Metastatic Non-squamous Non-small Cell Lung Research Articles

Nivolumab in renal cell carcinoma: latest evidence and clinical potential.

Similar to melanoma, renal cell carcinoma (RCC) has been historically considered as an immunogenic tumor, with interleukin 2 (IL-2) and interferon alpha (IFN-α) being the first approved treatments in the 1990s. However, these therapies were effective in only 10-20% of cases and were not well tolerated. Recently, new insights on the interaction between the immune system and tumor have identified the programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) pathway to be a key player in evading host immune responses. The strategy of immune checkpoint blockade is to reduce inhibitory signaling and restore the patient's natural tumor-specific T-cell-mediated immune responses. Nivolumab is the first PD-1 inhibitor to have gained approval for the treatment of patients with metastatic melanoma, squamous and nonsquamous non-small cell lung cancer (NSCLC), Hodgkin disease and recently RCC. In this review, we discuss results from studies of nivolumab in RCC, clinical experience with this agent, and its future development.

Toxicity management of immunotherapy for patients with metastatic melanoma

Checkpoint inhibitors have revolutionized the treatment of patients with metastatic melanoma offering improved responses and significant survival benefit. These agents are now approved for the treatment of metastatic melanoma, squamous and non-squamous non-small cell lung cancer (NSCLC) and kidney cancer, while they are now being investigated in a range of other malignancies. In addition, another anti-PD-L1 monoclonal antibody (atezolizumab) was recently approved for urothelial cancer. Ipilimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody and the anti-PD-1 agents nivolumab and pembrolizumab have followed large clinical development programs, therefore, information regarding their safety and toxicity profile is readily available. Unique toxicities have been observed, which stem from and relate to the immune activation by these agents and are thus termed as immune-related adverse events (irAEs). Clinicians and patients should be aware of this different toxicity profile, so as to promptly recognize, identify and manage symptoms related to irAEs. Indeed, clinical experience has shown that these immune events, when they are early recognized and timely managed, are mostly reversible otherwise they can evoke severe or even life-threatening situations. Several recommendations and guidelines have been developed for the management of irAEs and algorithms have been published based primarily on our knowledge from the ipilimumab trials.

A phase 1b study of famitinib plus docetaxel as 2nd line setting in patients with metastatic non-squamous non-small cell lung cancer and EGFR wild type.

e20603Background: This phase Ib study was designed to evaluate the safety and efficacy of famitinib plus docetaxel in previously 1st line treated non-squamous metastatic NSCLC patients with EGFR wi...

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer

The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.

A randomized Phase 3 study comparing first-line pemetrexed plus cisplatin followed by gefitinib maintenance (PC/G) with gefitinib monotherapy (G) in East Asian patients (pts) with locally advanced or metastatic nonsquamous non-small cell lung cancer (nSqNSCLC): Final survival results.

8041 Background: The primary analysis of this open-label, randomized, multicenter study found no significant difference in progression-free survival (PFS) between PC/G and G in pts with nSqNSCLC and unknown epidermal growth factor receptor (EGFR) mutation status, although the unadjusted hazard ratio (HR, PC/G vs G) favored PC/G (0.85, 95% CI: 0.63–1.13). Final overall survival (OS) data are reported here. Methods: Eligible pts were chemonaive, East Asian light ex-smokers/never-smokers aged ≥18 years with advanced nSqNSCLC, ECOG PS 0/1 and unknown EGFR mutation status. Pts (N = 236) were randomized (1:1) to PC/G (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2for six 21-day cycles then gefitinib 250 mg/day) or G (gefitinib 250 mg/day). EGFR mutation status was determined for 76 pts; 52 (68.4%) had mutations. OS was analyzed (intent-to-treat population) by unadjusted Cox regression analysis. Results: Baseline characteristics were similar between groups (both N = 118). Median OS was similar in the PC/G and G group...

