PFS Outcomes Research Articles

Phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib) (Cyto-KIK).

TPS371 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: AAAS6927 .

Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER.

308 Background: First-line NIVO+CABO met primary and secondary efficacy endpoints by improving progression-free survival (PFS; HR 0.51, P < 0.0001), overall survival (OS; HR 0.60, P = 0.0010), and objective response rate (ORR; 55.7% vs 27.1%; P < 0.0001) vs SUN in patients (pts) with aRCC in CheckMate 9ER (Choueiri et al. ESMO 2020). Efficacy benefits with NIVO+CABO vs SUN were consistent across prespecified subgroups including by IMDC risk group, and regardless of tumor PD-L1 expression (database lock for primary analysis, March 30, 2020). Updated analyses are needed to establish durability of benefit with first-line NIVO+CABO and assess outcomes in aRCC pts with sarcomatoid features (sRCC)—an aggressive histologic subtype associated with poor prognoses. Methods: In this phase III open-label trial, adults with confirmed aRCC (with a clear cell component including those with sRCC) were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, geographic region) to NIVO 240 mg IV Q2W + CABO 40 mg PO QD vs SUN 50 mg PO (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1-defined PFS by blinded independent central review (BICR) in all randomized (intent-to-treat [ITT]) pts; secondary endpoints included OS, ORR by BICR, and safety. Pts with and without sRCC were identified by local pathology report, and outcomes in these pts were evaluated via prespecified supportive subset analyses. Results: The presence of sRCC was assessed in ITT pts (N = 651) at enrollment. Overall, 75 (11.5%) pts had sRCC and 557 (85.6%) did not; sRCC status was not reported in 19 pts (2.9%). Overall, 34 vs 41 pts with sRCC were randomized to NIVO+CABO vs SUN, respectively. At a median follow-up of 18.1 months, NIVO+CABO improved PFS, OS, and ORR in sRCC pts vs SUN (Table). Notable PFS, OS, and ORR benefits were observed with NIVO+CABO vs SUN in the subgroup of pts without sRCC. Median PFS was doubled, the risk of death was lower, and ORR was consistently higher with NIVO+CABO vs SUN regardless of sarcomatoid status. Key updated PFS, OS, response, and safety outcomes in the ITT population and in pts with and without sRCC will be reported with additional follow-up based on a September 10, 2020 database lock. Conclusions: NIVO+CABO demonstrated improved efficacy and prolonged survival vs SUN in previously untreated aRCC pts regardless of sarcomatoid status. Updated results with extended follow-up will assess the durability of outcomes in this trial. Clinical trial information: NCT03141177 . [Table: see text]

