Combination Of Kinase Inhibitors Research Articles

Global Real-World Outcomes of Patients Receiving Immuno-Oncology Combinations for Advanced Renal Cell Carcinoma: The ARON-1 Study.

Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC). The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients. Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB). A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p=0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p<0.001). Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations. NCT05287464.

EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery

BackgroundPrimary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery.Patients and MethodsWe examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors.ResultsAmong 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001).ConclusionOur findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation.

Biological Biomarkers of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) represents around 2% of cancer-related deaths worldwide per year. RCC is an immunogenic malignancy, and treatment of metastatic RCC (mRCC) has greatly improved since the advent of the new immunotherapy agents, including immune checkpoint inhibitors (ICIs). However, it should be stressed that a large proportion of patients does not respond to these therapies. There is thus an urgent need to identify predictive biomarkers of efficacy or resistance associated with ICIs or ICI/Tyrosine kinase inhibitor (TKI) combinations; this is a major challenge to achieve precision medicine for mRCC in routine practice. To identify potential biomarkers, it is necessary to improve our knowledge on the biology of immune checkpoints. A lot of efforts have been made over the last decade in the field of immuno-oncology. We summarize here the main data obtained in this field when considering mRCC. As for clinical biomarkers, clinician and scientific experts of the domain are facing difficulties in identifying such molecular entities, probably due to the complexity of immuno-oncology and the constant adaptation of tumor cells to their changing environment.

Effect of CBM588 in combination with cabozantinib plus nivolumab for patients (pts) with metastatic renal cell carcinoma (mRCC): A randomized clinical trial.

LBA104 Background: We have previously demonstrated that the live bacterial product CBM588 may augment clinical outcomes in pts with mRCC receiving 1st-line (1L) therapy with dual immune checkpoint inhibitors (ICIs; Dizman et al Nature Medicine 2022). As tyrosine kinase inhibitors (TKIs) in combination with ICIs also represent a 1L standard of care in mRCC, we sought to determine if CBM588 would augment clinical outcome with the TKI cabozantinib (cabo) with nivo. Methods: Eligible pts were ≥18 yrs old (Karnofsky performance status ≥70%) with histologically verified (clear-cell, papillary or sarcomatoid component) mRCC and no prior systemic therapy for metastatic disease. Patients were randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg PO QD and 480mg IV monthly, respectively) alone or with CBM588 dosed at 80mg PO BID. The primary endpoint was the relative abundance of Bifidobacterium spp. in stool specimens at baseline and after 12 weeks of treatment. Secondary endpoints included assessment of response rate, overall survival, progression-free survival (PFS), systemic immunomodulation, and toxicity. A two-group t-test with a one-sided type I error of 0.05 was used to assess the study's primary endpoint, hypothesizing an increase in Bifidobacterium spp. with CBM588 therapy. Results: A total of 30 (20:10 M:F) pts were recruited; median age was 65 (36-84) and 5 pts (17%) had sarcomatoid features and 2 pts (7%) had predominant papillary histology. 12 (40%), 12 (40%) and 6 pts (20%) had good, intermediate and poor risk, respectively. Metagenomic sequencing of paired stool specimens showed a significant decrease in diversity from baseline to week 12 in patients receiving cabo/nivo (P=0.02); no significant difference was observed in those treated with cabo/nivo+CBM588. No significant change in Bifidobacterium spp. was observed. RR was 63% in pts receiving cabo/nivo+CBM588 vs 33% in pts receiving cabo/nivo alone. Median PFS was not reached in pts receiving CBM588 vs 5.8 mos in pts receiving cabo/nivo along (P=0.03). Grade 3/4 toxicities were observed in 44% and 42% of patients on control and experimental arms, respectively. Conclusions: In the second prospective trial assessing the addition of CBM588 to ICI-based therapy in mRCC, a consistent result with improved PFS and RR was observed. Further translational efforts are underway to characterize the mechanism through which CBM588 augments clinical activity. Clinical trial information: NCT05122546 .

