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KRAS mutations occur in approximately 30% of lung adenocarcinomas, mainly in codon 12 (83% of cases), p.G12C being the prevalent one (40%), followed by p.G12V and p.G12D (22 and 16%, respectively). Treatment options for advanced KRAS mutant non-small-cell lung cancer ( KRAS-MT NSCLC) are limited to chemotherapy and immune checkpoint inhibitors (CPIs). However, clinical trials exploring specific targeted agents are expected to change the treatment landscape of this disease. Here, we describe the design and scientific rationale of the randomized, phase II, open label, RAMP-202 study, which will evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib in advanced KRAS-MT NSCLC patients after failure of prior platinum-based chemotherapy and CPI.

Supplemental Figure 1. Study Design and Patient Disposition Supplemental Figure 2. Change in serum creatinine by visit Supplemental Figure 3. Change in blood urea nitrogen (BUN) by visit Supplemental Figure 4. Maximum observed value in cystatin C by visit Supplemental Figure 5. Minimum Observed Value in Neutrophils by Visit

Supplemental Table 1. Post-discontinuation therapies

Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor–positive (HR+), HER2− metastatic breast cancer (MBC).Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2− MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS).Results: Patients (n = 132) had a median of 3 (range, 1–8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3–27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%).Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2− metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity. Clin Cancer Res; 23(17); 5218–24. ©2017 AACR.

Methods that support the supplemental data provided

TPS263 Background: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors (NCT05453825). Cohort A will enroll colorectal cancer (CRC) patients. Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aggressive CRC remains difficult to treat owing to the aberrant activation of oncogenic signaling pathways including the NOTCH pathway. Preclinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway inhibition. We postulate that navicixizumab will demonstrate anticancer efficacy against CRC. Methods: Eligible CRC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 3 prior lines of standard therapy for metastatic disease, including an anti-VEGF monoclonal antibody. Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap ExTra with the Xerna TME Panel where patient samples will be classified into one of four tumor microenviroment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m2 on Days 1 and 15 of a 28-day cycle, Cohort A2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of

Background: Abemaciclib is an oral, selective inhibitor of cyclin-dependent kinases 4 & 6 that is dosed on a twice daily continuous schedule. In patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), abemaciclib has demonstrated clinical efficacy with a tolerable safety profile when administered as monotherapy in MONARCH 1 (NCT02102490), in combination with fulvestrant in MONARCH 2 (NCT02107703), and in combination with non-steroidal aromatase inhibitors (NSAI) in MONARCH 3 (NCT02246621). Inducing tumor response and delaying disease progression is of critical need in pts with liver metastases (mets). Methods: An exploratory subgroup analysis was conducted in pts with liver mets at baseline across the MONARCH 1, 2, and 3 studies. All pts had HR+, HER2- ABC. The primary endpoint of MONARCH 1 was objective response rate (ORR), and the primary endpoint of MONARCH 2 and 3 was investigator-assessed progression-free survival (PFS). Analysis methods for these endpoints were previously described. Key enrollment criteria and dosing information are listed in Table 1. Table 1. Eligibility criteria and dosing information for the MONARCH 1, 2, and 3 studiesKey enrollment criteriaMONARCH 1MONARCH 2MONARCH 3Prior endocrine therapyProgressed on or after ETProgressed while receiving adjuvant or first-line ET, or ≤ 12 months from the end of adjuvant ETET naïve or disease relapse >12 months after (neo)adjuvant ETChemotherapy regimens in advanced setting1 or 200Visceral crisisNo restrictionNot permittedNot permittedDose and Schedule abemaciclib200 mg, twice daily, continuous150 mg1, twice daily, continuous150 mg, twice daily, continuousfulvestrant-500 mg, per label-anastrozole2--1 mg, dailyletrozole2--2.5 mg, daily1post-amendment; 2physician's choice of NSAI (anastrozole or letrozole); ET: endocrine therapy Results: Efficacy results of pts with liver mets are described in Table 2. The most frequent adverse events observed in pts with liver mets in MONARCH 1 were diarrhea, nausea, and fatigue and in the abemaciclib arms of MONARCH 2 and 3 were diarrhea, neutropenia, and nausea. Table 2. PFS and response rates of pts with liver mets in MONARCH 1, 2, and 3 MONARCH 1MONARCH 2 abemaciclib armMONARCH 2 placebo armMONARCH 3 abemaciclib armMONARCH 3 placebo armPts with liver mets, n93115594830PFS, HR (95% CI)N/A.45 (.31, .64).47 (.25, .87)Median PFS, months5.611.63.115.07.2ORR, n (%)20 (21.5)54 (47.0)9 (15.3)26 (54.2)6 (20.0)CBR, n (%)39 (41.9)77 (67.0)21 (35.6)32 (66.7)12 (40.0)CBR: clinical benefit rate (complete response [CR] + partial response [PR] + stable disease ≥6 months); HR: hazard ratio; ORR: objective response rate (CR+PR); PFS: progression-free survival; pts: patients Conclusions: The results suggest that the combination of abemaciclib and endocrine therapy was an effective treatment option in pts with liver metastases, a population deriving modest benefit from single-agent endocrine therapy. Tolerability results were generally consistent with the safety populations previously reported for each study. Citation Format: Di Leo A, Dickler M, Sledge GW, Toi M, Forrester T, Nanda S, Koustenis A, Bourayou N, Johnston S. Efficacy and safety of abemaciclib in patients with liver metastases in the MONARCH 1, 2, and 3 studies [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-02.