129P - Effectiveness of First-Line Pemetrexed Plus Platinum for Advanced Nonsquamous Non-Small Cell Lung Cancer

Aim: Since 2010 that the combination of platinum / pemetrexed is approved as first line therapy for advanced (locally advanced or metastatic) nonsquamous non-small cell lung cancer (NSCLC). Our aim is to assess the effectiveness of first-line pemetrexed plus platinum for advanced nonsquamous NSCLC in clinical practice.

First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: A randomised, phase 3 trial

BackgroundIn the Iressa Pan-ASia Study (IPASS), gefitinib claimed improved progression-free survival (PFS) versus carboplatin-paclitaxel in clinically selected lung cancer patients. The primary objective of this study was to assess the PFS of pemetrexed-cisplatin (PC) followed by gefitinib maintenance versus gefitinib monotherapy in an IPASS-like population. MethodsIn this open-label, randomised, phase 3 trial, eligible patients were ⩾18years, chemonaïve, East Asian, light ex-smokers/never-smokers with advanced non-squamous non-small cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status 0–1 and unknown epidermal growth factor receptor (EGFR) mutation status who enrolled at 12 sites in Asia. Patients randomly received (1:1) pemetrexed (500mg/m2) plus cisplatin (75mg/m2) for six 21-day cycles, followed by gefitinib maintenance or gefitinib monotherapy (250mg/day). Patient tissue was retrospectively analysed for EGFR mutations. This study is registered with ClinicalTrials.gov, NCT01017874. FindingsBetween 23rd November 2009 and 27th April 2012, 253 patients entered, and 236 patients were randomly assigned to and treated with PC therapy (N=114) and gefitinib monotherapy (N=118). Between-arm baseline characteristics were balanced. PFS was not significantly different between treatment arms (p=0.217). The unadjusted hazard ratio (HR) was 0.85 (95% confidence interval (CI) 0.63–1.13). The HR should be cautiously interpreted as it was not constant. EGFR mutation status was determined for 74 tissue samples; 50 (67.6%) had mutations. In a pre-specified subgroup analysis, only the treatment-by-EGFR mutation interaction was significant (p=0.008) for PFS. For the entire treatment period, a higher proportion of patients in the PC/gefitinib arm versus gefitinib experienced possibly drug-related grade 3–4 treatment-emergent adverse events (39 of 114 [34%] versus 19 of 118 [16%]; p=0.002). InterpretationIn the intention-to-treat (ITT) population, PFS was not significantly different. In the biomarker-assessable population, front-line EGFR tyrosine kinase inhibitor monotherapy was not efficacious in patients with wild-type EGFR. Identification of EGFR mutation status is key in the management of advanced non-squamous non-small cell lung cancer. FundingEli Lilly and Company.

P0066 A randomised phase 3 study comparing first-line pemetrexed plus cisplatin followed by gefitinib as maintenance with gefitinib monotherapy in east Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer

<h3>Background</h3> The IPASS study reported that gefitinib provided superior progression-free survival (PFS) compared with carboplatin and paclitaxel in a clinically selected lung cancer patient population; the benefit was restricted to patients with epidermal growth factor receptor gene (EGFR)-mutant tumours because patients with wild-type (WT) tumours had inferior outcomes. The current study compared PFS for pemetrexed plus cisplatin induction therapy followed by gefitinib as maintenance therapy versus gefitinib monotherapy as first-line treatments in patients with non-squamous non-small cell lung cancer. <h3>Methods</h3> Patients (<i>n</i>=236) with unknown EGFR mutation status were randomised 1:1 to pemetrexed plus cisplatin for six cycles or gefitinib. Patients without progressive disease after six cycles received gefitinib maintenance therapy. Primary endpoint analysis (Wilcoxon test after 169 PFS events) provided 80% power if the true hazard ratio (HR) was 0.65. Tissue samples were analysed for EGFR mutation status. <h3>Findings</h3> Baseline characteristics were balanced across treatment arms. 50 (68%) of 74 samples had mutations. Primary PFS analysis showed no significant difference between treatment arms (Wilcoxon <i>p</i>= 0.217). Unadjusted HR was 0.85 (95% confidence interval [CI] 0.63–1.13). During most of the study, the Kaplain Meier curve for pemetrexed plus cisplatin remained above the curve for gefitinib. In a prespecified subgroup analysis, EGFR-by-treatment interaction was statistically significant (<i>p</i>=0.008), showing treatment effect significantly differed by EGFR status. The PFS HR favoured pemetrexed plus cisplatin in EGFR-mutated and EGFR-WT patients, but the magnitude of benefit was greater in EGFR-WT patients (EGFR-mutated: HR 0.83 [95% CI 0.42–1.62], <i>p</i>=0.585; EGFR-WT: HR 0.18 [95% CI 0.06–0.51], <i>p</i>=0.001). HRs for intention to treat (ITT) and EGFR-mutated patients were not constant and should be interpreted with caution. <h3>Interpretation</h3> In the ITT population, the PFS difference was not statistically significant. In the biomarker assessable population, EGFR-WT patients did not benefit from front-line EGFR tyrosine kinase inhibitor treatment. Identification of EGFR mutational status is key for management of advanced non-squamous non-small cell lung cancer.

