pneumonectomy). One patient (pt) progressed; 1 pt was deemed unresectable. 6 of 9 pts received postoperative CRT + E. No DLT was observed at DL I or DL II. One pt at DL 3 had prolonged postoperative recovery from respiratory failure (grade IV toxicity). Common grade I-II toxicities were, rash (6 pts), diarrhea (3 pts), and esophagitis (3 pts). One pt at DL I had reversible posterior leucoencephalopathy, thought to be unrelated to treatment. There were no unexpected surgical complications, and no treatment-related mortality. 4 pts were downstaged at surgery; to stage I: 1 pt, stage II: 2, and 1 pt had complete pathologic response. Maintenance E was started in 6 pts. 7 of 9 pts are progression free at a mean follow-up of 9.1 months (range: 5–15). Additional pts are being treated at DL III to further characterize toxicity. Conclusion: Erlotinib in combination with concurrent weekly P/C/AHFR is well tolerated. The recommended dose of E has not yet been determined. A phase II study is planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Genentech, Lilly Oncology, Pfizer, Bayer, Antigenics Amgen, Pfizer, Eyetech, Genentech, Genentech Genentech, Pfizer, Celgene, Antigenics, Amgen, Wyeth

A phase III randomized placebo controlled NCCTG trial of carboxyaminoimidazole (CAI) in patients with advanced non-small cell lung cancer (NSCLC)

7054 Background: Benefit from chemotherapy (ctx) for NSCLC has plateaued. Agents with novel mechanisms may provide further gain. CAI has in-vitro effects including inhibition of tumor cell motility, adhesion, and growth. Methods: CAI/placebo at 250 mg/day was given orally as maintenance therapy in stage 3 or 4 NSCLC patients within 6 weeks of completion of first line ctx (Stage 3 patients may have received thoracic radiotherapy). Eligible patients had stable or responding disease to one ctx regimen of 3–6 months (mo) duration; ECOG performance status of 0,1,2; absence of untreated brain metastases and adequate hematologic, hepatic and renal function. The study closed early due to slow accrual (targeted 360, observed 186). 360 patients followed for a minimum of 1 year would have provide 80% power to detect a 40% increase in the primary endpoint of median survival with a two-sided 5% type I error rate. The 154 observed deaths in the 186 patients accrued provide 80% power to detect a 60% increase in median survival. Results: Between 4/99 and 8/04, 186 patients (94 CAI, 92 placebo) were randomized with balance in median age, performance status, gender, histology, stage and response status to initial ctx. Incidence of severe (grade 3+) adverse events (AE) was not significantly different for CAI compared to placebo (42% vs. 34%, p=0.24). AE (primarily grade 1,2) observed more often in the CAI group included fatigue (55.6% vs 29.4%, p=0.0003), anorexia (31.1% vs 13.0%, p=0.003), nausea (61.1% vs 30.4%, p<0.0001), and vomiting (32.2% vs 14.1%, p=0.004); and grade 3+ AE included neurosensory (8.5% vs. 0.0%, p=0.004) and ataxia (11.1% vs. 3.3%, p=0.05). Patients discontinued treatment for AE/refusal more often in the CAI group (34.5% vs 6.8%, p<0.0001). Median follow-up is 20.0 mo. Both median survival and time to progression are not significantly different between the two groups (11.8 mo vs 10.5 mo, p= 0.93; 3.2 mo vs 2.5 mo, p=0.88). Conclusion: The addition of CAI following chemotherapy does not provide clinical benefit over placebo in advanced NSCLC. No significant financial relationships to disclose.