Background: VS-6766 is a unique small molecule inhibitor of both RAF and MEK. In contrast to several other MEK inhibitors available, VS-6766 blocks both MEK kinase activity and RAF phosphorylation of MEK. This sequential blockade mechanism enables VS-6766 to block MEK signaling more consistently without the compensatory and paradoxical activation of MEK that reduces the efficacy of other small molecule inhibitors of MEK and RAF. Defactinib (VS-6063), an orally active small molecule, is a potent adenosine 5'- triphosphate (ATP) competitive, reversible inhibitor of focal adhesion kinase (FAK). Defactinib has shown synergistic activity with BRAF and MEK inhibitors in both in vitro and in vivo preclinical solid tumor models. Specifically, in several human tumor cell lines with mutations in RAS or BRAF or wildtype RAS and BRAF, defactinib has shown synergy with MEK inhibitors or VS-6766. In mouse models of KRAS mutant ovarian cancer, BRAF-mutant melanoma or uveal melanoma, FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors, while the single agents have only induced tumor stasis. The combination of VS-6766 and defactinib is currently being evaluated in the Investigator Sponsored FRAME study. Preliminary efficacy results are available for a small number of subjects with KRAS mutated NSCLC treated with a combination of VS-6766 and defactinib. Of the 10 subjects with NSCLC, 1 subject with KRAS-G12V- mutated cancer achieved PR while 3/10 subjects received treatment for ≥24 weeks. In an updated analysis of response in 15 subjects with KRAS-mutant NSCLC, there were 2 PRs and 7 SDs (ORR: 13%). The two subjects with KRAS G12V- mutated NSCLC both achieved PR (ORR: 100%). Methods: This is an adaptive, two-part, Phase 2, multicenter, parallel cohort, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib in subjects with recurrent NSCLC(NCT04620330). The study will be conducted in two parts. Part A will determine the optimal regimen, either VS-6766 monotherapy or VS-6766 in combination with defactinib based on confirmed overall response rate as assessed by independent radiology review. Part A will consist of three arms in KRAS mutated NSCLC Arm 1 monotherapy of VS-6766, Arm 2 the combination of VS-6766 and defactinib in KRAS G12V mutated and Arm 3 the combination in other KRAS mutated. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS mutated NSCLC. Subjects enrolled must have histologic or cytologic evidence of NSCLC, measurable disease according to RECIST V1.1 and known KRAS mutation. The study will enroll up to 377 subjects globally with 57 subjects (32 KRAS G12V & 25 KRAS other) in Part A and an additional 144 KRAS G12V and 176 KRAS other in Part B. This study is open for enrollment. Citation Format: D. Ross Camidge, Jonathan Pachter, Andrew Koustenis, Gloria Patrick, David R. Spigel. A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) RAMP 202, as a single agent and in combination with defactinib (FAK inhibitor) in recurrent KRAS-mutant (KRAS-MT) non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P048.

Background: VS-6766 is a unique small molecule inhibitor that blocks MEK kinase activity and RAF phosphorylation of MEK. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Defactinib, (VS-6063), an orally active small molecule, is a potent adenosine 5'- triphosphate (ATP) competitive, reversible inhibitor of focal adhesion kinase (FAK). Defactinib has shown synergistic activity with BRAF and MEK inhibitors in both in vitro and in vivo solid tumor models. Prior molecularly unselected studies with single agent MEK inhibitors have shown response rates up to 26% in recurrent LGSOC. A third of patients with recurrent LGSOC harbor somatic KRAS mutations. FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors in in vivo models of KRAS mutant ovarian cancer. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof of concept study, durable objective responses have been reported in recurrent LGSOC patients, particularly those with KRAS mutations including patients who have had a prior MEK inhibitor (Banerji et al AACR 2020). Based on preclinical studies demonstrating efficacy of both VS-6766 and the VS-6766/defactinib combination and preliminary results of the FRAME study, the phase II ENGOT-ov60/GOG3052 has been developed in recurrent LGSOC. Methods: This is a Phase II, adaptive, two-part, multicenter, parallel cohort, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS-mutated LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS-mutated and KRAS wild-type LGSOC. The minimum expected enrollment is 52 subjects with KRAS-mutated tumors (32 subjects in Part A and 20 in Part B) and 36 with KRAS wild-type tumors in Part B. Patients will be randomized to receive VS-6766 (4.0 mg PO, twice weekly 3 weeks on, 1 week off) or VS6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off) till progression. Key inclusion criteria include histologically confirmed LGSOC, presence of KRAS mutation (Part A), prior systemic therapy for metastatic disease and up to 1 prior line of MEK/RAF inhibitor therapy permitted. This international study is open to enrollment. Citation Format: Susana N. Banerjee, Bradley J. Monk, Els Van Nieuwenhuysen, Kathleen N. Moore, Ana Oaknin, Michel Fabbro, Nicoletta Columbo, David M. O’Malley, Robert L. Coleman, Jonathan Pachter, Andrew Koustenis, Gloria Patrick, Lorna Leonard, Rachel Grisham. ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P046.

Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor–positive (HR+), HER2− metastatic breast cancer (MBC). Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2− MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS). Results: Patients (n = 132) had a median of 3 (range, 1–8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3–27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%). Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2− metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity. Clin Cancer Res; 23(17); 5218–24. ©2017 AACR.

Background: The MONARCH 1 (NCT0210249) study demonstrated durable single agent activity of abemaciclib in patients (pts) with HR+/HER2- breast cancer, with an objective response rate of 19.7% and median duration of response of 8.6 months1. The MONARCH 1 study population was heavily pretreated and had a high disease burden: all pts had previously received endocrine therapy and chemotherapy, had median of 3 prior systemic therapies for metastatic disease 90.2% had visceral disease and 85.6% had ≥ 2 metastatic sites. Methods: MONARCH 1 was a phase 2 single-arm study designed to evaluate safety and efficacy of abemaciclib monotherapy in women with HR+/HER2- MBC whose disease progressed on/after endocrine therapy and chemotherapy. Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours until disease progression. The primary objective planned to evaluate investigator-assessed objective response rate (ORR= complete response [CR] + partial response [PR]) in a sample size of approximately 128 pts) using RECIST v1.1. Subgroup analyses evaluating ORR by prior treatment and disease burden were performed. Results: A total of 132 pts were treated with abemaciclib monotherapy. Analyses of subgroups based on prior treatment and disease burden are summarized in Table 1. Conclusions: Abemaciclib monotherapy administered on a continuous schedule has consistent single agent activity across the subgroups analyzed. Table 1. Objective Response Rate Subgroup Analyses Number of PatientsObjective Response (CR + PR) n(%)ITT13226 (19.7)Number of Prior chemotherapies for metastatic disease 16714 (20.9)26411 (17.2)311 (100.0)Taxane use in the metastatic setting Yes9119 (20.9)No417 (17.1)Capecitabine use in the metastatic setting Yes7616 (21.1)No5610 (17.9)Number of prior endocrine therapies for metastatic disease 0173 (17.6)1489 (18.8)2 or more6714 (20.9)Fulvestrant use in the metastatic setting Yes6715 (22.4)No6511 (16.9)Number of metastatic sites 1194 (21.1)24610 (21.7)3 or more6712 (17.9)Liver metastases Yes9320 (21.5)No396 (15.4)References: 1. Dickler, M. et al. American Society of Clinical Oncology (ASCO), abstract #510 (2016). Citation Format: Rugo H, Nanda S, Koustenis A. Subgroup Analysis by prior treatment and disease burden in MONARCH 1: A phase 2 study of monotherapy abemaciclib, a CDK4 & 6 inhibitor, in patients with HR+/HER2 metastatic breast cancer (MBC) following chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-12.

Objective: Abemaciclib is an oral, selective inhibitor of CDK4 & 6 that exhibited single agent activity in the MONARCH 1 clinical trial1. The relationship between abemaciclib exposure as monotherapy and response for efficacy and adverse events was evaluated in patients with metastatic breast cancer. Methods: Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours in 28 day cycles until disease progression. Sparse pharmacokinetic samples (PK) were collected, cycle (C) 1 day (D) 1 pre dose, C1D15 4 and 7 hours post dose, C2D1 pre and 3 hours post dose, and pre dose on C3D1. Exposure metrics were predicted from a population PK model and included the minimum concentration after a single dose on D1(Cmin,d1), maximum concentration at steady state (Cmax,ss), and minimum concentration at steady state (Cmin,ss ). Exposure to abemaciclib, active metabolites LSN2839567 (M2) and LSN3106726 (M20), and total active species (abemaciclib + M2 + M20) were tested. Response endpoints including efficacy and adverse events were evaluated 12 months after the last patient entered treatment. The relationship between exposure and objective response rate (ORR) was evaluated by quartile analysis and logistic regression. The relationship between exposure and progression free survival (PFS) was evaluated by Kaplan Meier analysis of exposure quartiles and a Cox Proportional Hazard model with PFS as the response and exposure as a covariate. The relationship between exposure and neutropenia, diarrhea, fatigue, nausea, vomiting, and any treatment emergent adverse event (TEAE) was evaluated by logistic regression on the incidence of any grade, grade≥ 2, and grade ≥ 3 events. No adjustments for multiplicity were performed. Results: Analyses included 132 patients. A summary of the exposures in MONARCH 1 are presented in Table 1. The confirmed ORR was 19.7%, and median PFS was 5.95 months (95%CI: 4.2, 7.5). There was no statistically significant relationship between Cmin,d1, Cmin,ss, Cmax,ss for abemaciclib, M2, M20, or total analyte and ORR or PFS. There were no statistically significant and clinically relevant relationships between abemaciclib exposure and TEAEs. Conclusion: The results of the exposure-response analysis support the abemaciclib single agent starting dose of 200 mg twice daily and dose reductions in 50 mg decrements as needed for adverse events. Further studies to refine the PK model and evaluate relationships between exposure and response are warranted. Table 1 Abemaciclib exposures in MONARCH 1 Geometric Mean (µm) (CV%)AnalyteCmax,ss (µm)Cmin,d1 (µm)Cmin,ss (µm)Abemaciclib0.509 (42.6)0.136 (54.2)0.356 (59.9)M20.247 (62.4)0.0511 (51.4)0.187 (83.8)M200.395 (61)0.0687 (56.7)0.312 (79.9)Total Active Species1.19 (43.2)0.262 (47.6)0.888 (60.7)References: 1. Dickler, M. et al. American Society of Clinical Oncology (ASCO), abstract #510 (2016). Citation Format: O'Shaughnessy J, Chigutsa E, Kambhampati SRP, Sykes A, Frenzel M, Nanda S, Koustenis A, Smith I, Turner PK. Abemaciclib exposure-response relationship in patients with metastatic breast cancer in MONARCH 1 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-11.