Abstract GS3-01: Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer

Abstract Background: Pembrolizumab (pembro) monotherapy showed durable antitumor activity and manageable safety in patients (pts) with metastatic triple-negative breast cancer (TNBC) in the KEYNOTE-012, -086, and -119 studies. In a prespecified interim analysis of KEYNOTE-355 (NCT02819518), pembro combined with chemotherapy (chemo) showed a statistically significant improvement in PFS versus chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 CPS ≥10 (HR for progression or death, 0.65, 95% CI, 0.49-0.86; one-sided P=0.0012 [prespecified statistical criterion was alpha=0.00411 at this interim analysis]). Additionally, pembro + chemo was generally well tolerated, with no new safety signals. Here, we examine PFS outcomes for each chemo partner and present key secondary endpoints from KEYNOTE-355. Methods: 847 pts with measurable disease per RECIST v1.1, ECOG PS 0-1, and ≥6 mo DFI were randomized 2:1 to pembro + chemo (nab-paclitaxel 100 mg/m2 days 1, 8, and 15 every 28 days; paclitaxel 90 mg/m2 days 1, 8, and 15 every 28 days; or gemcitabine 1000 mg/m2 + carboplatin AUC 2 days 1 and 8 every 21 days) or pbo + chemo for up to 35 administrations of pembro/pbo or until progression/intolerable toxicity. Steroid premedication for paclitaxel was given according to local guidelines and practices, and was not restricted by the protocol. Crossover between arms was not allowed. Pts were stratified by chemo type (taxane vs gemcitabine/carboplatin), PD-L1 status (CPS ≥1 vs <1), and prior (neo)adjuvant treatment with same-class chemo (yes vs no). Dual primary endpoints are PFS (RECIST v1.1, blinded independent central review) and OS in pts with PD-L1 positive tumors (CPS ≥10 and ≥1) and in all pts. Secondary endpoints include ORR, DCR (CR + PR + SD ≥24 weeks), and DOR. The PFS treatment effect was assessed in subgroups descriptively using HRs and 95% CIs; although subgroup analysis by on-study chemo were pre-specified, the trial was not powered to compare efficacy among treatment groups by different chemo regimens. Results: As of Dec 11 2019, median follow-up was 25.9 mo for pembro + chemo (n=566) and 26.3 mo for pbo + chemo (n=281). The HR for PFS favored pembro regardless of choice of chemo or CPS population (Table). Results for the key secondary endpoints of ORR, DCR, and DOR favored pembro + chemo, with the treatment effect increasing as CPS increased (Table). Conclusion: In subgroup analysis, PFS with pembro + chemo compared to pbo + chemo in pts with metastatic TNBC was improved regardless of chemo partner. A trend toward improved efficacy with PD-L1 enrichment with pembro + chemo was observed for ORR, DCR and DOR endpoints. These data further support the potential of pembro + chemo as a first-line treatment option for metastatic TNBC. CPS ≥ 10CPS ≥ 1All ptsPembro + ChemoPbo + ChemoPembro + ChemoPbo + ChemoPembro + Chemo|Pbo + ChemoN = 220N = 103N = 425N = 211N = 566N = 281PFS, mo median (95% CI)9.7 (7.6 - 11.3)5.6 (5.3 - 7.5)7.6 (6.6 - 8.0)5.6 (5.4 - 7.4)7.5 (6.3 - 7.7)5.6 (5.4 - 7.3)HR (95% CI)0.65 (0.49 - 0.86)0.74 (0.61 - 0.90)0.82 (0.69 - 0.97)PFS by on-study chemo, (n [%)) mo median(95% CI)Nab-Paclitaxel(63 [28.6%]) 9.9(36 [35.0%]) 5.5(130 [30.6%]) 6.3(74 [35.1%)) 5.3(173 [30.6%]) 7.5(95 [33.8%]) 5.4HR (95% CI)0.57 (0.34 - 0.95)0.66 (0.26 - 0.82)0.69 (0.51 - 0.93)Paclitaxel(33 [15.0%]) 9.6(11 [10.7%]) 3.6(62 [14.6%]) 9.4(22 [10.4%]) 3.8(82 [14.5%]) 8.0(32 [11.4%]) 3.8HR (95% CI)0.33 (0.14 - 0.76)0.46 (0.26 - 0.82)0.57 (0.35 - 0.93)Gemcitabine-Carboplatin(124 [56.4%]) 8.0(56 [54.4%]) 7.2(233 [54.8%]) 7.5(115 [54.5%]) 7.5(311 [54.9%]) 7.4(154 [54.8%]) 7.4HR (95% CI)0.77 (0.53 - 1.11)0.86 (0.66 - 1.11)0.93 (0.74 - 1.16)ORR, % (95% CI)53.2 (46.4 - 59.9)39.8 (30.3 - 49.9)45.2 (40.4 - 50.0)37.9 (31.3 - 44.8)41.0 (36.9 - 45.2)35.9 (30.3 - 41.9)DCR, % (95% CI)65.0 (58.3 - 71.3)54.4 (44.3 - 64.2)58.6 (53.7 - 63.3)53.6 (46.6 - 60.4)56.0 (51.8 - 60.1)51.6 (45.6 - 57.6)DOR, mo, median (range)19.3 (1.6+ - 29.8)7.3 (1.5 - 32.5+)10.1 (1.0+ - 29.8)6.5 (1.5 - 32.5+)10.1 (1.0+ - 29.8)6.4 ( 1.5 - 32.5+)"+" indicates there is no progressive disease by the time of last disease assessment. Citation Format: Hope S. Rugo, Peter Schmid, David W. Cescon, Zbigniew Nowecki, Seock-Ah Im, Mastura Md Yusof, Carlos Gallardo, Oleg Lipatov, Carlos Henrique Barrios, Jose Perez-Garcia, Hiroji Iwata, Norikazu Masuda, Marco Torregroza Otero, Erhan Gokmen, Sherene Loi, Zifang Guo, Jing Zhao, Vassiliki Karantza, Gursel Aktan, Javier Cortes. Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-01.

Abstract PS10-49: Phase 3b CompLEEment-1 study of ribociclib plus letrozole in the treatment of HR+/HER2- advanced breast cancer: Final results from the UK cohort

Abstract Background: Ribociclib is an oral selective CDK4/6 inhibitor approved for use in combination with an aromatase inhibitor (AI) or fulvestrant, in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in several countries, including the UK. Ribociclib plus endocrine therapy (ET) significantly improved PFS outcomes in phase III registration studies (MONALEESA-2, -3, and-7) compared with placebo plus ET; and significantly increased OS in combination with AI in premenopausal women (MONALEESA-7), and in combination with fulvestrant in postmenopausal women (MONALEESA-3). This analysis aims to report the final efficacy and safety results for the UK cohort of CompLEEment-1, a phase 3b trial evaluating ribociclib plus letrozole in an expanded patient population.Methods: Patients with HR+, HER2- ABC, ≤1 line of prior chemotherapy (CT), and no prior ET in the advanced setting, received ribociclib + letrozole. Baseline characteristics and interim results of the UK cohort have been reported previously (Ring et al. SABCS 2019. Poster 443).Results: A total of 139 UK patients received ≥1 dose of study treatment at UK sites. At the cut-off date, November 8th 2019, 53 patients (38.1%) had completed treatment and 86 discontinued due to disease progression (30.9%), adverse events (24.5%), physician or subject/guardian decision (2.9% each), and protocol deviation (0.7%). The mean age of patients was 61.3 (SD10.67). 138 (99.3%) patients were female, 125 (89.9%) were post-menopausal and 50 (35.9%) had an ECOG status of ≥1. 85 (61.1%) patients had received prior chemotherapy in any setting.89 (64.0%) patients had measurable disease at baseline. 80 (60.4%) patients presented with visceral disease, 35 (25.2%) with bone-only metastases and 4 (2.9%) had CNS metastases. 59 (42.5%) of patients had ≥3 metastatic sites. The median duration of exposure to study treatment was 18.4 months with a median time to progression of 27.6 months. The overall response rate was 25.9% (95% CI: 18.8, 34.0) and clinical benefit rate was 74.1% (95% CI: 66.0, 81.2). Overall, the adverse event (AE) profile was consistent with previous phase III trials. Neutropenia (68.3%), nausea (59.7%), and fatigue (54%) and neutropenia (48.9%) were the most common adverse events (all grades). Neutropenia was the most common AE leading to dose reduction (12.2%) or interruption (33.8%), with ALT increase the most common cause for treatment discontinuation (10.1%). QT prolongation (all grades) led to 3 (2.2%) dose interruptions and 2 (1.4%) dose reductions, but no treatment discontinuations. Conclusions: This subgroup analysis of the COMPLEEMENT-1 study provides further clinically meaningful outcomes on first-line ribociclib and letrozole treatment in a UK cohort. This treatment combination showed consistent efficacy and side effect profile in UK HR+, HER2- ABC patients, consistent with the overall ITT population as well as results observed in the other pivotal ribociclib registration studies. NCT02941926. Citation Format: Mark Tuthill, Hardeep Marwaha, Christoph EA Hartmann. Phase 3b CompLEEment-1 study of ribociclib plus letrozole in the treatment of HR+/HER2- advanced breast cancer: Final results from the UK cohort [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-49.