A randomised phase II study of pemetrexed versus pemetrexed + erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer

IntroductionPemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed+erlotinib in patients with advanced non-squamous NSCLC. MethodsNSCLC stage III–IV patients who failed one prior platinum-based chemotherapy regimen, ≥1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status ≤2 were eligible. Patients received pemetrexed 500mg/m2 with vitamin B12 and folic acid q3w alone or combined with erlotinib 150mg daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity. ResultsOf 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed+erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed+erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P=0.0047). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus 11.83 (8.18, 16.66) for pemetrexed+erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P=0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed+erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P=0.0034). One patient died in pemetrexed+erlotinib arm due to febrile neutropenia. Grades 3/4 drug-related toxicities (in ≥5% of patients) in pemetrexed/pemetrexed+erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%). ConclusionsPemetrexed+erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone.

Bevacizumab treatment for advanced non-small cell lung cancer: A case report

The safety of Avastin in lung cancer (SAiL) study is a multi-center, open-source, stand-alone study. Patients with untreated, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered up to six cycles of chemotherapy combined with bevacizumab-humanized monoclonal antibodies, followed by maintenance therapy with bevacizumab until further progression of the disease. From August, 2006 to July, 2008 there were a total of 2,172 patients enrolled in the study, with a median progression-free survival time of 7.8 months and an overall survival time of 14.6 months. The present study describes the case of a 54-year-old male with lung cancer and T3N0M1 subcutaneous metastasis, which was initially treated with bevacizumab-combined carboplatin/paclitaxel (C/P) therapy and then maintained solely with bevacizumab for five years. Following six cycles of C/P bevacizumab treatment, the therapeutic evaluation revealed a stable disease (SD). The patient was kept on bevacizumab maintenance therapy for 50 months without disease progression until a persistent 3+ proteinuria was diagnosed in a follow-up review, which led to bevacizumab withdrawal and concomitant tumor growth. The present study concluded that the long-term application of bevacizumab monoclonal antibodies (mABs) was safe in a late-stage non-small cell lung cancer patient. The major adverse reaction that was exhibited was proteinuria, which was associated with the cumulative dose of bevacizumab and was able to be reversed by withdrawal. Patients with a prolonged SD may benefit from bevacizumab maintenance therapy.

Randomized, blinded, placebo-controlled phase II trial of docetaxel and bavituximab as second-line therapy in locally advanced or metastatic non-squamous non-small cell lung cancer.