A U.S. Food and Drug Administration–pooled Analysis of Frontline Combination Treatment Survival Benefits by Risk Groups in Metastatic Renal Cell Carcinoma

BackgroundWhile frontline immuno-oncology/tyrosine kinase inhibitor (IO/TKI) combination therapy has established a benefit in metastatic renal cell carcinoma (mRCC), this may differ by International Metastatic RCC Database Consortium (IMDC) risk grouping. Looking at individual trials, we noted an apparently smaller magnitude of benefit for favorable-risk disease. ObjectiveWe aimed to assess treatment benefit by risk groupings, especially in favorable-risk, augmenting patient numbers via a pooled analysis. Design, setting, and participantsWe pooled four frontline mRCC trials of IO/TKI combinations including 3,098 patients (839 favorable-risk) with approvals from 2019 to 2021. InterventionAll trials used IO/TKI combinations as the treatment option and sunitinib as the control. Outcome measurements and statistical analysisWe analyzed progression-free survival (PFS) and overall survival (OS) by IMDC groupings. To specifically address the favorable-risk group, we combined all others into an intermediate/poor-risk group. Results and limitationsIn this exploratory analysis adjusted for baseline covariates, IO/TKI combinations have yet to demonstrate an OS benefit in favorable-risk (hazard ratio [HR] 1.24; 95% confidence interval [CI]: 0.86, 1.78) despite demonstrating an OS benefit in the intermediate/poor-risk group (HR 0.64; 95% CI: 0.55, 0.75). In contrast, IO/TKI demonstrated a PFS benefit for both the favorable-risk (HR 0.63; 95% CI: 0.50, 0.79) and the intermediate/poor-risk (HR 0.52; 95% CI: 0.45, 0.60) group. For objective response rate, a smaller difference was observed between the combination and sunitinib arms in favorable-risk (68.2% vs 49.9%) versus intermediate/poor-risk (59.9% vs 36.5%) groups, while the difference in complete response rate was larger for favorable-risk (15.3% vs 6.0%) versus intermediate/poor-risk (9.1% vs 3.4%) groups. ConclusionsThe frontline IO/TKI combination therapy benefit was shown to be greater in the intermediate/poor-risk group than in the favorable-risk group. The OS benefit observed with IO/TKI for mRCC has yet to be demonstrated for favorable-risk patients; longer follow-up is needed. Patient summaryPatients with intermediate/poor-risk metastatic renal cell carcinoma derive an overall survival benefit from immuno-oncology/tyrosine kinase inhibitor combinations, while data for favorable-risk remain immature.

Combination of EGFR-Directed Tyrosine Kinase Inhibitors (EGFR-TKI) with Radiotherapy in Brain Metastases from Non-Small Cell Lung Cancer: A 2010-2019 Retrospective Cohort Study.

Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. A retrospective review of NSCLCBM patients diagnosed during 2010-2019 at a tertiary-care US center was performed and reported following the 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17-0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07). NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS.

CABIOS trial: A phase Ib study of cabozantinib and nivolumab in combination with abiraterone in patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC).

5084 Background: Androgen deprivation therapy (ADT) combined with novel hormonal agents +/- docetaxel is a standard of care treatment for mHSPC. The combination of tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) is FDA approved in renal cell carcinoma, and shows promising efficacy in preclinical models of prostate cancer by favorably altering the tumor immune microenvironment. There are currently ongoing trials of TKI + ICB in metastatic castration resistant prostate cancer. Here we present interim safety results from an ongoing phase Ib single-arm trial of cabozantinib + nivolumab + abiraterone/prednisone (cabo, nivo, abi/pred) in pts with newly diagnosed mHSPC (NCT04477512). Methods: Eligible pts had de-novo or recurrent mHSPC with up to 12 weeks ADT prior to enrollment, ECOG 0-1, and adequate organ function. Prior abi and docetaxel were excluded. Pts received cabo 20 mg or 40 mg daily (3+3 dose escalation in 2 cohorts) combined with nivo 480mg IV q4 weeks, and abi/pred 1,000mg/5mg daily until progression or unacceptable toxicity. The primary endpoint is safety and tolerability. Secondary endpoints include overall response rate (ORR) by RECIST 1.1, overall survival (OS), progression free survival (PFS), and PSA response. Exploratory analyses include CyTOF of peripheral blood and serum cytokine ELISA. Results: As of 19DEC2022, 17 pts were enrolled, 3 at 20mg and 14 at 40mg cabo with no dose-limiting toxicity (DLTs) observed. Median age was 65 yrs, 4/17 pts are Black, 11 had de-novo and 6 recurrent disease, with median baseline PSA 78ng/mL. Most had bone (n=16), lymph node (6), or lung (1) mets, and 11 (64.7%) had high-volume disease. With median follow-up 12.8 months, 9 pts (53%) remain on study. 1 withdrew, 3 discontinued due to disease progression (with 1 death), and 4 stopped due to toxicity. Grade ≥ 3 adverse events (AEs) include encephalitis (n=1, grade 4 likely nivo-related after 1yr on therapy), diarrhea (n=2), elevated AST/ALT (n=4), wound infection/dehiscence, adrenal insufficiency, hypertension, elevated lipase, and proteinuria (grade 3, n=1 each). No other AEs were reported outside the current safety labels for the study agents. Of 15 response evaluable pts, 7 had RECIST-measurable lesions; 4 had partial response and 3 had stable disease as best response at data cutoff. 9/14 (64.3%) evaluable had PSA &lt;0.2ng/mL at 7 months. Immune correlative studies are ongoing. Conclusions: Here we present the initial safety and preliminary efficacy results of the first trial of cabo + nivo in mHSPC patients receiving SOC ADT + abi. To date, the combination has a safety profile consistent with known AEs for these agents, no DLTs, and evidence of clinical benefit. Further follow up will be required to fully assess clinical safety, efficacy and immune responses. Future, larger studies could compare this combination to SOC ADT + abi. Clinical trial information: NCT04477512 .