CTNI-57. LOW-RISK MENINGIOMA: OUTCOMES FROM NRG ONCOLOGY/RTOG 0539

Abstract PURPOSE/OBJECTIVE(S) Outcomes of low-risk meningioma from NRG/RTOG-0539. MATERIALS/METHODS Outcomes of the intermediate and high-risk cohorts from this phase II trial have been previously reported. Low-risk (Group 1: new WHO grade 1) patients were observed after gross total (GTR) or subtotal resection (STR). Progression-free (PFS) and overall (OS) were estimated using Kaplan-Meier. CTCAE v3 AE grading was employed. RESULTS Group 1 enrolled 65 patients. 56/60 (93.4%) evaluable patients had investigator-reported GTR. Sufficient imaging for central confirmation was available for 48: GTR in 35 and STR in 13. Median follow-up for living patients was 9.1 years (y). For all evaluable patients 5 and 10 y PFS and OS rates were 89.4 and 85.0%, and 98.3 and 93.8%, respectively. For patients with centrally-confirmed STR, 5/10 y PFS rates were 72.7/72.7%, with 100% 10 y OS. For patients with centrally-confirmed GTR, 5/10 y PFS and OS rates were 94.3/87.6 and 97.1/90.4%, respectively. For combined study cohorts (Groups 1–3) with central-review (n=104), the median centrally-measured largest pre-operative tumor dimension was 4.3 cm (range 0.4 - 14.4); this was significantly associated with OS (hazard ratio [HR]=1.03, p=0.021) and PFS (HR=1.03, p=0.003). No grade 4 or 5 protocol-related adverse events were reported. There were 1 grade 3 (infection), 4 grade 2 (neurologic, pulmonary, gastrointestinal, and pain), and 5 grade 1 (3 neurologic, 1 occulovisual, 1 constitutional) events from 5 patients. CONCLUSION These results prospectively validate high OS and PFS outcomes for low-risk meningioma managed with surgery followed by observation, but raise questions regarding optimal management following STR (5 y PFS 72.7%), a subcohort that could potentially benefit from adjuvant therapy. However, we identified considerable discordance between local and central assessments of resection extent. Pre-operative tumor size has a significant impact on OS and PFS. Supported by: U10CA180868 and U10CA180822 from the National Cancer Institute (NCI)

Assessment of Minimal Residual Disease By Next-Generation Sequencing and Fluorodeoxyglucose-Positron Emission Tomography in Patients with Relapsed/Refractory Multiple Myeloma Treated with Venetoclax in Combination with Carfilzomib and Dexamethasone

Assessment of Minimal Residual Disease By Next-Generation Sequencing and Fluorodeoxyglucose-Positron Emission Tomography in Patients with Relapsed/Refractory Multiple Myeloma Treated with Venetoclax in Combination with Carfilzomib and Dexamethasone

Bendamustine Plus Rituximab for the Treatment of Waldenström Macroglobulinaemia: Patient Outcomes and Impact of Bendamustine Dosing

Bendamustine Plus Rituximab for the Treatment of Waldenström Macroglobulinaemia: Patient Outcomes and Impact of Bendamustine Dosing

Low Advanced Lung Cancer Inflammation Index Predicts Poor Prognosis in Locally Advanced Nasopharyngeal Carcinoma Patients Treated with Definitive Concurrent Chemoradiotherapy.

Purpose We aimed to retrospectively investigate the prognostic worth of pretreatment advanced lung cancer inflammation index (ALI) in locally advanced nasopharyngeal carcinoma (LA-NPC) patients treated with concurrent chemoradiotherapy (C-CRT). Patients and Methods. A total of 164 LA-NPC patients treated with cisplatinum-based definitive C-CRT were included in this retrospective cohort analysis. The convenience of ideal pre-C-CRT ALI cut-offs affecting survival results was searched by employing the receiver operating characteristic (ROC) curve analyses. The primary endpoint was the link between the ALI groups and overall survival (OS), while cancer-specific survival (CSS), locoregional progression-free survival [LR(PFS)], distant metastasis-free survival (DMFS), and PFS comprised the secondary endpoints. Results The ROC curve analyses distinguished a rounded ALI cut-off score of 24.2 that arranged the patients into two cohorts [ALI ≥ 24.2 (N = 94) versus < 24.2 (N = 70)] with significantly distinct CSS, OS, DMFS, and PFS outcomes, except for the LRPFS. At a median follow-up time of 79.2 months (range: 6–141), the comparative analyses showed that ALI < 24.2 cohort had significantly shorter median CSS, OS, DMFS, and PFS time than the ALI ≥ 24.2 cohort (P < 0.001for each), which retained significance at 5- (P < 0.001) and 10-year (P < 0.001) time points. In multivariate analyses, ALI < 24.2 was asserted to be an independent predictor of the worse prognosis for each endpoint (P < 0.001for each) in addition to the tumor stage (T-stage) (P < 0.05 for all endpoints) and nodal stage (N-stage) (P < 0.05 for all endpoints). Conclusion As a novel prognostic index, the pretreatment ALI < 24.2 appeared to be strongly associated with significantly diminished survival outcomes in LA-NPC patients treated with C-CRT independent of the universally recognized T- and N-stages.

