Egbert. F. Smit

Ramucirumab plus docetaxel improved survival in REVEL, a randomized phase 3 trial for patients with Stage IV non-small cell lung cancer after standard platinum-based chemotherapy. This exploratory analysis evaluated the exposure–response relationship of ramucirumab from REVEL.

E20503 Background: Most ALK+ NSCLC patients (pts) receiving CRZ eventually experience disease progression. Based on promising activity in a phase 1/2 trial, a randomized phase 2 trial of the ALK inhibitor BRG in pts with CRZ-refractory, advanced ALK+ NSCLC (ALTA; NCT02094573) was initiated. Responses and adverse events (AEs) varied with starting dose; therefore, ALTA was designed to evaluate 2 distinct BRG regimens. Methods: Pts were stratified by presence of baseline (BL) brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1. Results: In 222 pts (arm A/B, n=112/n=110), median age was 51/57 y; 71%/67% had brain metastases. As of May 31, 2016, 51%/56% (A/B) continued to receive BRG; median follow-up was 10.2/11.0 mo. Table shows efficacy. In pts with measurable BL brain metastases (A/B, n=26/n=18), confirmed intracranial ORR was 46%/67%. Most common treatment-emergent AEs (A/B) were: nausea 36%/43%, diarrhea 21%/39%, cough 23%/36%, headache 28%/30%, vomiting 28%/26%; grade ≥3 AEs included increased CPK 3%/10%, hypertension 6%/6%, pneumonia 3%/5%, increased lipase 5%/3%. A subset of pulmonary AEs with early onset (median: Day 2) occurred in 14/219 (6%) treated pts (3%, grade ≥3); 7/14 pts were successfully retreated. Dose reductions (8%/23%, A/B) and discontinuations (3%/10%) due to AEs were reported. Conclusions: BRG showed substantial activity, robust PFS, and acceptable safety at both dose levels, with numerically improved efficacy (particularly PFS and intracranial ORR) at 180 mg (with lead-in). Clinical trial information: NCT02094573. [Table: see text]

9061 Background: To treat LCNEC with non-small cell lung carcinoma type chemotherapy (NSCLC-ct, i.e. gemcitabine/taxanes or pemetrexed) or small cell lung carcinoma type (SCLC-ct, i.e. platinum-etoposide) is subject of debate. Molecular studies have identified two mutually exclusive subtypes in LCNEC, the co-mutated TP53 and RB1and the STK11/ KEAP1 (predominantly RB1 wildtype(^wt)) group. We investigated if overall survival (OS) and progression free survival (PFS) correlates with targeted next-generation sequencing (TNGS) results in LCNEC treated with NSCLC-ct or SCLC-ct. Methods: For this population based retrospective cohort study all diagnoses of stage IV ct treated high grade neuroendocrine carcinomas (NEC, not being SCLC) were retrieved from the Netherlands Cancer Registry and Pathology Registry (PALGA) (2003-2012). Panel-consensus pathology revision of original tumor slides was performed on (N = 230) and TNGS for genes TP53, RB1, STK11 and KEAP1 analyzed with a multi-sample variant caller (Needlestack). Results: LCNEC was consensus diagnosed in 146/230 and 77 passed quality control for TNGS. Mean coverage was 2832x, a mutation(^mt) in TP53 was present in 87%, RB1^mt in 46%, STK11^mt in 13% and KEAP1^mt in 18% of sequenced LCNEC. RB1 was co-altered with TP53 in 94% of LCNEC; mutually exclusive to STK11^mt (100%) but not KEAP1^mt (57%). NSCLC-ct or SCLC-ct was specified in 92% of patients and RB1^wt LCNEC treated with NSCLC-ct (n = 22) showed a trend to better OS compared to SCLC-ct (n = 13) (8.5 months (95% confidence interval (CI): [6.3-10.6]) vs. 5.8 [5.5-6.1] months, p = 0.055). Due to reported resistance in NECs we analyzed NSCLC-ct without pemetrexed-ct; OS was significantly longer for NSCLC-ct (n = 15) compared to SCLC-ct (9.6 [7.7-11.6] vs. 5.8 [5.5-6.1] months, p = 0.026). PFS of RB1^wt NSCLC-ct treated patients was significantly longer than SCLC-ct (p = 0.044), without pemetrexed (p = 0.018). In patients with RB1^mt LCNEC OS/PFS was not significantly different for NSCLC-ct vs. SCLC-ct. Conclusions: In LCNEC with RB1^wt, NSCLC-ct correlates with a more favorable outcome compared to SCLC-ct. However, RB1^mt LCNEC treated with NSCLC-ct do similarly worse as SCLC-ct. Prospective studies should be initiated.

