VISION Trial Research Articles

1380P Treatment (Tx) sequencing with tepotinib in previously treated patients (pts) with MET exon 14 (METex14) skipping NSCLC in the VISION trial

1380P Treatment (Tx) sequencing with tepotinib in previously treated patients (pts) with MET exon 14 (METex14) skipping NSCLC in the VISION trial

Tolerability of lutetium-177–PSMA-617 in men with prostate cancer and baseline cytopenia.

e17057 Background: Results from the VISION trial (NCT03511664) led to the approval of lutetium-177 (177Lu)–PSMA-617 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This trial excluded patients with baseline cytopenias, thus safety in this frequently encountered patient population is unknown. We aimed to use real-world data to describe the tolerability of radioligand therapy in those with poorer bone marrow reserve. Methods: We retrospectively reviewed the records of all patients, who received a first dose of 177Lu–PSMA-617 at Mayo Clinic in the interval of April 26, 2022, to December 1, 2022. Patients were categorized as having poor marrow reserve on the basis of pre-treatment hematologic parameters, including: (1) an anemia cohort with hemoglobin (Hg) less than 9 g/dL, (2) a thrombocytopenia cohort with platelets (Plt) less than 100 x 109/L, (3) a leukopenia cohort with white blood cell count (WBC) less than 2.5 x 109/L, and (4) a multiple cytopenia cohort. These were exclusionary parameters from the VISION trial. Longitudinal laboratory data and clinical outcomes were collected and analyzed using descriptive statistics. Results: At data cutoff, 185 patients had received one or more doses of 177Lu, including 26 (14%) with at least one baseline cytopenia prior to their first cycle of treatment. In total, there were 19 (73%) patients with anemia, 3 (12%) with thrombocytopenia, 2 (8%) with leukopenia, and 2 (8%) with multiple cytopenias at baseline. The median number of cycles received thus far is 3, including 14 (54%) who are still receiving therapy and 12 (46%) who have permanently discontinued treatment. Median longitudinal changes in blood counts for the anemia cohort are presented in Table 1. Reasons for treatment discontinuation include: toxicity (n = 2), disease progression (n = 5), death (n = 4), or other (n = 1). Dose reductions or treatment delays for worsening myelosuppression were utilized in 3 (12%) and 5 (19%) patients, respectively. Transfusions of packed red blood cells or platelets were required for 16 (62%) patients. A total of 6 (23%) received care in the emergency department or were hospitalized. Conclusions: Treatment discontinuation for toxicity was rare among men with mCRPC and baseline cytopenias, while receiving 177Lu; however, these patients have an overall poor prognosis. [Table: see text]

Tumor dosimetry of [177Lu]Lu-PSMA-617 for the treatment of metastatic castration-resistant prostate cancer: Results from the VISION trial sub-study.

5046 Background: In VISION, lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) plus protocol-permitted standard of care (SoC) significantly improved overall survival and radiographic progression-free survival compared with SoC alone, in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. In a VISION dosimetry sub-study, 177Lu-PSMA-617 had a good safety profile with low radiotoxicity in at-risk organs. Here, we estimated the dosimetry of tumors after administration of 177Lu-PSMA-617. Methods: The VISION sub-study was performed in a separate cohort of 29 non-randomized participants at four sites in Germany. Eligible patients received 177Lu-PSMA-617 (7.4 GBq every 6 weeks, ≤ 6 cycles) plus SoC. Patients underwent single-photon emission computed tomography/computed tomography (SPECT/CT) scans at approximately 2, 24, 48 and 168 hours after the first administration of 177Lu-PSMA-617 (Cycle 1). Up to five tumors in each patient were selected according to tumor size and relative activity uptake. Tumor delineation, volume and morphology were determined using positron emission tomography (PET)/CT images. Kinetic (time-activity) data was determined using SPECT images and the application of phantom derived recovery coefficients. Tumor dosimetry was estimated using the standard Medical Internal Radiation Dose/Radiation Dose Assessment Resource (MIRD/RADAR) method for internal dosimetry. S-values were determined using CT-derived tumor volumes and tissue type as input to the Internal Dose Assessed by Computer (IDAC-Dose) 2.1 program. Tumor dosimetry estimates were reported as absorbed dose per unit activity (Gy/GBq) and cumulative estimated absorbed dose (Gy) over all 6 cycles (44.4 GBq cumulative activity). Results: In total, 104 tumors were analyzed after administration of 177Lu-PSMA-617 in Cycle 1. Tumor sites included bone (n = 84), lymphatic tissue (n = 18), lung tissue (n = 1) and soft tissue (n = 1). Mean tumor mass by site was 14.6 (standard deviation [SD], 29.8; range, 0.49–224) g for bone and 12.5 (15.9; 0.68–60.7) g for lymphatic tissue. The mean radiation-absorbed dose for all tumors was 6.5 (SD, 8.4; range, 0.13–55) Gy/GBq, and the median absorbed dose was 4.4 Gy/GBq. The mean radiation-absorbed dose by tumor site was 5.4 (SD, 6.0; range, 0.13–45) Gy/GBq for bone and 9.7 (12; 0.99–55) Gy/GBq for lymphatic tissue. The 6-cycle cumulative estimated absorbed dose for all tumors was 287 (SD, 373; range, 5.7–2432) Gy. The 6-cycle cumulative estimated absorbed dose by tumor site was 240 (SD, 268; range, 5.7–2010) Gy for bone and 429 (549; 44–2432) Gy for lymphatic tissue. Conclusions: Tumor dosimetry estimates after administration of 177Lu-PSMA-617 in the VISION sub-study patient population were consistent with previously published estimates. Clinical trial information: NCT03511664 .