8095 Background: Bavituximab (B) is a monoclonal antibody against phosphatidylserine (PS) with a selective tumor vascular-directed immune response. The purpose of this trial is to evaluate the efficacy and safety of B or placebo (P) combined with docetaxel (D) in patients with locally advanced or metastatic non-squamous NSCLC. Methods: Patients were randomized 1:1:1 to receive 75 mg/m2 of D every 21 days for up to 6 cycles combined with weekly blinded infusions of P, 1mg/kg B or 3 mg/kg B until disease progression or unacceptable toxicity. Primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). Safety was evaluated by adverse events (AEs), vital signs, CBC, biochemistry, urinalysis, coagulation, ECG. Post study unblinding, a PK substudy revealed vial coding discrepancies in the P and 1 mg/kg vials. As a result, data from these two groups were pooled to form the control (C) arm in the analysis. Results: Forty-one patients were entered into the 3mg/kg B+D arm and 80 into the control arm. No significant differences were seen in age, gender, ethnicity or disease stage. ECOG 2 was 13% in C and 24% in 3 mg/kg B+D arms. At this analysis, 54% death events have been reported in 3 mg/kg B+D and 71% in C arm. ORR is 17.1%/13.8% and median PFS is 4.5/3.3 months for 3 mg/kg B+D/C. Median OS is 11.7 months for 3 mg/kg B+D and 7.3 months for C. The safety profile for 3 mg/kg B+D was similar to that of C in severity and frequency. No other safety signal was identified. Conclusions: This randomized, placebo-controlled phase 2 trial demonstrated a positive trend favoring 3 mg/kg B+D in ORR, PFS and OS. 3 mg/kg B in combination with D was well tolerated and is the planned dose forPhase 3. Clinical trial information: NCT01138163.

1329 - A Multicenter, Randomized Phase II Study of V (Vinorelbine)/C (Cisplatin)/B (Bevacizumab) Followed by D (Docetaxel)/G (Gemcitabine)/B Versus D/ C /B as a First-Line Therapy for Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background The combination of D/G has shown equal activity compared to the platinum-based doublets, which is considered the cornerstone for the treatment of NSCLC, with a more favorable toxicity profile. Sequential therapy with four active drugs, including C, was recently investigated and attributed a favorable response rate (Pallis A, et al; Lung Cancer 2006 52(2): 165-71). Incorporation of B to the standard platinum-based regimen improved its clinical outcome. The efficacy of sequential four drug treatment in combination with B was compared to the standard non platinum-based regimen combined with B. Methods Seventy-seven treatment-naive patients with unresectable stage IIIB and IV non-squamous NSCLC were randomized to receive V 60 mg/m2 PO on day 1 and 8, C 80mg/m2 IV on day 1 and B 15 mg/kg IV on day 1, for 3 cycles followed by D 75 mg/m2 IV, G 1100 mg/m2 IV and B 15 mg/kg IV, all on day 1 (Arm A) or D 75 mg/m2 IV, C 80mg/m2 IV and B 15 mg/kg IV on day. The cycles were repeated every 3 weeks for a total of 6 cycles. The primary endpoint was response rate (RR) and the secondary end points overall survival (OS) and progression free survival (PFS). Results Thirty-nine patients were randomized to arm B (control) and 38 patients to the sequential arm. The overall RR was 36.8% and 46.2% in arm A and B, respectively (p= 0.49). There were 3 complete responses, one in arm A. Median PFS was 5.77 and 5.53 months in arm A and B, respectively (p= 0.368). Median OS was 16.9 and 10.9, respectively (p= 0.39). The estimated 1 and 2-year survival for arm A versus B were 64.1% and 35% versus 48.4% and 24%, respectively. No difference in the toxicity profile was observed between the 2 arms, although more cycle-delays were observed in the experimental arm (29.5 versus 12.2; p Conclusion Sequential treatment with four active drugs is feasible and safe. The combination attributes encouraging results compared to the standard platinum-based regimen. Disclosure All authors have declared no conflicts of interest.