9075 Background: BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas and act as oncogenic drivers. Initial cohorts of the BRF113928 (NCT01336634) trial evaluated efficacy and safety of D monotherapy (cohort A; n = 78) or D + T (cohort B; n = 57) in pts with previously treated BRAFV600E–mutant metastatic NSCLC. At primary analysis, overall response rates (ORRs) were 33.3% and 63.2% in pts who received D or D + T, respectively. Furthermore, durable response (median duration of response [DOR], 9.0 mo) was observed in D + T pts. Here, we present an updated survival analysis based on additional follow-up. Methods: In this phase 2 trial, 2 cohorts (A and B) of pts with previously treated metastatic BRAFV600E–mutant NSCLC were enrolled sequentially. The primary endpoint was investigator-assessed ORR. Secondary efficacy endpoints included progression-free survival (PFS), DOR, and overall survival (OS). D and T were dosed orally at the established phase 2 dose of D 150 mg twice daily and T 2 mg once daily. Results: This updated analysis had a median follow-up of 16.2 mo, which represented an additional 10 mo of follow-up. Median OS was 12.7 mo (95% CI, 7.3-16.3) with 57 deaths reported for pts treated with D monotherapy and 18.2 mo (95% CI, 14.3-not estimable [NE]) with 33 deaths reported for pts treated with D + T. Detailed efficacy results are presented in the table. Investigator-assessed ORR, DOR, and PFS were supported by independent review committee assessments. No new safety signals were observed for D + T. Conclusions: This update of the BRF113928 study confirms that durable responses and encouraging survival were achieved with combination D + T in pts with BRAFV600E–mutant NSCLC. Clinical trial information: NCT01336634.

8502 Background: Brain metastases are one of the major sites of tumor failure in patients (pts) with radically treated stage III NSCLC. The value of PCI in these pts remains unsettled. This study is designed to investigate whether PCI reduces the incidence of symptomatic brain metastases (sBM). Methods: Pts were randomized between observation and PCI after concurrent or sequential chemo-RT with or without surgery. PCI dose was left to the physician(36 Gy/18F, 30 Gy/12F, 30 Gy/10F). Pts were registered before randomization, those progressing after chemo-RT were not randomized. Pts were followed for sBM (defined as increased intracranial pressure, headache, nausea, vomiting, cognitive, affective disturbances, seizures, focal neurological symptoms andMRI/CT), side effects, survival, quality of life (QLQ-C30, EuroQol 5D). The primary endpoint is the proportion of patients developing sBM. Randomizing 300 pts the study has 90% (2-sided p = 0.05) power to detect 17% decrease in pts developing sBM at 24 months (mo). Results: Between 2009 and 2015, 195 pts were registered, 175 were randomized, 87 received PCI and 88 pts were in the observation arm. In 2013 due to slow accrual, it was decided to reduce the number of randomized pts to 175 pts. With 75 events a 2-sided log-rank test would have 80% power to detect HR 0.52 and alpha 0.05. One pt in PCI arm was withdrawn after randomization. Pts characteristics were male (n = 114, 66%); adeno/squa/other 72 (41%), 62 (36%), 40 (23%); PS 0/1/2 66 (38%), 99 (57%), 9 (5%); stage IIIA/B 93 (53%), 80 (46%), unknown 1 (1%). Median follow up was 48.5 mo (95% CI, 39 - 54). Proportion of pts with sBM was 4/86 (4.6%) in PCI and 25/88 (28.4 %) in observation (p < 0.00001). Seven (8.1%) pts in PCI and 26 (29.7%) pts in observation arm had BM on imaging (p < 0.001). Median time to sBM was not reached in either arm. Median OS was 24.2 mo in PCI and 21.9 mo in observation arm (p = 0.52). Global QoL at 3 mo was worse in PCI arm (p = 0.02) but not afterwards. Conclusions: PCI significantly decreases the proportion of patients developing both symptomatic BM without influencing overall survival. PCI decreases 3 months global quality of life measures but not beyond. Clinical trial information: NTR 1601.

Background: Methods: Results: Conclusions:

The literature on surgical salvage, i.e. lung resections in patients who develop a local recurrence following stereotactic ablative radiotherapy (SABR), is limited. We describe our experience with salvage surgery in nine patients who developed a local recurrence following SABR for early stage non-small cell lung cancer (NSCLC). Patients who underwent surgical salvage for a local recurrence following SABR for NSCLC were identified from two Dutch institutional databases. Complications were scored using the Dindo-Clavien-classification. Nine patients who underwent surgery for a local recurrence were identified. Median time to local recurrence was 22 months. Recurrences were diagnosed with CT- and/or 18FDG-PET-imaging, with four patients also having a pre-surgical pathological diagnosis. Extensive adhesions were observed during two resections, requiring conversion from a thoracoscopic procedure to thoracotomy during one of these procedures. Three patients experienced complications post-surgery; grade 2 (N = 2) and grade 3a (N = 1), respectively. All resection specimens showed viable tumor cells. Median length of hospital stay was 8 days (range 5–15 days) and 30-day mortality was 0 %. Lymph node dissection revealed mediastinal metastases in 3 patients, all of whom received adjuvant therapy. Our experience with nine surgical procedures for local recurrences post-SABR revealed two grade IIIa complications, and a 30-day mortality of 0 %, suggesting that salvage surgery can be safely performed after SABR.