STK11(LKB1) mutations in metastatic NSCLC: Prognostic value in the real world.

BackgroundMutations in STK11 (STK11m) and frequently co-occurring KRAS mutations (KRASm/STK11m) are associated with poor survival in metastatic NSCLC (mNSCLC) immuno-oncology trials. There are limited data regarding the prognostic significance of these mutations in a real-world setting.MethodsThis retrospective cohort study analyzed de-identified electronic medical records from the Flatiron Clinico-Genomic database to identify patients with mNSCLC who had initiated first-line immunotherapy (IO; alone or in combination) or chemotherapy under routine care between January 1, 2013 and June 30, 2017. The primary objectives were to assess the prevalence of STK11m and KRASm/STK11m and to determine associations of these mutations with overall and progression-free survival (OS, PFS).ResultsOf 2407 patients with mNSCLC, STK11m and KRASm/STK11m were present in 13.6% and 6.5% of patients, respectively. Worse OS outcomes were observed in patients with STK11m versus STK11wt mNSCLC receiving IO (first-line, HR [95% CI], 1.4 [0.9–2.3; p = 0.1]; second-line [subset of first-line cohort], HR, 1.6 [1.3–2.0; p = 0.0002]) or chemotherapy (first-line, HR, 1.4 [1.2–1.6; p < 0.0001]); PFS outcomes showed similar trends. KRASm/STK11m double mutations were associated with worse OS and PFS outcomes versus KRASwt/STK11wt with IO and chemotherapy, similar to the single mutation (STK11m vs STK11wt) findings.ConclusionsThis large observational genomic study among patients receiving routine care highlights the negative prognostic impact of STK11m in patients with mNSCLC treated with IO or chemotherapy. These results complement previous clinical trial data and provide further evidence in the real world of a patient population that would benefit from new treatment options.

First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC (CASPIAN): Impact of brain metastases on treatment patterns and outcomes.

9068 Background: In the Phase 3, randomized, open-label CASPIAN study, first-line durvalumab (D) added to etoposide plus either cisplatin or carboplatin (EP) significantly improved OS vs EP alone (HR 0.73 [95% CI 0.59–0.91]; p = 0.0047) in pts with ES-SCLC at the planned interim analysis. Here we describe treatment patterns and outcomes for pts according to brain metastases. Methods: Treatment-naïve pts (WHO PS 0/1) with ES-SCLC received 4 cycles of D 1500 mg + EP q3w followed by maintenance D 1500 mg q4w until disease progression (PD) or up to 6 cycles of EP q3w and optional prophylactic cranial irradiation (PCI; investigator’s discretion). Pts with either asymptomatic or treated and stable brain metastases were eligible. Brain imaging was suggested for pts with suspected brain metastases, but was not mandated at screening or during treatment. The primary endpoint was OS. Analysis of OS and PFS in pt subgroups with and without brain metastases was prespecified. Other analyses in these subgroups were post hoc. Data cutoff: Mar 11, 2019. Results: At baseline, 28 (10.4%) of 268 pts in the D + EP arm and 27 (10.0%) of 269 pts in the EP arm had known brain metastases; of these, only 3 pts (~11% of those with baseline brain metastases) in each arm received radiotherapy (RT) to the brain prior to study entry. D + EP consistently improved OS vs EP in pts with or without known brain metastases at baseline (HR 0.69 [95% CI 0.35–1.31] and 0.74 [0.59–0.93], respectively); PFS was also consistently improved with D + EP regardless of the presence or not of baseline brain metastases (HR 0.73 [0.42–1.29] and 0.78 [0.64–0.95]). Among pts without known brain metastases at baseline, similar proportions developed new brain metastases at first PD in the D + EP (20/240; 8.3%) and EP arms (23/242; 9.5%), despite 19 (7.9%) pts in the EP arm having received PCI. Overall, 48 of 268 (17.9%) and 49 of 269 (18.2%) pts in the D + EP and EP arms received RT to the brain subsequent to study treatment; rates remained similar across the D + EP and EP arms regardless of baseline brain metastases (11 of 28 [39.3%] and 11 of 27 [40.7%] pts with known baseline brain metastases, compared to 37 of 240 [15.4%] and 38 of 242 [15.7%] pts without known baseline brain metastases). Conclusions: In CASPIAN, OS and PFS outcomes were improved with D + EP vs EP regardless of baseline brain metastases, consistent with the ITT analyses. Rates of new brain metastases at first PD were similar between arms, although PCI was permitted only in the control arm. Rates of subsequent RT to the brain were also similar in both arms. Clinical trial information: NCT03043872.