Combination targeted therapy with avapritinib and sunitinib in patients with refractory gastrointestinal stromal tumors after failure of standard treatments: A small prospective pilot study.

11538 Background: There is currently no standard treatment after ripretinib beyond the fourth-line setting for refractory gastrointestinal stromal tumors (GISTs). A combination of tyrosine kinase inhibitors (TKIs) is rational to be potentially effective after failure of standard therapies. The objective of this study was to explore the efficacy and safety of avapritinib plus sunitinib in refractory GISTs. Methods: This was a prospective cohort study in part of a real-world trial (NCT05461664) exploring avapritinib in GIST patients (pts) after failure of standard treatments. Participants received avapritinib 100–200 mg once a day (QD) combined with sunitinib 25–37.5 mg QD continuously in 28-day cycles until disease progression (PD) or discontinuation from January 2022 to January 2023. Clinical outcomes including objective response rate (ORR), survival and safety were assessed. Results: A total of 11 pts with a median age of 57 years were enrolled. Median follow-up duration was 4.1 months (range, 1.4–12.8 months). Median sum of target lesions was 28.2 cm (range, 6.6–47.0 cm). Four pts had primary KIT exon 11 mutation, 6 had exon 9 and one had exon 17, secondary mutation KIT exon 13 was in 2 pts, exon 14 in one, exon 16 in 2 and exon 17 in 7 pts. Seven pts received more than 4 lines of prior TKIs, three received 3 and one had 2 lines of prior TKIs. One patient (9.1%) achieved partial response (PR) with 48.7% lesion length reduction, 9 (81.8%) had stable disease (SD) with 8 out of 9 pts achieving tumor shrinkage (median sum of lesion reduction of 20.8% [range, 9.8–27.3%]), and one (9.1%) had PD according to mRECIST1.1. Eight pts (72.8%) achieved PR, one (9.1%) had SD, and 2 (18.2%) had PD according to the Choi criteria. Until last follow-up, 4 pts progressed, one withdrew from the study and one discontinued treatment after surgery. Five pts were still receiving treatment, one exceeded 1 year with 26.3% lesion reduction in the seventh line setting. Progression-free survival and overall survival results were immature. ORR and lesion reduction trended favorably in those with KIT activation loop (AL) mutations, but this was not statistically significant. The dose of avapritinib (100–150 mg/d) and sunitinib (25–37.5 mg/d) could be tolerated. Common adverse events (AEs) were anemia, leukopenia, diarrhea, fatigue, periorbital and face oedema, and memory impairment. Common grade ≥3 AEs included anemia (54.5%), leukopenia (36.4%), diarrhea (36.4%), tumor hemorrhage (27.3%) and gastrointestinal hemorrhage (18.2%). Conclusions: The preliminary results from this study demonstrated meaningful clinical benefit with avapritinib plus sunitinib, achieving significant lesion reduction in refractory GISTs, especial those with KIT AL secondary mutations. Further studies are warranted to determine the optimal dosing regimen of two targeted drugs. Clinical trial information: NCT05461664 .

Response to immune checkpoint inhibitor (ICI) rechallenge in patients with metastatic renal cell carcinoma who progressed on prior ICI: A systematic review and meta-analysis.