Weekly paclitaxel and bevacizumab as fourth-line treatment or beyond for metastatic nonsquamous non-small cell lung cancer.

e18066 Background: Paclitaxel (P) and bevacizumab (B) showed synergistic antitumor efficacy in preclinical models. In combination with carboplatin, PB prolonged progression-free survival (PFS) and overall survival (OS) in selected metastatic non-squamous Non Small Cell Lung Cancer (NSCLC) patients compared to carboplatin and paclitaxel. Currently, there are no standard treatments beyond third-line therapy in NSCLC. We sought to determine the efficacy of weekly paclitaxel and bevacizumab (wPB) in non-squamous NSCLC as fourth-line therapy or beyond. Methods: we retrospectively reviewed patients with metastatic non-squamous NSCLC who have been treated with wPB in our institution. Patients were identified from a prospective database. Treatment consisted in P 80mg/m² on days 1, 8, 15 and B 15mg/kg on day 1, every 3 weeks until progression or unacceptable toxicity. Patients were evaluated every 3 cycles. PFS and OS were calculated from the date of initiation of wPB and analyzed using the Kaplan-Meier method. Results: Twenty patients received at least one cycle of wPB between 2008 and 2011. All patients received wPB as fourth-line treatment or beyond. Eight patients (40%) had a partial response, 7 patients (35%) had stable disease and 5 patients (25%) had progressive disease. Grade 3-4 adverse events included neutropenia (20%), onycholysis (10%), infection (10%), pulmonary haemorrhage (5%), neuropathy (5%) and hypertension (5%). One patient died from a bowel perforation following second cycle of wPB. The median PFS was 6.4 months (CI95% 4.1-9) and the median OS was 9.6 months (CI95% 7-19.7). One patient who previously received bevacizumab as part of first-line chemotherapy and another patient harbouring an ALK rearrangement benefited from wPB during more than 8 months and 18 months, respectively. Conclusions: In our experience, wPB exhibited acceptable toxicity and had encouraging anti-tumor efficacy as fourth-line treatment or beyond in non-squamous NSCLC patients, supporting further evaluation in larger prospective studies.

A multicenter, randomized phase II study of sequential vinorelbine (V)/cisplatin (C)/bevacizumab (B) followed by docetaxel (D)/gemcitabine (G)/B versus D/C/B as a first-line therapy for advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC).

e18105 Background: The combination of D with G has been shown equally active compared to the platinum-based doublets, which is considered the cornerstone for the treatment of NSCLC, with a more favorable toxicity profile (Georgoulias V. Lancet 2001 357: 1478-84). Sequential therapy with four active drugs (two doublets) in NSCLC, including C, was recently investigated and attributed a promising response rate (Pallis A. Lung Cancer, 2006, 52(2): 165-71). Incorporation of B to the standard platinum-based regimen improved its clinical outcome. Aim of this trial was to compare the efficacy of sequential four drug treatment in combination with B to the standard non platinum-based regimen combined with B. Methods: Seventy-seven treatment naïve patients (pts) with stage IIIB and IV non-squamous NSCLC were randomized to receive V 60 mg/m2 PO on day 1 and 8, C 80mg/m2 IV on day 1 and B 15 mg/kg IVon day 1, for 3 cycles followed by D 75 mg/m2 IV, G 1100 mg/m2 IV and B 15 mg/kg IV, all on day 1 (Arm A) or D 75 mg/m2 IV, C 80mg/m2 IV and B 15 mg/kg IV on day. The cycles were repeated every 3 weeks for a total of 6 cycles. The primary endpoint of the study was response rate (RR) and the secondary outcome measures were overall survival (OS) and progression free survival (PFS). Results: Thirty-nine pts were randomized to the control arm (Arm B) and 38 pts to the sequential arm. Pt demographics were balanced in both the arms. The overall RR was 36.8% and 46.2% in arm A and B, respectively (p= 0.49). There were 3 complete responses, one in arm A. Median PFS was 6.87 and 5.53 months in arm A and B, respectively (p= 0.368). Median OS was 19.6 and 10.33, respectively (p= 0.239). The estimated 1 and 2-year survival for arm A versus B were 71.1% and 36% versus 45.3% and 28%, respectively. No statistically significant difference in the toxicity profile was observed between the 2 arms. Conclusions: Sequential treatment with four active drugs is feasible and safe. The combination attributes encouraging results compared to the standard platinum-based regimen.