Efficacy and toxicity of immunotherapy with immune checkpoint inhibitors in gynecologic cancers.

e18092 Background: There is limited data on outcomes for gynecologic cancer patients treated with immune checkpoint inhibitors (ICI) outside the scope of clinical trials. Here we present our Institutional experience with a cohort of endometrial (EC) and ovarian cancer (OC) treated with ICI. Methods: 59 patients who received ICI were included (23 OC and 36 EC). Progression-free (PFS) and Overall survivals (OS) were determined by Kaplan-Meier (KM) curve and log rank test. Comparison of duration of response (DOR) and stable disease (DOSD) was done with unpaired t-test or one-way ANOVA. Rates of objective response (ORR) including partial response (PR) and complete response (CR), and stable disease (SD) were compared by Fischer’s exact test. Results: Median age was 66 years. 23 patients were microsatellite stable (MSS), 23 microsatellite instability high (MSI-H). Median number of prior lines was 2 (0-11). PFS and OS for EC and OC were overlapping; therefore outcomes for both were combined [(PFS 6.4m OC vs 7.3 m EC, p = 0.61), (OS 15.9 m OC vs 14.2 m EC, p = 0.78)]. Response rates consisted of 20.3% PR, 8.5% CR, 37.3% SD. Differences in responses were noted for clear cell carcinoma (CC) (33.3% PR, 11.1% CR, 33.3% SD) and MSI-H (36.4% PR, 18.2% CR, 22.7% SD) compared to MSS (11.8% PR, 0% CR, 47% SD). MSI-H had higher ORR vs. MSS (54.1% vs 11.8%, p = 0.0078). CC trended toward improved ORR vs. MSS (44.4% vs 11.8%, p = 0.14). PFS was improved for MSI-H vs. MSS (10m v 5.0m, p = 0.03). OS for CC compared to any other histology was improved (NR vs 12.8m respectively, p = 0.009). 5 recurrent MSI-H EC patients received ICI as first line monotherapy. Responses included 4 PR and 1 SD (80% ORR, 100% clinical benefit). PFS was 9.2m (3.3-13.3). 80% remained progression-free at last follow up. Overall, 38.9% experienced toxicity: hypothyroidism (15%), dermatitis (5%), pneumonitis (10%), LFT elevation (2%), amylase/lipase elevation (3%), colitis or diarrhea (5%), uveitis (2%) or nephritis (5%). 10% of patients required discontinuation of ICI secondary to toxicity. Trends for PFS and OS favored improved outcomes in patients with toxicity vs. no toxicity [(PFS 12.9m vs 5.6m, p = 0.07), (OS 22.9m vs 13.1m, p = NS)] respectively. Conclusions: In this study, immunotherapy with ICI outcomes favor MSI-H and CC compared to MSS disease. CC had promising OS compared to other histology types. ICI showed promising efficacy in MSI-H EC with 100% clinical benefit rate in chemonaive patients. First line ICI should be investigated in these patients. Positive correlation between toxicity and outcome is noted and will be further investigated.

The prognostic value of neutrophil-to-lymphocyte ratio in patients with epidermal growth factor receptor mutated advanced non-small cell lung cancer (NSCLC).

e21675 Background: An elevated neutrophil-to-lymphocyte ratio (NLR) indicates a poor prognosis across multiple cancers, including non-small cell lung cancer (NSCLC). Our study aims to validate these findings in EGFR-mutated NSCLC patients receiving tyrosine kinase inhibitor (TKI) therapy, and to evaluate other factors that may impact NLR. Methods: We retrospectively analyzed 95 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and The University of Chicago Medical Center from August 2011 to August 2018. The prognostic value of NLR was assessed at the start of therapy, and after 6 and 12 weeks of treatment. The median progression free survival (mPFS) and median overall survival (mOS) were calculated by the Kaplan-Meier method and compared with the log rank test. Spearman rank correlation was used to correlate number of disease sites with NLR at diagnosis. T test analysis compared mean NLR between patients with high grade (≥ 3) toxicity versus low or no (grades 0-2) toxicity. The relationship between NLR and body mass index (BMI) changes were analyzed using Pearson correlation. Results: At therapy start, patients with NLR &lt; 5 (n = 57) had a mPFS of 15.3 months and a mOS of 56.7 months, while those with NLR ≥ 5 (n = 35) had a mPFS of 13.8 months ( p= 0.024) and mOS of 40.0 months ( p= 0.0056). After 6 weeks of treatment, patients with NLR &lt; 5 (n = 69) had a mPFS of 14.6 months and mOS of 56.2 months, while those with NLR ≥ 5 (n = 23) had a mPFS of 10.0 months ( p= 0.052) and a mOS of 37.74 months ( p= 0.049). After 12 weeks of treatment, patients with NLR &lt; 5 (n = 66) had a mPFS of 14.2 months and mOS of 54.8 months, while those with NLR ≥ 5 (n = 17) had a mPFS of 3.0 months ( p= 0.0016) and a mOS of 22.4 months ( p= 0.0012). Patients who had a decrease in NLR did not have significantly better mPFS or mOS compared to patients whose NLR increased at either 6 or 12 weeks. Baseline number of disease sites and BMI did not correlate with NLR at diagnosis. Changes in BMI did not correlate with a change in NLR at 6 weeks or at 12 weeks. There was no significant difference in NLR between patients with high grade (≥ 3) versus no or low grade (0-2) drug toxicities. Conclusions: NLR can be used as a prognostic factor to predict which EGFR mutated NSCLC patients on TKI therapy may have worse PFS or OS outcomes. Closer monitoring and potential therapeutic escalation may be beneficial in patients with elevated NLR ≥ 5. Further work studying NLR in patients being treated with a larger osimertinib cohort is ongoing.

Study of anlotinib combined with icotinib as the first-line treatment in non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations (ALTER-L004).