4547 Background: Several immune checkpoint inhibitor (ICI)-based combination regimens are standard-of-care for first-line treatment of metastatic renal cell carcinoma (mRCC). These include dual ICI and ICI-tyrosine kinase inhibitor (TKI) combinations. While single-agent ICI is recommended as subsequent-line therapy for ICI-naïve patients, there is limited knowledge regarding efficacy of rechallenging with a different ICI or using different ICI combinations in patients who have progressed on prior ICI therapy. This is a clinically critical question as most mRCC patients would have already received ICI therapy at progression. The aim of this study is to address the above by performing a systematic review and meta-analysis. Methods: PubMed, Cochrane Library and Web of Science were systematically searched to identify studies of later-line ICI rechallenge after progression on any previous ICI in mRCC patients from database inception to December 31st, 2022. Patients who had progressed on prior ICI and rechallenged with ICI as single agent/dual/TKI combination as any subsequent line of therapy in both retrospective and prospective studies were included. Exclusion criteria were phase I or any phase studies combining ICI with unapproved drugs, case reports and case series. We calculated the pooled objective response rate (ORR) and disease control rate (DCR) using mixed effects model treating individual studies as a random effect. We further stratified studies into prospective and retrospective and performed subgroup analyses. Results: A total of 11 studies, 6 prospective and 5 retrospective with a total of 603 patients were initially identified. Out of the 6 prospective studies, 3 had an adaptive design of using salvage ipilimumab/nivolumab in patients who had either progressed or had stable disease as the best overall response on nivolumab monotherapy. These studies were excluded as they did not meet our inclusion criteria. A total of 8 studies with 400 patients were included in the final analysis. The ORR was 28% (95% CI, 0.27-0.36) and the DCR was 70% (95% CI, 0.47-0.85) with no significant differences between prospective and retrospective studies. Our ORR is higher than an earlier meta-analysis reporting an ORR of 14% with salvage ipilimumab/nivolumab after previous treatment with ICI. Conclusions: This meta-analysis demonstrates a modest ORR and an impressive DCR. Therefore, it provides strong clinical rationale to consider rechallenging with ICI-based therapy for later-line treatment of mRCC patients who have progressed on prior ICI. [Table: see text]

FDA analysis of treatment-free survival in frontline advanced immuno-oncology–VEGF TKI renal cell carcinoma trials.

e13602 Background: Treatment-free survival (TFS) with and without (w/o) toxicity are outcome measures that describe health states where patients are experiencing clinically stable disease while off anti-cancer treatment, a clinically meaningful attribute seen with some immune-oncology (IO) regimens. We sought to characterize TFS with and w/o ongoing toxicity in addition to time on protocol therapy (combination and monotherapy) in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in pts with advanced renal cell carcinoma (aRCC). Methods: We pooled randomized trials submitted to FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months (mos) of median follow-up. OS was partitioned into health states, including TFS, defined as area between Kaplan-Meier curves for 2 time-to-event endpoints originating at randomization: 1) time to all protocol therapy cessation and 2) time to subsequent systemic therapy initiation or death. Health state areas under the curve were estimated by 30-mo restricted mean times. We pooled data by treatment arm. Results: Three trials (KEYNOTE-426, JAVELIN Renal 100, CheckMate 9ER) met criteria for analysis; in total, 1183 pts received IO-TKI vs. 1184 on control arms receiving sunitinib (SUN). IO-TKI and SUN groups spent 9% (2.7 mos [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 mos [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free. Mean TFS with grade ≥3 toxicity were 1 and 0.6 mos in the IO-TKI and SUN groups, respectively. Mean TFS w/o grade ≥3 toxicity were 1.7 and 2.3 mos in IO-TKI and SUN groups, respectively. In IO-TKI group, the 30-mo mean time on combination therapy was 13.7 mos (46% of 30-mo period) and 3.9 mos on monotherapy (13% of 30-mo period). Following cessation of one drug in IO-TKI arm, monotherapy duration of TKI was longer than IO: 2.9 and 1 mos, respectively. Conclusions: In this descriptive, exploratory analysis, TFS and TFS w/o toxicity were similar in IO-TKI group compared to SUN group, in contrast to improved TFS in IO-IO vs. SUN seen in published literature. Among pts on IO-TKI, more time was spent on TKI monotherapy than IO monotherapy. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials, and may inform individual pt choice of IO-IO vs. IO-TKI. [Table: see text]

Efficacy of subsequent immunotherapy-tyrosine kinase inhibitor combinations after TKI monotherapy failure in patients with intermediate/poor risk metastatic clear cell renal cell carcinoma: A real-world retrospective study.