Detection and comparison of peptide nucleic acid-mediated real-time polymerase chain reaction clamping and direct gene sequencing for epidermal growth factor receptor mutations in patients with non-small cell lung cancer

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are recommended as first-line therapy in patients with advanced, recurrent, or metastatic non-squamous non-small cell lung cancer (NSCLC) that have active EGFR mutations. The importance of rapid and sensitive methods for the detection of EGFR mutations is emphasized. The aim of this study is to examine the EGFR mutational status by both direct DNA sequencing and peptide nucleic acid (PNA)-mediated real-time PCR clamping and to evaluate the correlation between the EGFR mutational status and the clinical response to EGFR-tyrosine kinase inhibitors. Clinical specimens from 240 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20 and 21. All clinical data and tumor specimens were obtained from 8 centers of the Korean Molecular Lung Cancer Group (KMLCG). After genomic DNA was extracted from paraffin-embedded tissue specimens, we performed PNA-mediated real-time PCR clamping and direct DNA sequencing for the detection of EGFR mutations. Of 240 tumor samples, PNA-mediated PCR clamping was used to detect genomic alterations in 83 (34.6%) samples, including 61 identified by sequencing and 22 additional samples (10 in exon 19, 9 in exon 21, and 3 in both exons); direct DNA sequencing was used to identify a total of 63 (26.3%) mutations that contained 40 deletion mutations in exon 19 (63.5%) and 18 substitution mutations (28.6%) in exon 21. PNA-mediated PCR clamping was used to identify more mutations than clinical direct sequencing, whereas clinical outcomes were not significantly different between the groups harboring activating mutations detected by each method. These data suggest that PNA-mediated real-time PCR clamping exhibits high sensitivity and is a simple procedure relative to direct DNA sequencing that is a useful screening tool for the detection of EGFR mutations in clinical settings.

Revisiting cutaneous adverse reactions to pemetrexed.

Pemetrexed (Alimta®) is a multitargeted antifolate drug approved as a single agent or in combination with cisplatin for the treatment of a small number of malignancies including advanced and metastatic non-squamous non-small cell lung cancer (NSCLC), and malignant pleural mesothelioma. This review reports the recent peer-reviewed publications and original findings regarding cutaneous adverse reactions (CARs) to pemetrexed. Pemetrexed-related CARs are frequently reported under the unspecific term 'skin rash'. However, more specific diseases were tentatively identified as alopecias, urticarial vasculitis, acute generalized exanthematous pustulosis, toxic epidermal necrolysis, radiation recall dermatitis and pityriasis lichenoides. Most of the skin reactions occur shortly after pemetrexed administration. As with methotrexate-related CARs, the cell cycle arrest in the S phase may be regarded as a direct and major cause of the cytotoxic pathobiology. An adverse immune reaction is unlikely. In conclusion, pemetrexed is responsible for CARs exhibiting a variety of clinical presentations. Their origin is likely attributed to direct cytotoxicity following the cell cycle arrest in the S phase and cell necrosis.

Bevacizumab (B) and erlotinib (E) as first-line therapy in metastatic nonsquamous non-small cell lung cancer (NSCLC) followed by platinum-based chemotherapy (CT) at disease progression (PD): A multicenter phase II trial, SAKK 19/05.