TPS5603 Background: VS-6766 is a unique small molecule inhibitor that blocks MEK kinase activity and RAF phosphorylation of MEK. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Defactinib, (VS-6063), an orally active small molecule, is a potent adenosine 5'- triphosphate (ATP) competitive, reversible inhibitor of focal adhesion kinase (FAK). Defactinib has shown synergistic activity with BRAF and MEK inhibitors in both in vitro and in vivo solid tumor models. Prior molecularly unselected studies with single agent MEK inhibitors have shown response rates up to 26% in recurrent LGSOC. A third of patients with recurrent LGSOC harbor somatic KRAS mutations. FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors in in vivo models of KRAS mutant ovarian cancer. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof of concept study, durable objective responses have been reported in recurrent LGSOC patients, particularly those with KRAS mutations including patients who have had a prior MEK inhibitor (Banerji et al AACR 2020). Based on preclinical studies demonstrating efficacy of both VS-6766 and the VS-6766/defactinib combination and preliminary results of the FRAME study, the phase II ENGOT-ov60/GOG3052 has been developed in recurrent LGSOC. Methods: This is a Phase II, adaptive, two-part, multicenter, parallel cohort, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS-mutated LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS-mutated and KRAS wild-type LGSOC. The minimum expected enrollment is 52 subjects with KRAS-mutated tumors (32 subjects in Part A and 20 in Part B) and 36 with KRAS wild-type tumors in Part B. Patients will be randomized to receive VS-6766 (4.0 mg PO, twice weekly 3 weeks on, 1 week off) or VS6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off) till progression. Key inclusion criteria include histologically confirmed LGSOC, presence of KRAS mutation (Part A), prior systemic therapy for metastatic disease and up to 1 prior line of MEK/RAF inhibitor therapy permitted. This international study is open to enrollment. Clinical trial information: NCT04625270.

In recent years, ophthalmology has experienced significant developments with respect to imaging modalities. Optical coherence tomography angiography is one such technology that seeks to improve diagnostics for retinal diseases. Using standard structural ocular coherence tomography hardware, optical coherence tomography angiography demonstrates the ability to non-invasively visualise the vasculature in the retina and the choroid with high resolution, allowing greater insight into retinal vascular pathologies. In addition, retinal and choroidal vessel density and blood flow can be quantified, offering potential to assist in the diagnosis of a variety of retinal diseases. To date, numerous retinal diseases, such as open-angle glaucoma, have been found to possess a vascular component. Specifically, ischaemia of the optic nerve head and lamina cribrosa has been theorised as a causative factor in ganglion cell death; however, confirmation of this mechanism has been prohibited by the limitations of currently existing imaging modalities. Optical coherence tomography angiography provides clear imaging of these regions and the possibility to elucidate further understanding of vascular factors that contribute to glaucoma development and progression. Furthermore, this imaging modality may provide insight to neural pathologies with vascular components such as Alzheimer's disease. Herein, the authors discuss the theory of operation for optical coherence tomography angiography and the current findings from pilot studies with a focus on open-angle glaucoma. In addition, speculation is offered for future applications of the technology to study other diseases with microvascular contributions.