Randomised clinical trial: 3-year interim analysis results of the VISION trial to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive oesophagitis

BackgroundVISION is a randomised, phase 4, open-label, parallel-group, multicentre study conducted in 33 centres in Japan. The aim of this study was to assess the long-term safety of vonoprazan for maintenance treatment of healed erosive oesophagitis versus lansoprazole.MethodsPatients with endoscopically diagnosed erosive oesophagitis were randomised 2:1 to once-daily vonoprazan 20 mg or lansoprazole 30 mg, for a 4- to 8-week healing phase. Patients with endoscopically confirmed healing entered a 260-week maintenance phase with a once-daily starting dose of vonoprazan 10 mg or lansoprazole 15 mg. Primary endpoint was change in gastric mucosal histopathology.ResultsOf 208 patients (vonoprazan, n = 139; lansoprazole, n = 69) entering the healing phase, 202 entered the maintenance phase (vonoprazan, n = 135; lansoprazole, n = 67). At 3 years, 109 vonoprazan-treated and 58 lansoprazole-treated patients remained on treatment. Histopathological evaluation of gastric mucosa showed that hyperplasia of parietal, foveolar and G cells was more common with vonoprazan than lansoprazole at week 156 of the maintenance phase. There was no marked increase in the occurrence of parietal, foveolar and G cell hyperplasia among patients in the vonoprazan group from week 48 to week 156. Histopathological evaluation of the gastric mucosa also showed no neoplastic changes in either group. No new safety issues were identified.ConclusionsIn this interim analysis of VISION, no new safety concerns were identified in Japanese patients with healed erosive oesophagitis receiving vonoprazan or lansoprazole as maintenance treatment for 3 years. (CT.gov identifier: NCT02679508; JapicCTI-163153; Japan Registry of Clinical Trials: jRCTs031180040).

PSMA-Directed Theragnostics: Transforming Prostate Cancer Landscape

Early diagnosis and the detection of distant metastases and recurrences in patients with prostate cancer (PCa) have been notably improved in recent decades through advances in imaging techniques. More recently, positron emission tomography (PET) hybrid imaging (PET/computed tomography \[CT] and PET/magnetic resonance imaging \[MRI]) using small molecule radiopharmaceuticals to selectively bind targets unique to PCa has permitted more accurate staging of patients with localized, locally advanced and metastatic disease. Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein overexpressed in most PCa cells, has emerged as one of many specific targets for PCa imaging. Since its introduction in Switzerland in 2016, PSMA-targeted PET/CT with ^68^Gallium(^68^Ga)-labeled and, less commonly, ^18^Flourine(^18^F) -labelled radiotracers, has shown unparalleled precision in detecting metastatic PCa compared with conventional imaging techniques. Furthermore, radioligand therapies such as lutetium-177 (^177^Lu)-PSMA-617 can selectively deliver β-radiation to PSMA-expressing cells. The phase III VISION trial showed that this treatment significantly improved survival outcomes in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). This article discusses the value and impact of ^68^Ga/^18^F-PSMA PET/CT imaging compared with conventional imaging modalities for accurately detecting PCa lesions in a primary setting and for local recurrence or metastases. In addition, an overview of the PSMA ligand therapy, a treatment modality for patients with advanced PCa is presented.

