Kenneth K. Ng

Phase I/II Trial of Weekly Intravenous 130-nm Albumin-Bound Paclitaxel As Initial Chemotherapy in Patients With Stage IV Non–Small-Cell Lung Cancer

PURPOSE Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) is an albumin-bound formulation of paclitaxel that has demonstrated improved efficacy compared with paclitaxel in the treatment of metastatic breast cancer. We undertook this trial to determine the maximum-tolerated dose (MTD) and single-agent activity of NAB-paclitaxel administered on a weekly basis to patients with stage IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was an open-label, single-arm, phase I/II study. Patients were treated with NAB-paclitaxel intravenously during 30 minutes without corticosteroid or antihistamine premedications on days 1, 8, and 15 of a 28-day cycle. Radiologic tumor assessment was performed every 8 weeks. RESULTS Dose levels of 100 and 125 mg/m(2) were tolerated without dose-limiting toxicities (DLTs). At 150 mg/m(2) the MTD was exceeded; two of three patients experienced a DLT (grade 3 sensory neuropathy and febrile neutropenia). The 125 mg/m(2) dose level was expanded and determined to be the MTD. A total of 40 patients were treated at 125 mg/m(2). The objective response rate was 30% (12 of 40 patients; 95% CI, 16% to 44%), median time to progression was 5 months (95% CI, 3 to 8 months), and median overall survival was 11 months (95% CI, 7 months to not reached). The 1-year survival was 41%. CONCLUSION NAB-paclitaxel 125 mg/m(2) administered on days 1, 8, and 15 of a 28-day cycle was well tolerated and demonstrated encouraging single-agent activity. No corticosteroid premedication was administered and no hypersensitivity reactions were seen. Additional studies of single-agent NAB-paclitaxel as well as platinum-based combinations are warranted.

Phase II Trial of Docetaxel and Vinorelbine in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE Docetaxel and vinorelbine are active agents in advanced non-small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2. We show that docetaxel (60 mg/m(2)) and vinorelbine (45 mg/m(2)) can be safely combined when given on an every 2-week schedule with filgrastim, with encouraging antitumor activity observed. PATIENTS AND METHODS Thirty-five chemotherapy naïve patients with advanced NSCLC received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks. Prophylactic corticosteroids, ciprofloxacin, and filgrastim were used. RESULTS We delivered median doses of 450 mg/m(2) of vinorelbine and 600 mg/m(2) of docetaxel. The major objective response rate was 51% (95% confidence interval [CI], 34% to 68%). With a median follow-up of 14 months, the predicted median survival time was 14 months, and the 1-year survival rate was 60% (95% CI, 44% to 80%). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. No dose-limiting neurotoxicity occurred. Symptomatic onycholysis and excessive lacrimation were observed after several months or more of therapy. CONCLUSION Docetaxel 60 mg/m(2) and vinorelbine 45 mg/m(2), both given every 2 weeks, is a highly active combination for the treatment of advanced NSCLC. Filgrastim largely obviates neutropenic fever and allows for the single-agent dose-intensity of both drugs to be delivered. The occurrence of certain late toxicities can limit use in some cases and suggests that the combination could also be beneficial in settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy.

A phase II trial of chemotherapy and surgery for non-small cell lung cancer patients with a synchronous solitary metastasis