Background: Abemaciclib is a potent oral cyclin-dependent kinase (CDK) 4 and 6 inhibitor that demonstrated statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) in combination with endocrine therapy (ET) in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced and metastatic breast cancer patients in Phase 3 studies. In contrast to NCCN guidelines, cytotoxic chemotherapy is still often initiated early in the course of HR+, HER2- advanced breast cancer despite absence of visceral crises, potentially denying patients effective and tolerable standard-of-care regimens containing ET. The current study aims to compare the efficacy and safety of abemaciclib in combination with ET to chemotherapy in patients with HR+, HER2- advanced breast cancer with ≥1 site of visceral metastases. Trial design: I3Y-MC-JPCU is a multicenter, open-label, randomized, controlled study of abemaciclib in combination with fulvestrant compared to physician’s choice of chemotherapy in women with HR+, HER2- locally advanced or metastatic breast cancer who have poor prognosis due to visceral metastases. Approximately 300 patients will be randomized 1:1 to Arm A (abemaciclib, 150 mg BID, in combination with fulvestrant, n=150) or Arm B (physician’s choice of chemotherapy [capecitabine, docetaxel, nab-paclitaxel, or paclitaxel], n=150). Stratification factors will include liver metastasis, sensitivity to endocrine therapy (sensitive vs primary resistance vs secondary resistance, and postmenopausal status (natural/surgical/therapeutic radiation vs GnRH use). It will be conducted in the USA. Accrual is planned to start in 2019. Eligibility: Key inclusion criteria are postmenopausal HR+, HER2- patients with locally advanced recurrent and unresectable or metastatic HR+, HER2- breast cancer and ≥1 site of visceral metastasis as well as disease progression after ≥1 line of ET in (neo)adjuvant or metastatic setting. Individuals will be excluded if they have visceral crisis, have received prior systemic therapy other than ET for metastatic disease, have received >1 prior ET for metastatic disease, and/or have been treated with fulvestrant or any CDK 4 and F6 inhibitor for any duration. Objectives: The primary objective is ORR. Secondary objectives include PFS, time to response, duration of response, time to second disease progression (PFS2), and safety. Exploratory objectives include healthcare resource utilization, patient reported outcomes, and relationship of pharmacogenomics/biomarkers to clinical outcomes. Statistical Methods: Comparability of abemaciclib in combination with fulvestrant to chemotherapy will be evaluated with respect to ORR and PFS. The study is designed to demonstrate comparability using a 10% ORR margin and a 20% PFS margin. Comparability will declared if the posterior probability the true difference is less than the comparability margin is at least 80%. PFS comparability will be assessed only if ORR comparability is declared after a gatekeeping testing strategy. The tested hypotheses will be 1) ORR comparability: ≥80% posterior probability that true ORRArm B - true ORRArm A Citation Format: Peter Kaufman, John Glaspy, Wei Zhang, Andrew Koustenis, Yanyun Chen, Adam Brufsky. A randomized trial of abemaciclib in combination with fulvestrant compared to chemotherapy in women with HR+, HER2- advanced breast cancer with visceral metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-05.

Introduction PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Methods Patients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m 2 , carboplatin, area under the curve=6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m 2 , carboplatin, area under the curve=6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed. Results Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio=0.85, 90% confidence interval, 0.7–1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms. Conclusions Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.

Although lung cancer prognosis remains poor for most patients, treatments developed in the past 2 decades have extended survival for many. For those with disease that responded to or those with stable disease after receipt of platinum-based chemotherapy, maintenance regimens enable continued targeting of tumors beyond the induction phase, which is limited by toxicity. This overview summarizes completed phase 3 trials of pemetrexed continuation maintenance treatment in nonsquamous, non-small-cell lung cancer with a focus on 2-year survival, and highlights similar ongoing trials. Some studies showed survival benefits of pemetrexed maintenance treatment versus control arms, with the potential for added benefit when combined with bevacizumab. Two-year survival rates underscore the value of maintenance therapy and suggest progress toward a clinical goal of managing non-small-cell lung cancer as a treatable chronic disease.

e12516 Background: Patient and tumor characteristics, such as tumor grade (TG), site of metastases, hormone receptor status, and endocrine resistance, affect the prognosis for patients (pts) with HR+, HER2- metastatic breast cancer (MBC). This study explored the impact of multiple clinical prognostic factors on pt overall survival (OS) and real-world progression-free survival (rwPFS). Methods: This retrospective study used electronic health record (EHR) data of US pts from a network of community oncology practices maintained in the Vector Oncology Data Warehouse from 1/1/2008 to 4/30/2017. Eligibility included HR+, HER2- MBC diagnosis in 2008 or later and prior systemic therapy for MBC. An index variable was created to assess the effect of multiple clinical prognostic factors collectively, including liver metastases (LM), primary endocrine resistance (PER) (Cardoso F et al. 2018), negative progesterone receptor (PR-) status, and high TG. Pts were grouped based on the number of prognostic factors present at MBC diagnosis: 0, 1, and 2+. Differences in rwPFS and OS from start of first line therapy were evaluated by Kaplan-Meier method and multivariable Cox proportional hazards regression. Results: Eligible pts (n=378) had a mean age of 60.3 years. Among these 57.1% were white, 36.5% were de novo metastatic, 22% had LM, 27.2% had high TG, and 27.1% were PR- at baseline. Among all pts, 170 (45%) had received endocrine therapy as first-line treatment, followed by chemotherapy (28%), CDK4 & 6 inhibitor (17%), or other anti-cancer treatment (9%). After adjustment, rwPFS and OS were significantly (p

Purpose The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy. Patients and Methods Patients with stage IIIA/B unresectable nonsquamous non–small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m2 and cisplatin 50 mg/m2 intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05. Results Enrollment was stopped early because of futility. Five hundred ninety-eight patients were randomly assigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated. Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median, 26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P < .001), during the overall treatment period. Conclusion Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non–small-cell lung cancer.