7561 Background: Standard CT is toxic and yields unsatisfactory results in advanced NSCLC. The aim of this trial was to evaluate feasibility and efficacy of BE first-line combination, followed by CT at PD. Methods: Eligibility criteria included non-squamous NSCLC stage IIIB-IV, WHO PS 0-1, no brain metastases. B 15 mg/kg i.v. day 1 of each 21-day cycle and E 150 mg p.o. daily were given until PD or unacceptable toxicity, followed by CT with gemcitabine 1250 mg/m2 i.v. on days 1 and 8 and either cisplatin 80 mg/m2 or carboplatin AUC 5 i.v. on day 1 (every 3 weeks) for a maximum of 6 cycles. The primary endpoint was disease stabilization rate (DSR) after 12 weeks of BE. Secondary endpoints were overall survival (OS), response rate, time to progression (TTP), DSR at 6 and 18 weeks, safety, quality of life, response to subsequent CT, molecular pathology (mutations), allele-specific polymerase chain reaction (PCR) for mutations (tumor, serum), serum proteomics and other translational analyses. Results: 103 patients (pts) were enrolled, 101 were evaluable. Under BE, DSR at week 12 was 54.5% (95% CI: 44.2-64.4%). 73 pts had at least SD (72.3%), including 1 CR (1.0%) and 17 PR (16.8%). No unexpected toxicities were observed. Median TTP under BE was 4.1 months (mo). 62 (61.4%) pts started CT; 35 received at least 4 cycles. Six PR and 32 SD were observed. At a median follow-up of 36 mo, median OS was 14 mo (95% CI: 10.7-19.0 mo). Twelve pts had an activated EGFR mutation in exons 19 or 21; their exclusion did not change overall TTP or OS, and DSR at week 12 remained 50.6%. Thirteen pts had KRAS mutation. Allele-specific PCR detected EGFR mutations in serum of > 50% of pts with tumor mutations. PCR also detected identical EGFR mutations in 66% of tumors tested by sequencing method. Conclusions: The BE regimen followed by CT at PD is feasible in advanced non-squamous NSCLC with low toxicity and promising activity. OS is similar to the observed OS using up-front standard CT regimens.

Approval Summary: Pemetrexed Maintenance Therapy of Advanced/Metastatic Nonsquamous, Non-Small Cell Lung Cancer (NSCLC)

On July 2, 2009, the U.S. Food and Drug Administration approved pemetrexed injection (Alimta® Injection; Eli Lilly and Company, Indianapolis, IN) for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based doublet induction chemotherapy. A double-blind study of pemetrexed plus best supportive care versus placebo plus best supportive care was conducted. Pemetrexed, 500 mg/m(2) i.v., was administered every 21 days until disease progression. Folic acid, vitamin B(12), and a corticosteroid were given to all study patients. There were 663 randomized patients (pemetrexed, 441; placebo, 222). Treatments were well balanced with respect to baseline disease characteristics and stratification factors. The median overall survival (OS) time for intent-to-treat (ITT) patients was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65-0.95; p = .012). Median OS times were 15.5 months versus 10.3 months for patients with nonsquamous histologies receiving pemetrexed and placebo, respectively (HR, 0.70; 95% CI, 0.56-0.88). The median OS time in patients with squamous histology receiving pemetrexed was 9.9 months, versus 10.8 months for those receiving placebo (HR, 1.07; 95% CI, 0.77-1.50). A significantly longer progression-free survival interval for both the ITT and nonsquamous patient populations receiving pemetrexed maintenance therapy was also observed. The most common (>5%) adverse reactions in patients receiving pemetrexed were hematologic toxicity, an increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy, and skin rash.

Maintenance Therapy of Patients with Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer&amp;mdash;Role of Pemetrexed

Although progress could have been achieved in treatment of patients with advanced non-small cell lung cancer (NSCLC), outcome still remains poor. One of the strategies to improve survival currently under investigation is maintenance therapy, e.g. prolongation of treatment duration with the administration of an agent at the end of a defined number of initial chemotherapy cycles. This can consist of molecularly targeted or chemotherapeutic drugs which were already included in the induction therapy or different, potentially noncross-resistant agents. The latter represents the perhaps most promising strategy according to currently available data. Drugs chosen for this form of maintenance should be well tolerated with favorable toxicity profile. In the search for this, pemetrexed has classified as an encouraging agent for maintenance therapy as it can be easily delivered, has a favorable toxicity profile and has already demonstrated significant efficacy in advanced NSCLC. Here we review the current status of maintenance therapy with emphasis on pemetrexed in advanced NSCLC.

Phase II study of bevacizumab in combination with cisplatin and docetaxel as first-line treatment of patients (p) with metastatic non-squamous non-small cell lung cancer (NSCLC): Final report.

e19023 Background: Bevacizumab (B), in addition to platinum-based chemotherapy, is indicated for 1st-line treatment of p with advanced NSCLC other than predominantly squamous cell histology. B has ...