9573 Background: Anti-angiogenic monoclonal antibodies plus EGFR TKIs have previously shown to prolong PFS in patients with EGFR-mutated NSCLC (JO25567 and NEJ026). Unlike bevacizumab, anlotinib is more convenient with orally administered and can inhibit more targets. Monotherapy using anlotinib has significantly prolonged median PFS and OS compared with the placebo values for third-line treatment or beyond in advanced NSCLC. We conducted a study to investigate the activity of anlotinb combined with icotinib, an oral EGFR TKI. Methods: This is a prospective, single-arm, multicenter clinical trial. Patients with locally advanced and/or metastatic IIIB, IIIC or IV non-squamous NSCLC are enrolled. Patients with EGFR exon 19 deletion and/or exon 21 L858R mutation who have not received prior therapies are eligible. The regimen consists of anlotinib (12 mg p.o, qd, day 1 to 14 every 21-day cycle) and icotinib (125mg p.o, tid). The primary endpoint is PFS. Secondary endpoints are OS, ORR, DCR and safety. Results: Between Jul 2018 and Dec 2019, 35 patients were enrolled in five centers and treated with anlotinb and icotinib. At data cutoff (Jan 7, 2020), patients were followed up for a median of 6.01 months.32 tumors were analyzed with 30 evaluable. Preliminary efficacy results: ORR was 59% (0 CR, 19 PR), DCR was 88% (0 CR, 19 PR, 9 SD). 26 patients are still receiving treatment and the longest exposure was 14 cycles. 10 (67%) of 15 patients with exon 19 deletions and 9 (53%) of 17 patients with L858R mutations achieved an objective response. 18 patients harbored aberrations in additional oncogenic drivers (PIK3CA or AKT1) and/or tumor suppressors (TP53, RB1, and PTEN) with an ORR of 72%. Upon analyses, AEs were observed in 97% (34/35) of patients. No Gr 5 AEs were reported. The most common Grade 3 AEs were hypertension (6 [ 17% ]), hypertriglyceridemia (2 [6% ]), diarrhea (1 [ 3% ]), hyperuricemia (1 [ 3% ]), hand and foot skin reaction (1 [3%]), asthenia (1 [3%]), and acute coronary syndrome (1 [ 3% ]). Hypertriglyceridemia was the only grade 4 AE (2 [ 6% ]). Three patients had to adjust treatment dosage. Conclusions: The strategy of anlotinib plus icotinib showed encouraging efficacy for previously untreated, EGFR-mutated advanced NSCLC patients. The combination was well tolerated and the AEs were manageable. The follow-up time is not sufficient and the PFS and OS outcomes need further evaluation. Clinical trial information: NCT03736837 .

CDK 4/6 drug target activation mapping of HR+/HER2- metastatic breast cancer for treatment selection and response prediction.

e13029 Background: Despite the fact that a number of CDK 4/6 inhibitors have become FDA approved as the main frontline therapy for HR+/HER2- metastatic breast cancer (MBC), there are no validated predictive markers of response to this class of drugs. Additionally, approximately 30-40% of patients (pts) have little to no response to these agents, with disease progression occurring in weeks to a few months after therapy initiation. We have initiated a clinical trial (NCT03195192) to utilize cutting edge proteomic technologies to map the functional activation of the signaling architecture of tumors taken from HR+/HER2- MBC pts at diagnosis. We plan to correlate these functional phosphoprotein-based signaling patterns with PFS intervals to identify candidate markers associated with response to CDK 4/6 inhibitor therapy. Methods: Pre-treatment diagnostic FFPE biopsy material from 26 individuals enrolled on study were analyzed by an LCM- reverse phase protein array workflow. Quantitative measurements of a focused set of 8 qualifying (pre-hypothesized) protein/phosphoprotein CDK 4/6 kinase pathway biomarkers, total Rb, Rb (S780), total Cyclin D1, Cyclin D1 (S286), total pI6INK, total p27, p27 (T187), FoxM1 (T600) were measured. Results: Baseline tumor tissue was successfully analyzed for 26 pts, 17 (65%) White, 8 (31%) African American, and 1 (4%) Asian; average age 62 (range 36-79); 4 pts (15%) had prior endocrine therapy and 4 (15 %) had chemotherapy in the adjuvant setting. Seven pts remain on study treatment. Unsupervised analysis revealed substantial concordance between a number of the total-phosphoprotein paired biomarkers, with 8/26 (31%) patients having relatively low activation/expression pattern (within the bottom quartile of the data range of the 8 markers) and 6/26 (23%) having relatively high activation/expression pattern within the top quartile of the data range of the 8 markers). Conclusions: Functional CDK 4/6 drug target pathway mapping analysis is possible from the pre-treatment diagnostic FFPE material and revealed sub-populations of patients who had systematically low and high levels of CDK 4/6 kinase substrate proteins and phosphoproteins that indicate overall drug target activity. Correlations of those patterns with PFS outcome data is ongoing with final analysis planned for Summer 2020. Clinical trial information: NCT03195192 .