Item does not contain fulltext BACKGROUND: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum-based chemotherapy is often a first-line treatment. Pemetrexed has shown single-agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed-cisplatin for SCCHN. METHODS: In a double-blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m(2) ) plus cisplatin (75 mg/m(2) ; n = 398) or placebo plus cisplatin (75 mg/m(2) ; n = 397) to assess overall survival (OS) and secondary endpoints. RESULTS: Median OS was 7.3 months in the pemetrexed-cisplatin arm and 6.3 months in the placebo-cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75-1.02; P = .082). Median progression-free survival (PFS, months) was similar in both treatment arms (pemetrexed-cisplatin, 3.6; placebo-cisplatin, 2.8; HR, 0.88; 95% CI, 0.76-1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed-cisplatin (n = 347) led to longer OS and PFS than placebo-cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed-cisplatin (n = 86) resulted in longer OS and PFS than placebo-cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed-cisplatin toxicity was consistent with studies in other tumors. CONCLUSIONS: Pemetrexed-cisplatin compared with placebo-cisplatin did not significantly improve survival for the intent-to-treat population. However, in a prespecified subgroup analysis, pemetrexed-cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers. Cancer 2012. (c) 2012 American Cancer Society.

Introduction L’efficacite et la tolerance du pemetrexed + cisplatine (PC) et radiotherapie thoracique concomitante (RTTc), suivie d’une consolidation par P vs autres chimiotherapies ont ete evaluees ; les resultats intermediaires de tolerance ont ete presentes (Vokes et al., 2013). Methodes Cinq cent quatre-vingt-dix-huit patients (268 en Europe, 22 en France) avec un CBNPC non epidermoide de stade III non resecable ont ete randomises entre 3 cycles de PC + RTTc (66 Gy) suivi de 4 cycles de consolidation par pemetrexed vs le bras controle 2 cycles etoposide + cisplatine (EC) + RTTc (66 Gy) suivi de 2 cycles de consolidation par EC, vinorelbine + Cis ou paclitaxel + carboplatine. L’objectif principal est la survie globale (SG). La survie sans progression (SSP), le taux de reponse objective et la tolerance sont des objectifs secondaires. Cet essai de superiorite est concu pour atteindre 80 % de puissance en supposant un HR = 0,74 avec 355 evenements et un risque α bilateral a 0,05. Resultats Cinq cent cinquante-cinq patients ont ete traites : 283 par PC, 272 par EC. Les caracteristiques initiales etaient equilibrees : âge : 60/59 ; %femme : 41/40 ; %stade IIIB : 54/51 ; %stade par TEP-scan : 83/81 ; %ECOG PS1 : 51/50. La SG mediane pour PC vs EC etait de 26,8 m vs 25,0 m (HR 0,98 ; IC95 % : 0,79–1,20 ; p = 0,831) et la SSP mediane de 11,4 m vs 9,8 m (HR 0,86 ; IC95 % : 0,71–1,04 ; p = 0,130). Le taux de reponse pour PC vs EC etait de 35,9 % vs 33,0 % (p = 0,458) et le taux de controle de la maladie de 80,7 % vs 70,7 % (p = 0,004). Des toxicites de G3/4 possiblement liees au traitement (PC vs EC) sont survenues chez 64,0 % vs 76,8 % des pts (p = 0,001). Une incidence plus faible de neutropenie/granulocytopenie de G3/4 possiblement liees au traitement a ete observee dans le bras PC : 24,4 % vs 44,5 % (p Conclusion Le bras PC n’a pas ameliore la SG, mais montre un meilleur profil de tolerance que le bras EC.

Background: Abemaciclib is an oral, selective inhibitor of CDK4 and CDK6 dosed on a continuous schedule. MONARCH 1 (NCT02102490) is a phase 2 single-arm study designed to evaluate safety and efficacy of abemaciclib monotherapy in women with HR+/HER2- MBC whose disease progressed on or after endocrine therapy and chemotherapy. Final analysis of the primary endpoint, objective response rate (ORR) at 12 months (mo), showed that abemaciclib monotherapy induced objective tumor responses in patients (pts) with refractory HR+/HER2- MBC following multiple prior therapies. Treatment was well tolerated, allowing prolonged exposure to therapy. We report the final 18 mo overall survival results. Methods: Eligible pts had measurable disease, ECOG PS of 0/1, no CNS metastases, and received at least 1 but no more than 2 lines of chemotherapy in the metastatic setting. Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours until disease progression. The primary objective was to evaluate ORR per RECIST v1.1. at 12 mo after the last pt enrolled. Secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR = CR + PR + SD), clinical benefit rate (CBR= CR + PR + SD ≥ 6 mo) and safety. Final OS analysis occurred 18 mo after the last pt was enrolled. Results: A total of 132 pts received abemaciclib monotherapy. The primary endpoint of ORR by investigator assessment at 12 mo was 19.7% (95% CI: 13.3, 27.5) and did not change at 18 mo. Of the 26 responding pts, 19 (73.1%) had responses ≥ 6 mo, and 6 pts still on treatment have response durations ranging from 9.5+ to 20.5+ mo. There was no change at 18 mo vs 12 mo for DCR (67.4%) or CBR (42.4%). Median PFS (6.0 mo, 95% CI: 4.2, 7.5) and median DoR (8.9 mo, 95% CI: 6.1, 14.0) were also consistent with 12 mo follow up. At the 18 mo update, 7 pts (5.3%) remained on treatment (6 PR and 1 SD). At 18 mo, the median OS was 22.3 mo (95% CI: 17.7, NR), and the survival rate was 58.7%. TEAEs ≥ Grade 3 were experienced by 93 pts (70.5%) at 18 mo, compared to 90 pts (68.2%) at 12 mo. The most common Grade 3/4 TEAEs were neutropenia (25.0%), diarrhea (19.7%), fatigue (13.6%), leukopenia (6.8%), anemia (4.5%) and nausea (4.5%). Treatment discontinuations due to AEs were infrequent (7.6 %). Conclusions: The results of the 18 month analysis are consistent with the 12 month results of MONARCH 1. Median OS was 22.3 months. The efficacy results from the MONARCH 1 study indicate that continuous administration of single-agent abemaciclib induces durable confirmed tumor responses. There were no clinically significant changes in safety. The results of the 18 month analysis support the earlier results and indicate that single-agent abemaciclib may offer a more favorable benefit-risk profile than expected from available cytotoxic chemotherapies. Citation Format: Hope S. Rugo, Sara M. Tolaney, Javier Cortés, Véronique Diéras, Debra A. Patt, Hans Wildiers, Shivani Nanda, Andrew G. Koustenis, Maura N. Dickler, José Baselga. MONARCH 1: Final overall survival analysis of a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT044. doi:10.1158/1538-7445.AM2017-CT044