e16537 Background: The randomized phase 3 trials KEYNOTE-426, CheckMate 9ER, and CLEAR have demonstrated the efficiency of immunotherapy-based drug combinations as first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC). Immunotherapy-tyrosine kinase inhibitor (IO-TKI) has shown significant benefits over sunitinib monotherapy with respect to overall survival in mccRCC patients with intermediate/poor international metastatic database consortium (IMDC risk group). However, most of the patients received second-line TKI or immune checkpoint inhibitors therapy after TKI monotherapy failure in those clinical trials. The role of IO-TKI after disease progression in sunitinib monotherapy cohort was not fully investigated. We sought to evaluate the efficacy of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk who had previously received at least one line of TKI monotherapy. Methods: We conducted retrospective analysis of IMDC intermediate/poor risk mccRCC patients treated with IO-TKI during any treatment line at our center from June 2019 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The primary end point was overall survival (OS), defined as the time from initiation of treatment to death from any cause or last follow-up. The secondary end point was progression-free survival (PFS), defined as the time to the first documented disease progression. Results: Overall, 81 IMDC intermediate/poor risk mccRCC patients were enrolled, with a median follow-up of 17 months. 49 patients received first-line IO-TKI therapy, 32 patients who had previously received at least one line of TKI monotherapy received second-line IO-TKI after disease progression. The objective response rate (ORR) and median PFS of second-line IO-TKI after TKI monotherapy failure was 28.6% and 9 months, respectively. OS between first-line IO-TKI therapy and second-line IO-TKI after TKI monotherapy failure was not statistic significant (30 months vs. 26 months, p = 0.630). Conclusions: In this real-world retrospective study, we observed antitumor activity of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk after disease progression. Notably, first-line IO-TKI therapy did not have superior OS when TKI monotherapy patients received second-line IO-TKI therapy. Randomized trials are needed to evaluate optimal combination strategies and sequencing of therapies in mccRCC.

Analysis of Tumor Heterogeneity Through AXL Activation in Primary Resistance to EGFR Tyrosine Kinase Inhibitors

IntroductionEGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. MethodsWe investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab. ResultsQuantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab. ConclusionsOur observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.

First report of PhALLCON: A phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

398868 Background: The standard of care in patients (pts) with newly diagnosed (dx) Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy (chemo) or steroids. Treated with 1st- or 2nd-generation TKIs, pts eventually progress due to emergence of resistance. Multiple studies have reported promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with pon in combination with chemo or chemo-free regimens. PhALLCON (NCT03589326), the first randomized study comparing TKIs in pts with Ph+ALL, evaluates pon vs im in combination with reduced-intensity chemo. Methods: This phase 3 open-label trial randomized adult newly dx Ph+ALL pts 2:1 to receive pon (30 mg once daily [QD]) or im (600 mg QD) with reduced-intensity chemo through end of induction (EOI; Cycles 1–3), consolidation (Cycles 4–9), and post-consolidation (Cycles 10–20). After Cycle 20, pts received single-agent pon or im until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% ) complete remission (CR) for 4 weeks at EOI. Event-free survival (EFS: any cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. Results: 245 pts were randomized to pon (n=164) or im (n=81); median age was 54 y (37% ≥60 y). At data cutoff (Aug 2022), 78 pts (pon vs im: 42% vs 12%) were on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (31% vs 37%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). Median follow-up was 20 mo vs 18 mo (pon vs im). The primary endpoint was met (Table) by significantly higher MRD-neg CR rate for pon vs im (34.4% vs 16.7%; p=0.0021). Survival data were not mature; however, the median EFS was reached in im and not in pon, with a trend toward improvement (HR=0.652, 95% CI 0.385–1.104). Time to treatment failure reported an improvement as well (HR=0.455). The treatment-emergent adverse event (TEAE) rates (any grade [Gr] and Gr3/4/5) were comparable between treatment arms. Arterial occlusive events (AOEs) were infrequent and similar between the arms (Table). Conclusions: Pon was superior to im in combination with reduced-intensity chemo in pts with newly dx Ph+ALL, with a significantly higher MRD-neg CR rate at the EOI. Pon was associated with deeper and more durable responses, with a trend toward improved EFS and comparable safety vs im. Clinical trial information: NCT03589326 . [Table: see text]

Role of β-Catenin Activation in the Tumor Immune Microenvironment and Immunotherapy of Hepatocellular Carcinoma

Recently, the therapeutic combination of atezolizumab and bevacizumab was widely used to treat advanced hepatocellular carcinoma (HCC). According to recent clinical trials, immune checkpoint inhibitors (ICIs) and molecular target agents are expected to be key therapeutic strategies in the future. Nonetheless, the mechanisms underlying molecular immune responses and immune evasion remain unclear. The tumor immune microenvironment plays a vital role in HCC progression. The infiltration of CD8-positive cells into tumors and the expression of immune checkpoint molecules are key factors in this immune microenvironment. Specifically, Wnt/β catenin pathway activation causes “immune exclusion”, associated with poor infiltration of CD8-positive cells. Some clinical studies suggested an association between ICI resistance and β-catenin activation in HCC. Additionally, several subclassifications of the tumor immune microenvironment were proposed. The HCC immune microenvironment can be broadly divided into inflamed class and non-inflamed class, with several subclasses. β-catenin mutations are important factors in immune subclasses; this may be useful when considering therapeutic strategies as β-catenin activation may serve as a biomarker for ICI. Various types of β-catenin modulators were developed. Several kinases may also be involved in the β-catenin pathway. Therefore, combinations of β-catenin modulators, kinase inhibitors, and ICIs may exert synergistic effects.