BMK_PANC: Search for new predictive/prognosis biomarkers (BKs) in potentially resectable pancreatic adenocarcinoma (PDAC).

e16782 Background: New BKs are urgently needed in order to improve PDAC patient’s outcome. In this sense, the main aim of this multicenter and prospective project is to find predictive and/or prognostic BKs based on many cytokines that are produced in cancer microenvironment and can nowadays be accurately analyzed. Methods: Patients diagnosed of potentially resectable PDAC with poor prognostic factors and treated with neoadjuvant treatment are being included. Serial analyses (basal, with TC, with surgery and time of relapse/or after 1y of follow-up) of serum levels of 80 cytokines are being done. Results: With a median follow-up of 11,25 months (m) (4,67-38,28) 22 patients (pt) with median of age of 62,5 y-0, most of them men (63.6%) have been included, with radical surgery performed in 14 of them (2 pts with bypass). Seven operated pt received adjuvant treatment and 12 operated pt developed progression of disease. 18 pt have received nab-paclitaxel and gemcitabine as perioperative treatment and 4 received Folfirinox. Perineural and vascular invasion were confirmed after surgery in 45,5% and 27,3% of cases, respectively. Positive nodes were found in 40,9% of them, being the median of positive and resected nodes of 1 (0-14) and 26 respectively. Surgical margins were negative (R0) in 64,3% of cases (35,7% R1). Pathological response was described as partial in 13,6%, with no changes in 31,8% and progression in 13,6%. Globally, PFS and OS were 13,50 m (CI95%: 6,44-20,55) and 17,31 m (CI 95% 8,86-25,76). Significant differences (p = 0,002) were observed in cases in which radical surgery had been performed with PFS of 13,5 m (9,34-17,66) and 3.97 m (0-8,23) for unresectable patients. Regarding the cytokine array, we observed different PFS outcome based on basal MCP3 levels (low: 16,32 m CI 95%: 5,02-27,63; high: 7,52 m CI95%: 6,23-8.81, p = 0,023), basal Oncostatin (high: 7,12 m CI95%: 3,09-11,15, low: not reached; p = 0,007) or basal Eotaxin (low: 7,12 m CI 95%: 5,75-8,50; high: not reached, p = 0,029). A cytokine score was created based on these results, maintained significant differences for PFS (16,32 m CI95%: 5,07-27,57 vs 6,53 m CI95%: 2,75-10,32, p = 0.003). Our cytokine score showed a significant role as independent prognosis factor in multivariate analysis (HR: 0,196 CI95%: 0,042-0,918; p = 0.039). Conclusions: In potentially resectable/borderline PDAC our basal cytokine score seems to be able to discriminate as independent prognosis factor between those patients that will get significant benefit from neoadjuvant treatment from those that will not

Variation in genetic polymorphisms and gene expression of HLA-E to predict outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI/cetuximab: Data from the phase III FIRE-3 trial.

245 Background: HLA-E is an MHC Class I antigen which inhibits NK cell activity by binding to CD94 receptor. Overexpression of HLA-E on crc cells is associated with poor prognostic outcomes and has recently been associated with microsatellite instability. As cet enhances NK cell activity which is dependent on HLAE, this study aims to assess whether differences in HLAE gene expression and polymorphisms lead to different outcomes. Methods: Genomic DNA from blood samples of pts treated with first-line FOLFIRI-cetuximab (cet, n = 129) and FOLFIRI-bevacizumab (bev, n = 107) was genotyped through the OncoArray, a custom array manufactured by Illumina. Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. PFS and OS outcomes were investigated for an HLAE genetic polymorphism, rs1264457, where G &gt; A leads to glycine &gt; arginine, where glycine has stronger affinity for NK cell receptor. Results: FOLFIRI/cet and FOLFIRI/bev cohort characteristics: median FU (29.1/26.7mo); PFS (12.8/11.5mo); OS (49.8/31.4mo); RAS WT (64%/62%) and RAS mut (15%/16%). Overexpression of HLAE was associated with poor OS (log2 &gt; 13, 30 vs 34 mo) in cet arm (P &lt; .05). No significant association was observed with PFS. Multivariable analysis showed that HLAErs1264457 carriers with any A allele (n = 65) had better PFS than pts with G/G genotype (n = 18) in RAS WT pts treated with FOLFIRI/cet (12.9 vs 12.3 mo; HR = 2.36; 95%CI = 1.14-4.88; p = 0.021). A non-significant trend of improved OS was seen among carriers of A allele than G/G genotype (56.2 vs 40 mo). These effects were not observed in Ras mut pts. No significance was observed in FOLFIRI/bev overall or FOLFIRI/bev RAS WT pts. Conclusions: Overexpression of HLAE leads to poor OS among pts treated with FOLFIRI/cet. Poor PFS was seen among pts treated with cet who are RAS wt carrying polymorphisms allowing for increased binding to NK cell receptor, which in turn enhances HLAE inhibitory function of NK cell lysis. Addition of mAb against HLAE, which have been shown to restore NK cell mediated cell lysis, needs investigation in this pt population.

Effect size as a tool to identify subpopulations with improved clinical outcomes in metastatic colorectal cancer.