510Background: Abemaciclib is an oral, selective inhibitor of CDK4 and CDK6 dosed on a continuous schedule. In a phase 1 trial, abemaciclib demonstrated single-agent activity in refractory HR+ meta...

Summary Pemetrexed has been evaluated as a novel chemotherapeutic for head and neck cancer (HNC). In this review, we examined the efficacy and tolerability of pemetrexed in patients with HNC. Relevant English-language literature was identified via PubMed and a review of published abstracts from the American Society of Clinical Oncology and European Society for Medical Oncology annual meetings from January 2000 through September 2012. Search terms were “pemetrexed” (or “LY231514”) and “head and neck cancer.” Completed prospective phase I to III trials of pemetrexed alone or in combination with other agents or radiotherapy evaluating objective response rate (ORR), progression-free survival (PFS), and/or overall survival (OS) were eligible; ten studies were reviewed. Results for ORR, PFS, and/or OS in patients receiving pemetrexed in combination with other chemotherapeutic agents and/or radiotherapy were promising in the first-line treatment setting. Pemetrexed was associated with acceptable grade 3–4 hematologic toxicities; it did not result in nonhematologic toxicities commonly seen with cisplatin, such as nephrotoxicity, ototoxicity, and neuropathy. In a single phase III randomized trial, although median OS was longer for patients treated with pemetrexed plus cisplatin (7.3 months) versus cisplatin plus placebo (6.3 months), the difference did not reach statistical significance ( P = .082). Results of this review suggest that pemetrexed is an active chemotherapeutic in combination with other agents or radiotherapy in patients with HNC. In particular, the role of pemetrexed as a radiosensitizer and potential alternative to cisplatin warrants investigation. More research is needed to clearly define the role of pemetrexed in HNC treatment.

LBA8003 Background: PemC and PCB are regimens used for first-line treatment of advanced NS-NSCLC. The primary objective was to compare progression-free survival without Grade 4 toxicity (G4PFS) between two vs three drug regimen arms. Methods: Patients ≥18 years, Stage IV NS NSCLC, AJCC (v7.0), and ECOG PS 0/1 were enrolled. Patients were randomized (1:1); received 4 cycles of induction (PemC: Pem, 500 mg/m2 and C, AUC = 6; PCB: P, 200 mg/m2, C, AUC = 6, and B, 15 mg/kg) followed by Pem (PemC Arm) or B (PCB Arm) maintenance therapy in the absence of progressive disease or discontinuation. Secondary endpoints were PFS, overall survival (OS), overall response rate (ORR), and disease control rate (DCR). The study was powered for G4PFS; assuming hazard ratio (HR) of 0.75; there was 80% power to detect superiority of PemC over PCB with a 2-sided type I error of 0.10. Efficacy data were analyzed by intent-to-treat principle using the log-rank test for time-to-event variables, and an exact test for ORR and DCR. Safety data were evaluated using CTCAE v3 for patients who received ≥1 dose of study treatment. Results: Patients were randomized to PemC (N = 182) or PCB (N = 179). Baseline factors were balanced between arms: median age 66/66 years; % female 42/42; % PS=0, 47/47; % stage IV M1a 29/30; for PemC vs PCB, median G4PFS (months) was 3.91/2.86 (HR = 0.85, 90% CI 0.7, 1.04, p = 0.176); PFS and OS had HR = 1.06 (95% CI 0.84, 1.35), p = 0.610, and HR = 1.07 (95% CI 0.83, 1.36), p = 0.616, respectively. The ORR (%) 23.6/ 27.4 and DCR (%) 59.9/57.0 were for PemC vs PCB, respectively. Significantly more drug-related grade 3/4 anemia (18.7% vs 5.4%), and thrombocytopenia (24.0% vs 9.6%) were seen on PemC; significantly more grade 3/4 neutropenia (48.8% vs 24.6%) and grade 1/2 alopecia (28.3 % vs 8.2%) were seen on PCB. Conclusions: PemC was not superior to PCB in G4PFS; no difference in PFS or OS was observed for the two- vs three-drug regimens. There were no unexpected toxicities; the toxicity profiles demonstrated distinctions by arm, and both regimens demonstrated tolerability. Clinical trial information: NCT00948675.