Abstract 4876: A systems pharmacology approach to discover synergistic targeted therapy combinations

Abstract The discovery of oncogenic signal transduction in cancer has enabled the development and clinical use of dozens of kinase-directed targeted therapies, but patient response is often transient and resistance invariably develops. In the setting of BRAF-mutant melanoma, for instance, a majority of patients relapse within one year of initiating targeted therapy. Combination therapies blocking compensatory signaling pathways provide a strategy for boosting treatment efficacy and delaying resistance. To find synergistic kinase inhibitor combinations, we used a multimodal systems pharmacology approach to quantify the early adaptive signaling and gene regulatory dynamics in patient-derived BRAFV600E-mutant melanoma cells under oncogene inhibition. Cells were treated with vemurafenib or vehicle and sampled longitudinally at timepoints spanning minutes to days. To measure signaling dynamics, thousands of protein phosphorylation sites covering commonly altered signaling axes in cancer were motif-enriched by immunoprecipitation, barcoded with isobaric tandem mass tags (TMT), and quantified by high-resolution mass spectrometry (MS). The resulting time-resolved phosphoproteomics data showed rapid (&amp;lt;15 minutes) and potent (&amp;gt;8-fold) downregulation of ERK1/2, confirming strong BRAF inhibition. Statistical integration of signaling measurements with time-series RNA-seq data collected at the same timepoints enabled reconstruction of multi-scale regulatory networks governing the adaptive response to oncogene inhibition. In particular, we observed early induction of SRC-family kinase (SFK) signaling and a broad cytoskeletal signaling module, implicating a compensatory prosurvival signaling program. The induction intensified over the 3-day treatment window and was fully reversed following a 6-day drug holiday, suggesting a reversible nature of drug adaptation. Immunoblotting confirmed sustained loss of ERK1/2 activity and concomitant elevated SFK phosphorylation following drug treatment. Accumulation of reactive oxygen species, a known activator of SFKs, strongly correlated with SFK activity, and both were ablated following treatment with the antioxidant precursor N-acetylcysteine. This adaptive response predicted a significant degree of synergy between vemurafenib and the pan-SFK inhibitor dasatinib, which was validated in a panel of patient-derived melanoma cell lines and in melanoma xenograft mouse models. Targeted MS of phospho-ERK1/2 and canonical SFK substrates, including CTTN, PXN, and PAG1, validated the mechanism of action of this combination. Complementary data from patient-derived non small-cell lung cancer (NSCLC) cells under tyrosine kinase inhibitor treatment demonstrates the generality of our integrative approach, and supports the notion that SFK activation may be a hallmark response to oncogenic RTK-RAS-ERK pathway inhibition. Citation Format: Cameron T. Flower, Chunmei Liu, James R. Heath, Wei Wei, Forest M. White. A systems pharmacology approach to discover synergistic targeted therapy combinations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4876.

Complex formulation strategies to overcome the delivery hurdles of lapatinib in metastatic breast cancer

Breast cancer (BC) is the most prevalent cause of death in women due to cancer worldwide. In 2020, globally, almost 3 million new cases of BC were recognized out of which approximately 684,900 BC-associated deaths were reported due to consequences of metastatic BC (MBC). For its efficient treatment lapatinib (LTN), a dual receptor tyrosine kinase inhibitor (TKI) combination with capecitabine was approved by USFDA. It is a Biopharmaceutical Classification System (BCS) class II drug with water solubility of (0.0223 mg/mL) and exhibits a positive food effect (2.67–4.25-fold). The lower aqueous solubility of LTN restricts its dissolution in a gastrointestinal fluid resulting in variable absorption and poor bioavailability. Furthermore, 99% of LTN binds to plasma proteins resulting in minimal accessibility of free LTN at the cancer site. Hence, a large daily dose of LTN is required to be prescribed. The patent expiry on the innovated product in 2021 has fuelled up the need to develop complex delivery system to overcome the biopharmaceutical hurdles of the drug. The present review critically analyses the various intrinsic fundamental properties of drug molecule that should be taken into consideration while designing a complex delivery system for LTN and the such several formulation approaches reported in literature so far to enhance the pharmacokinetic and pharmacodynamic properties of LTN. This review also discusses the various combinational approaches reported with LTN to overcome the hurdles related to the drug. It also covers various recent ongoing clinical trials on LTN and to provide new perspectives for the development of complex formulations.