PURPOSE Retrospective reports suggest that selected patients with non-small cell lung cancer (NSCLC) and a solitary synchronous site of M(1) disease may be effectively treated by resection of all disease sites. The feasibility and potential benefit of combining surgery and chemotherapy in this setting are unclear. Therefore, we performed a prospective trial to test this therapeutic approach. METHODS Patients with solitary synchronous M(1) NSCLC with or without N(2) disease were to receive three cycles of mitomycin, vinblastine, cisplatin (MVP) chemotherapy, followed by resection of all disease sites, and then two cycles of VP chemotherapy. Solitary brain metastases were to be resected before chemotherapy. RESULTS From 10/92-2/99, 23 patients (12 men, 11 women, median age = 55 years) were enrolled. Mediastinoscopy, performed in 22 patients, showed involved N(2) nodes in 12. The M(1) sites included brain (14 patients) adrenal (3), bone (3), spleen (1), lung (1), and colon (1). Of 12 patients who completed all three induction therapy cycles, 8 underwent R(0) resections. Another 5 patients had R(0) resections without completing induction therapy. Eight of the 13 patients undergoing R(0) resections completed postoperative chemotherapy. The median survival was 11 months; 2 patients survived to 5 years without disease. CONCLUSIONS (1) The number of patients with solitary M(1) disease who qualified for this combined modality therapy was small; (2) MVP was poorly tolerated as induction chemotherapy in this patient population; (3) Compared to historical experience with surgery alone, overall survival does not appear to be superior with this treatment strategy.

Induction chemotherapy plus three-dimensional conformal radiation therapy in the definitive treatment of locally advanced non-small-cell lung cancer.

PURPOSE To evaluate our institutions experience using chemotherapy in conjunction with three-dimensional conformal radiation therapy (3D-CRT). METHODS AND MATERIALS From 1991 to 1998, 152 patients with Stage III non-small-cell lung cancer (NSCLC) were treated with 3D-CRT at Memorial Sloan-Kettering Cancer Center. A total of 137 patients (90%) were surgically staged with either thoracotomy or mediastinoscopy. The remainder were staged radiographically. Seventy patients were treated with radiation therapy alone, and 82 patients received induction chemotherapy before radiation. The majority of chemotherapy-treated patients received a platinum-containing regimen. Radiation was delivered with a 3D conformal technique using CT-based treatment planning. The median dose in the radiation alone group was 70.2 Gy, while in the combined modality group, it was 64.8 Gy. RESULTS The median follow-up time was 30.5 months among survivors. Stage IIIB disease was present in 36 patients (51%) in the radiation-alone group and 57 patients (70%) in the combined-modality group. Thirty-nine patients had poor prognostic factors (KPS < 70 or weight loss > 5%), and they were equally distributed between the two groups. The median survival times for the radiation-alone and the combined-modality groups were 11.7 months and 18.1 months, respectively (p = 0.001). The 2-year rates of local control in the radiation-alone and combined-modality groups were 35.4% and 43.1%, respectively (p = 0.1). Grade 3 or worse nonhematologic toxicity occurred in 20% of the patients receiving radiation alone and in 16% of those receiving chemotherapy and radiation. Overall, there were only 4 cases of Grade 3 or worse esophagitis. CONCLUSION Despite more Stage IIIB patients in the combined-modality group, the addition of chemotherapy to 3D-CRT produced a survival advantage over 3D-CRT alone in Stage III NSCLC without a concomitant increase in toxicity. Chemotherapy thus appears to be beneficial, even in patients who are receiving higher doses of radiation therapy than are typically given with conventional techniques. Because locoregional failure remains a major challenge in patients with advanced disease, 3D-CRT in conjunction with chemotherapy may allow safe treatment to the dose levels required to further enhance local control.

Gemcitabine-induced peripheral edema: report on 15 cases and review of the literature.

Some degree of peripheral edema occurs in up to 20% of patients treated with gemcitabine (Gemzar). The edema is typically mild, requiring discontinuation of the drug in less than 1% of patients. Most patients require no therapy. However, in cases of peripheral edema, grade II or higher, suspension of gemcitabine and treatment with corticosteroids are often necessary, and permanent discontinuation of gemcitabine may be required on occasion. We have identified 15 cases of peripheral edema, grade II or greater, developing in patients receiving gemcitabine chemotherapy at Memorial Sloan-Kettering Cancer Center. The diagnosis was made based on temporal association with drug administration, and exclusion of other potential acute causes of edema including progression of disease and deep vein thrombosis. The 15 patients in this series represent less than 1% of all patients treated with gemcitabine at this institution over the same time period. Gemcitabine was immediately discontinued at the time of the onset of edema in 7 of the 15 patients due to severity of the symptoms. Thirteen of the 15 patients in this case series had experienced peripheral edema previously, and 6 had active low-grade edema at the time the gemcitabine was first administered. Patients receiving gemcitabine should be advised of this potential complication and urged to promptly report its development so that comorbid conditions can be excluded and proper supportive measures initiated. Patients predisposed to peripheral edema from some other cause may be at increased risk for developing severe peripheral edema with gemcitabine.