252 Background: ASCO defined meaningful trial endpoints in colorectal cancer (CRC) to include OS HR ≤0.67 (Ellis, JCO 2014). This measure is limited in identifying treatment benefit for subgroups from heterogeneous populations. Effect size (Glass’s Δ) calculates the absolute difference in median clinical outcomes normalized to the control group standard deviation. We hypothesized that durable effect sizes ≥2 would be useful in predicting which trials possess subgroup populations of clinical significance despite a HR &gt; 0.67. Methods: Prospective phase II-III trials in metastatic CRC from the ASCO Meeting Library (2016-2019) were cataloged by clinical outcomes of PFS and OS. Effect size was calculated from trials reporting confidence intervals and compared with absolute difference in clinical outcome, hazard ratio and therapeutic intervention. Trials with an indeterminant HR, yet effect size &gt; 2 were reviewed in subgroup analyses. Results: 385 abstracts were reviewed with 99 clinical analyses available for effect size calculation. Absolute difference in PFS correlated with effect size (R = 0.64) and was inversely proportional to HR (R = -0.63). The absolute difference in OS correlated with effect size (R = 0.69) and was inversely proportional to HR (R = -0.57). When stratified by clinically significant HR (defined ≤0.67), median effect size for PFS was 13.7±13.3 (SD) which was significantly different from HR &gt; 0.67 with median effect size 1.0±3.8 (p &lt; 0.001). Median effect size for OS when stratified by HR ≤0.67 was 3.7±2.5 which was significantly different when compared to endpoints with HR &gt; 0.67 with median effect size 0.9±1.4 (p &lt; 0.003). Subgroup populations with survival benefit included combination checkpoint blockade durvalumab/tremelimumab vs supportive care with effect size 3.1 (HR 0.72; NCT02870920). First-line PFS benefit was predicted in KRAS wildtype liver-limited CRC treated with FOLFOX+cetuximab vs FOLFOX+bevacizumab by effect size of 3.2 (HR 0.80; NCT01836653). Conclusions: Effect size holds potential as a measure to delineate improved clinical outcomes from heterogeneous populations and could identify those trials for which further subgroup analysis should be explored.

Progression-Free Survival Analysis of Denosumab Vs Zoledronic Acid in Intent to Transplant Multiple Myeloma Patients Based on Treatment Regimen and Baseline Characteristics

Introduction: Denosumab is a monoclonal antibody targeting Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) that has been shown to reduce skeletal related events associated with bone lesions in patients with multiple myeloma and solid tumors. Results from the full primary analysis of 1718 patients with newly diagnosed multiple myeloma in an international double blind, randomized, controlled phase 3 (20090482) study that assessed the efficacy of denosumab (Dmab) vs zoledronic acid (ZA) for preventing SREs met its primary end point of non-inferiority regarding time to first SRE. The analysis of the PFS exploratory endpoint showed a clinically meaningful 10.7 months median PFS benefit (HR, 0.82; 95% CI, 0.68-0.99; descriptive P= 0.036) of Dmab vs ZA. This benefit was most pronounced in patients who were stratified into the "intent to undergo Autologous Stem Cell Transplant (ASCT)" group at randomization. Thus, we present an in-depth analysis of relevant baseline characteristics, treatment regimens and PFS outcome in patients with intent to undergo transplant receiving Dmab and ZA. Methods: Adult patients with newly diagnosed multiple myeloma (NDMM) and stratified as "intent to undergo ASCT" at randomization were included in this analysis. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo in 4-week cycles. In this subgroup, the PFS outcome was examined. Baseline characteristics and treatment regimens were compared between treatment arms. Results: 54.1% of the 1718 enrolled patients were stratified into "intent to undergo ASCT" as part of their front-line therapy, and 61.8% of "intent to undergo ASCT" did receive an ASCT. In the "intent to undergo ASCT" group, 19.6% patients had disease progression in the Dmab arm compared to 28.0% in the ZA arm (HR 0.65 (0.49-0.85)) (Figure 1). No imbalance in terms of triplet therapy use between the two study arms (TABLE 1). 55.1% in Dmab vs 52.6% in ZA arm received Triplet Therapies which included Bortezomib, Cyclophosphamide, Dexamethasone (VCD), Bortezomib, Thalidomide, Dexamethasone (VTD), Cyclophosphamide, Thalidomide, Dexamethasone (CTD), or Bortezomib, Lenalidomide, Dexamethasone (VRD). The percentage of triplet therapies used in the "intent to undergo ASCT"patients was higher than in patients with no intent to undergo ASCT. Percentage of patients with ECOG performance status 2 was 19.4% in the Dmab group vs 18.6% in the ZA group. 26.2% of patients in the Dmab arm and 25% in the ZA arm had Multiple Myeloma ISS stage III upon diagnosis. Among intent to transplant patients there was no imbalance in terms of age, performance status, ISS stage, risk status, weight, bone marrow plasma cell % between the ZA and the Dmab arm Conclusion: Results from this post-hoc subgroup analysis suggest a more profound PFS benefit in the "intent to undergo ASCT" patient subgroup. Multiple myeloma treatment received in the intent to undergo transplant subjects was similar between the denosumab and zoledronic acid arms. No significant imbalance in demographics or baseline disease characteristics was observed between the two treatment arms. Disclosures Terpos: Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria. Shimizu:Medical Biological Laboratory: Consultancy; Takeda: Speakers Bureau; Daiichi: Consultancy; Amgen: Consultancy; Fujimoto: Consultancy. Willenbacher:Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; oncotyrol: Employment, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commission: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Fujimoto: Consultancy, Honoraria; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees. Glennane:amgen: Employment, Equity Ownership. Dai:Amgen: Employment, Equity Ownership. Pasteiner:Amgen: Employment, Equity Ownership. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

Lenalidomide Induction and Maintenance Maximizes Outcome for Newly Diagnosed Transplant Eligible Myeloma Patients Irrespective of Risk Status: Long-Term Follow-up of the Myeloma XI Trial

Lenalidomide Induction and Maintenance Maximizes Outcome for Newly Diagnosed Transplant Eligible Myeloma Patients Irrespective of Risk Status: Long-Term Follow-up of the Myeloma XI Trial

Characterization of Relapse and Second-Line Therapy in Lenalidomide-Refractory, Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: A Subanalysis of the Phase 3 First Trial

Characterization of Relapse and Second-Line Therapy in Lenalidomide-Refractory, Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: A Subanalysis of the Phase 3 First Trial