MP28-10 COMPARISON OF THE IMPACTS OF IMMUNE-RELATED ADVERSE EVENTS ON THE PROGNOSIS OF PATIENTS WITH ADVANCED RENAL CELL CARCINOMA BETWEEN PATIENTS TREATED WITH IO-IO AND IO-TKI COMBINATION THERAPY

You have accessJournal of UrologyCME1 Apr 2023MP28-10 COMPARISON OF THE IMPACTS OF IMMUNE-RELATED ADVERSE EVENTS ON THE PROGNOSIS OF PATIENTS WITH ADVANCED RENAL CELL CARCINOMA BETWEEN PATIENTS TREATED WITH IO-IO AND IO-TKI COMBINATION THERAPY Hiroki Ishihara, Yuki Nemoto, Kazutaka Nakamura, Hidekazu Tachibana, Hironori Fukuda, Kazuhiko Yoshida, Hirohito Kobayashi, Junpei Iizuka, Hiroaki Shimmura, Yasunobu Hashimoto, Tsunenori Kondo, and Toshio Takagi Hiroki IshiharaHiroki Ishihara More articles by this author , Yuki NemotoYuki Nemoto More articles by this author , Kazutaka NakamuraKazutaka Nakamura More articles by this author , Hidekazu TachibanaHidekazu Tachibana More articles by this author , Hironori FukudaHironori Fukuda More articles by this author , Kazuhiko YoshidaKazuhiko Yoshida More articles by this author , Hirohito KobayashiHirohito Kobayashi More articles by this author , Junpei IizukaJunpei Iizuka More articles by this author , Hiroaki ShimmuraHiroaki Shimmura More articles by this author , Yasunobu HashimotoYasunobu Hashimoto More articles by this author , Tsunenori KondoTsunenori Kondo More articles by this author , and Toshio TakagiToshio Takagi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Several studies have highlighted the prognostic impact of immune-related adverse events (irAEs) in patients with solid cancers including renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs). However, similar data in patients with advanced RCC treated with ICI-based combination therapy as first-line therapy are scarce. METHODS: We retrospectively evaluated the data of 148 patients with advanced RCC receiving either ICI-dual combination therapy (i.e., IO-IO) or ICI plus tyrosine kinase inhibitor (TKI) combination therapy (i.e., IO-TKI) as first-line therapy at our affiliated institutions. Between the IO-IO and IO-TKI regimens groups, progression-free survival (PFS), overall survival (OS), and objective response rates (ORRs) were compared. RESULTS: Overall, a significantly higher proportion of patients experienced at least one irAEs during treatment in the IO-IO than in the IO-TKI group [67/91 (74%) vs. 30/57 (53%), respectively; p=0.0126]. PFS (median: 11.8 vs. 2.50 months, p<0.0001), OS (median: not reached vs. 31.0 months, p=0.0102), and ORR (55% vs. 17%, p=0.0028) were significantly superior in patients with irAEs than in those without irAEs in the IO-IO group (Figure 1). Multivariate analyses further showed that irAE development was an independent prognostic factor for longer PFS (hazard ratio: 0.25, p<0.0001) and OS (hazard ratio: 0.42, p=0.0287) in the IO-IO group. Contrarily, irAE development was not associated with PFS (median: 37.9 vs. 16.1 months, p=0.894), OS (not reached vs. not reached, p=0.846), or ORR (53% vs. 56%, p=0.539) in the IO-TKI group (Figure 2). CONCLUSIONS: In the first-line setting of systemic therapy for advanced RCC, the IO-IO regimen was associated with a higher incidence rate of irAEs than the IO-TKI regimen. Depending on the regimen used, the prognostic impact of irAEs might be different, even though we need appropriate optimal treatment for irAEs regardless of the regimens. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e373 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiroki Ishihara More articles by this author Yuki Nemoto More articles by this author Kazutaka Nakamura More articles by this author Hidekazu Tachibana More articles by this author Hironori Fukuda More articles by this author Kazuhiko Yoshida More articles by this author Hirohito Kobayashi More articles by this author Junpei Iizuka More articles by this author Hiroaki Shimmura More articles by this author Yasunobu Hashimoto More articles by this author Tsunenori Kondo More articles by this author Toshio Takagi More articles by this author Expand All Advertisement PDF downloadLoading ...