Phase I and Pharmacokinetic Study of the Novel Oral Cell-Cycle Inhibitor Ro 31-7453 in Patients With Advanced Solid Tumors

PURPOSE To determine maximum tolerated dose, pharmacokinetics (PK), and safety of Ro 31-7453, a novel, oral cell-cycle inhibitor. PATIENTS AND METHODS Using an accelerated dose-escalation schedule, 48 patients with advanced solid tumors were treated with doses of Ro 31-7453 ranging from 25 to 800 mg/m(2)/d given for 4 consecutive days, every 3 weeks. The total daily dose was taken as a single dose (schedule A) or divided into two equal doses taken 12 hours apart (schedule B). PK samples of blood and urine were collected on the first and last days of dosing in cycles 1 and 2. RESULTS Forty-five patients completed at least one cycle of therapy. Myelosuppression and stomatitis were dose-limiting toxicities, occurring at the 800 mg/m(2)/d dose level for both schedules. Toxicity was independent of body-surface area, leading to the recommended phase II flat dose of 1,000 mg daily for 4 days for both schedules. Common adverse events included diarrhea, nausea, vomiting, fatigue, alopecia, and elevated liver-function tests. One death, related to neutropenic sepsis, occurred on study. The PK of the parent compound and major metabolites were apparently linear, with a half-life of approximately 9 hours and a maximum concentration of approximately 4 hours. Minor antitumor activity was observed against carcinoma of the lung, breast, pancreas, and ovary. CONCLUSION Ro 31-7453 was well tolerated, with manageable adverse effects. Significant PK variability (absorption, metabolism, and excretion) was observed, and a substantial number of additional patients are needed to confirm the recommended phase II dose. Additional pharmacology and phase II studies are under way to explore the dose-toxicity relationship.

A phase I trial of the Hedgehog inhibitor, sonidegib (LDE225), in combination with etoposide and cisplatin for the initial treatment of extensive stage small cell lung cancer

OBJECTIVES The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC. MATERIALS AND METHODS Patients received 4-6 21-day cycles of etoposide/cisplatin with daily sonidegib. Patients with response or stable disease were continued on sonidegib until disease progression or unacceptable toxicity. Two dose levels of sonidegib were planned: 400mg and 800mg daily, with 200mg daily de-escalation if necessary. Next generation sequencing was performed on available specimens. Circulating tumor cells (CTCs) were quantified at baseline and with disease evaluation. RESULTS Fifteen patients were enrolled. 800mg was established as the recommended phase II dose of sonidegib in combination with etoposide/cisplatin. Grade 3 or greater toxicities included: anemia (n=5), neutropenia (n=8), CPK elevation (n=2), fatigue (n=2), and nausea (n=2). Toxicity led to removal of one patient from study. Partial responses were confirmed in 79% (11/14; 95% CI: 49-95%). One patient with SOX2 amplification remains progression-free on maintenance sonidegib after 27 months. CTC count, at baseline, was associated with the presence of liver metastases and after 1 cycle of therapy, with overall survival. CONCLUSIONS Sonidegib 800mg daily was the MTD when administered with EP. Further genomic characterization of exceptional responders may reveal clinically relevant predictive biomarkers that could tailor use in patients most likely to benefit.

Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686-95. ©2018 AACR.See related commentary by Wilson and Politi, p. 676This article is highlighted in the In This Issue feature, p. 663.