LBA8003 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

7002 Background: There is no consensus chemotherapy regimen with concurrent radiation therapy (CRT) for inoperable stage IIIA/B NSCLC. P synergizes with ionizing radiation, as well as with Cb and C in preclinical models. These doublets have shown efficacy and favorable toxicity profiles in phase II/III trials. Methods: In this open-label randomized phase II trial, 98pts with inoperable stage IIIA/B NSCLC (all histologies) were randomized (1:1) to P 500 mg/m2 plus Cb AUC 5 (PCb) or P 500 mg/m2 plus C 75 mg/m2 (PC) intravenously (IV) every 21 days for 3 cycles. All pts received CRT 64–68 Gy (2 Gy/day, 5 days/week, Days 1–45). Consolidation P 500 mg/m2 IV every 21 days for 3 cycles began 3 weeks after completion of CRT. The primary endpoint was 2-year overall survival (OS); secondary endpoints included median OS, time to progression (TTP), overall response rate (ORR), and toxicity. Results: Since Jun 2007, 98 pts were enrolled (PCb: 46; PC: 52).Pts were followed until Oct 2011. Mean dose compliance was PCb: 95.7% P, 97.1% Cb; PC: 89.7% P, 89.1% C. Mean dose compliance for CRT was PCb: 95.7%; PC: 88.1%. CRT dose interruptions occurred in PCb: 32.6% and PC: 40.4%. Two-year OS was PCb: 45.2% (95% confidence interval [CI], 29.3-59.8); PC: 57.6% (95% CI, 41.6-70.7); p=0.270. Median OS (months) was PCb: 18.7 (95% CI, 12.9-not assessable [N/A]); PC: 27.0 (95% CI, 23.2-N/A). Median TTP (months) was PCb: 8.8 (95% CI, 6.0-10.7); PC: 13.1 (95% CI, 8.3-N/A); p=0.057. The ORR rates were PCb: 52.2% (complete response [CR], 6.5%; partial response [PR], 45.7%); PC: 46.2% (CR, 3.8%; PR, 42.3%). Grade 4 treatment-related toxicities (% PCb/% PC) were: anemia, 0/1.9; neutropenia, 6.5/3.8; thrombocytopenia, 4.3/1.9; and esophagitis, 0/1.9. No drug-related deaths were reported. Conclusions: While conclusions are limited by the size of the trial, this study suggests OS and TTP advantages for the C-containing arm. Both combinations with CRT appear well tolerated.

5531 Background: Recurrent and metastatic head and neck cancers (HNC) are generally incurable, with ~20% 1-year survival rate. The objective of this analysis was to examine the prognostic factors (...

7082 Background: There is no consensus chemotherapy regimen with concurrent radiation therapy (CRT) for inoperable stage IIIA/B non-small cell lung cancer (NSCLC). Pemetrexed (P) is synergistic wit...

Introduction There is no consensus chemotherapy regimen with concurrent radiotherapy (RT) for inoperable stage IIIA/B non-small-cell lung cancer. This trial evaluated pemetrexed with carboplatin (PCb) or cisplatin (PC) with concurrent RT followed by consolidation pemetrexed. Methods In this open-label, noncomparative phase II trial, patients with inoperable stage IIIA/B non-small-cell lung cancer (initially all histologies, later restricted to nonsquamous) were randomized (1:1) to PCb or PC with concurrent RT (64-68 Gy over days 1-45). Consolidation pemetrexed monotherapy was administered every 21 days for three cycles. Primary endpoint was 2-year overall survival (OS) rate. Results From June 2007 to November 2009, 98 patients were enrolled (PCb: 46; PC: 52). The 2-year OS rate was PCb: 45.4% (95% confidence interval [CI], 29.5-60.0%); PC: 58.4% (95% CI, 42.6-71.3%), and in nonsquamous patients was PCb: 48.0% (95% CI, 29.0-64.8%); PC: 55.8% (95% CI, 38.0-70.3%). Median time to disease progression was PCb: 8.8 months (95% CI, 6.0-12.6 months); PC: 13.1 months (95% CI, 8.3-not evaluable [NE]). Median OS (months) was PCb: 18.7 (95% CI, 12.9-NE); PC: 27.0 (95% CI, 23.2-NE). The objective response rates (ORRs) were PCb: 52.2%; PC: 46.2%. Grade 4 treatment-related toxicities (% PCb/% PC) were: anemia, 0/1.9; neutropenia, 6.5/3.8; thrombocytopenia, 4.3/1.9; and esophagitis, 0/1.9. Most patients completed scheduled chemotherapy and RT during induction and consolidation phases. No drug-related deaths were reported during chemoradiotherapy. Conclusions Because of study design, efficacy comparisons cannot be made. However, both combinations with concurrent RT were active and well tolerated.

7506 Background: Efficacy and safety of concurrent Pem+Cis and TRT followed by consolidation Pem vs other CTX regimens were evaluated; interim safety results (concurrent phase) were presented previ...