The role of irreversible pan-HER tyrosine kinase inhibitors in the treatment of HER2-Positive metastatic breast cancer.

Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is the leading cause of cancer death in women. For patients with HER2-positive MBC, after the failure of multiple lines of treatment, there is no optimal line of therapy. A series of clinical trials confirmed that treatment with irreversible pan-HER tyrosine kinase inhibitors (TKIs) in combination with chemotherapy significantly improves patients' survival outcomes. This review focuses on the pathogenesis of HER2-positive breast cancer, current standard treatments, mechanisms of approved irreversible TKIs, and key clinical trials. The available findings suggest that irreversible pan-HER TKIs, such as pyrotinib and neratinib, in combination with chemotherapy, represent a beneficial salvage therapy for patients with HER2-positive MBC with manageable toxicity. However, further studies are needed to assess the efficacy and safety of this combination therapy.

Economic Evaluation for Palbociclib Plus Fulvestrant vs Ribociclib Plus Fulvestrant and Abemaciclib Plus Fulvestrant in Endocrine-Resistant Advanced or Metastatic Breast Cancer in Italy.

To date, no study evaluated the cost-effectiveness of palbociclib (PAL) plus fulvestrant (FUL) vs ribociclib (RIB) plus FUL and abemaciclib (ABM) plus FUL in Italy. Cost-effectiveness analysis comparing the three cyclin-dependent 4/6 kinase inhibitors in combination with endocrine therapies for the management of postmenopausal women with HR+, HER2- advanced or metastatic breast cancer in Italy was developed. To assess the cost-effectiveness of PAL plus FUL vs RIB plus FUL and ABM plus FUL, a cost-minimization has been carried out with a conservative scenario considering three CDK4/6 inhibitors with equal effectiveness in terms of overall survival (OS) (MAIC, Rugo et al 2021). Adverse events (AEs) associated with all therapies were obtained from clinical trials. Ad-hoc analysis was performed to estimate the cost-effectiveness considering the quality-of-life (QoL) data (Lloyd et al 2006). Cost-minimization inputs were drugs, visits and exams, AE monitoring and best supportive care (BSC) before the progression state, active and BSC in the progression and terminal phase of the last two weeks of life. Given the comparability of PAL, RIB and ABM in terms of efficacy, this analysis demonstrated slight economic savings over a lifetime for PAL. Results showed saving per patient of €305 (lifetime) when PAL is compared with RIB; for PAL vs ABM a saving of €243 (lifetime) in a conservative scenario. Results of a budget impact analysis showed a potential savings of €319,563 for PAL vs RIB and €297,544 for PAL vs ABM. When QoL data were considered, results may favor PAL due to the lower impact of AE with savings and improvement in the QoL related to fewer AE. From the Italian perspective, a cost-saving profile associated with the use of PAL+FUL for the management of advanced/metastatic HR+/HER2- breast cancer compared to RIB+FUL and ABM+FUL emerged.

Urachal carcinoma: The journey so far and the road ahead.

Urachal carcinoma, a rare cancer arising from urachus, accounts for about 1% of bladder cancer. The diagnosis at stage I shows about 63% 5-year survival whereas only 8% of the patients at stage IV shows a 5-year survival. Above 90% of urachal carcinomas are adenocarcinomas and most of the urachal carcinoma cases are invasive, showing a high resemblance to adenocarcinoma of various origins, making it hard for a conclusive diagnosis. Even though inconclusive, immunohistochemistry can play a significant role in identifying urachal carcinoma. Most cases show the biomarkers CK20 and CDX2, whereas CK7 and β-catenin are expressed at a lesser frequency. Due to the few cases available, there is a lack of evidence regarding specific markers differentiating urachal carcinoma from colorectal or primary bladder adenocarcinomas. In addition to immunohistochemistry, genomic characterization is emerging to play a role in the classification and treatment of the disease. Urachal carcinoma has been reported to have a molecular level similarity with colorectal malignancies regarding certain gene expressions. The TP53 mutations inactivating the tumor suppressor can probably be explored as a possible target in treating urachal carcinoma. Additionally, certain targets identified in gastric and breast cancer along with anti-HER2 treatment strategies can be explored. Immuno-oncology utilizes immune checkpoint inhibitors for the treatment of MSI-H tumors whereas a combination of tyrosine kinase inhibitors along with immune checkpoint inhibitors are being studied to treat MSI stable tumors. The article is an in-depth overview of urachal carcinoma addressing the current landscape with an emphasis on the future scenario.