Early outcomes from lutetium Lu-177 vipivotide tetraxetan treatment in patients selected for therapy with piflufolastat F-18 PET imaging.

191 Background: The Vision trial utilized Ga 68 PSMA 11 imaging to select patients for treatment with Lutetium Lu 177 Vipivotide Tetraxetan. Current guidelines allow not only Ga 68 PSMA 11 PET but also Piflufolastat F 18 PET when selecting patients for Lutetium Lu 177 Vipivotide Tetraxetan but little is published on outcomes to this approach. Methods: Patients were enrolled on an IRB approved managed access protocol and were treated by a single investigator at a single institution. Eligible patients had mCRPC and had received previous treatment with at least one androgen receptor pathway inhibitor and at least one round of taxane based chemotherapy. Baseline imaging, demographics, treatment history, and tumor characteristics were collected. Patients were treated with 7.4 GBq of Lutetium Lu 177 Vipivotide Tetraxetan every 6 weeks for up to six cycles. Adverse events and PSA response were collected. Results: Fourteen patients were enrolled between August 2021 and August 2022. All patients had advanced mCRPC, were heavily pre-treated, and had failed both hormonal as well as chemotherapeutic options. The average number of androgen receptor pathway inhibitor courses for the cohort is 2.4 (range 1-4) and the average number of taxane courses for the cohort is 1.5 (Range 1-3). 11 patients underwent Piflufolastat F 18 PET and 3 patients had Ga 68 PSMA 11 PET. Baseline PSA varied significantly from 2.51 - 961.71 ng/mL. Declines of 50% in PSA were observed in 8/14 patients. 2 patients had greater than 80% PSA reductions. Conclusions: PSA treatment responses were similar to those reported in the Vision trial in this cohort of patients selected with either Piflufolastat F 18 PET or Ga 68 PSMA 11 PET supporting the guideline recommendations. Clinical trial information: NCT04825652 .

PSMA-Targeted Radiopharmaceuticals in Prostate Cancer: Current Data and New Trials.

Radiopharmaceuticals have been utilized for men with advanced prostate cancer for decades. Older agents, seldom used today, provided palliation for bone metastatic pain. In 2013, the alpha emitter radium-223 provided a catalyst for the field by prolonging survival in men with metastatic castrate-resistant prostate cancer (mCRPC). Recently radioisotopic therapies have gained further interest with the development and FDA approval of 177 lutetium (177Lu)-PSMA-617 (also known as lutetium Lu-177 vipivotide tetraxetan). This agent targets the prostate-specific membrane antigen (PSMA) expressed on the cell surface of prostate cancer cells with a beta-emitting isotope (177Lu). This clinical review summarizes key data reported from 177Lu-PSMA-617 clinical trials, including data from the phase III VISION trial which were pivotal for regulatory approval in heavily pretreated PSMA-PET-positive patients with mCRPC. The current field of radiopharmaceuticals is in a rapid state of flux. Additional phase III trials are now ongoing in patients with mCRPC and in patients with metastatic castrate-sensitive prostate cancer. The results from these potential practice-changing trials are highly anticipated. Earlier phase trials (I/II) are in progress examining combination therapies, radiolabeled monoclonal antibodies, and novel compounds. Studies of PSMA-targeted therapies using both beta emitters such as 177Lu and novel alpha emitters such 225 actinium are in progress. During the next decade, radiopharmaceuticals will likely play a central role in the management of patients with advanced prostate cancer.

Health Utility Analysis of Tepotinib in Patients With Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping

ObjectivesThe VISION trial showed durable activity of tepotinib in MET exon 14 (METex14) skipping non-small cell lung cancer. We analyzed health state utilities using patient-reported outcomes from VISION. Methods5-level version of EQ-5D (EQ-5D-5L) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 responses were collected at baseline, every 6 to 12 weeks during treatment, and at the end of treatment and safety follow-up. EQ-5D-5L and European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D) utilities were derived using United States, Canada, United Kingdom, and Taiwan value sets, where available. Utilities were analyzed with linear mixed models including covariates for progression or time-to-death (TTD). ResultsUtilities were derived for 273/291 patients (EQ-5D-5L, 1545 observations; QLU-C10D, 1546 observations). Mean (± SD) US EQ-5D-5L utilities increased after tepotinib initiation, from 0.687 ± 0.287 at baseline to 0.754 ± 0.250 before independently assessed progression, and decreased post progression (0.704 ± 0.288). US QLU-C10D utilities showed similar trends (0.705 ± 0.215, 0.753 ± 0.195, and 0.708 ± 0.209, respectively). Progression-based models demonstrated a statistically significant impact of progression on utilities and predicted higher utilities pre versus post progression. TTD-based models showed statistically significant associations of TTD with utilities and predicted declining utilities as TTD decreased. Prior treatment (yes/no) did not significantly predict utilities in progression- or TTD-based models. Utilities for Canada, United Kingdom, and Taiwan showed comparable trends. ConclusionsIn this first analysis of health state utilities in patients with METex14 skipping non-small cell lung cancer, who received tepotinib, utilities were significantly associated with progression and TTD, but not prior treatment.

Cost-Effectiveness Analysis of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer

Metastatic castration-resistant prostate cancer poses a therapeutic challenge with poor prognosis. The VISION trial showed prolonged progression-free and overall survival in patients treated with lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) radioligand therapy compared with using the standard of care (SoC) alone. The objective of this study was to determine the cost-effectiveness of 177Lu-PSMA-617 treatment compared with SoC therapy. A partitioned survival model was developed using data from the VISION trial, which included overall and progression-free survival and treatment regimens for 177Lu-PSMA-617 and SoC. Treatment costs, utilities for health states, and adverse events were derived from public databases and the literature. Because 177Lu-PSMA-617 was only recently approved, costs for treatment were extrapolated from 177Lu-DOTATATE. Outcome measurements included the incremental cost, effectiveness, and cost-effectiveness ratio. The analysis was performed in a US setting from a healthcare system perspective over the lifetime horizon of 60 months. The willingness-to-pay threshold was set to $50,000, $100,000, and $200,000 per quality-adjusted life years (QALYs). The 177Lu-PSMA-617 group was estimated to gain 0.42 incremental QALYs. Treatment using 177Lu-PSMA-617 led to an increase in costs compared with SoC ($169,110 vs $85,398). The incremental cost, effectiveness, and cost-effectiveness ratio for 177Lu-PSMA-617 therapy was $200,708/QALYs. Sensitivity analysis showed robustness of the model regarding various parameters, which remained cost-effective at all lower and upper parameter bounds. In probabilistic sensitivity analysis using Monte Carlo simulation with 10,000 iterations, therapy using 177Lu-PSMA-617 was determined as the cost-effective strategy in 37.14% of all iterations at a willingness-to-pay threshold of $200,000/QALYs. Treatment using 177Lu-PSMA-617 was estimated to add a notable clinical benefit over SoC alone. Based on the model results, radioligand therapy represents a treatment strategy for patients with metastatic castration-resistant prostate cancer with cost-effectiveness in certain scenarios.

Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials.

Metastatic prostate cancer continues to be an incurable disease. Despite all the novel therapies approved in the past two decades, overall patient outcomes remain relatively poor, and these patients die on a regular basis. Clearly, improvements in current therapies are needed. Prostate-specific membrane antigen (PSMA) is a target for prostate cancer given its increased expression on the surface of the prostate cancer cells. PSMA small molecule binders include PSMA-617 and PSMA-I&T and monoclonal antibodies such as J591. These agents have been linked to different radionuclides including beta-emitters such as lutetium-177 and alpha-emitters such as actinium-225. The only regulatory-approved PSMA-targeted radioligand therapy (PSMA-RLT) to date is lutetium-177-PSMA-617 in the setting of PSMA-positive metastatic castration-resistant prostate cancer that has failed androgen receptor pathway inhibitors and taxane chemotherapy. This approval was based on the phase III VISION trial. Many other clinical trials are evaluating PSMA-RLT in various settings. Both monotherapy and combination studies are underway. This article summarizes pertinent data from recent studies and provides an overview of human clinical trials in progress. The field of PSMA-RLT is rapidly evolving, and this therapeutic approach will likely play an increasingly important role in the years to come.

Theranostics in prostate cancer

SummaryThis review summarizes current evidence of “theranostics” for patients with prostate cancer. Prostate-specific membrane antigen (PSMA) is a glycoprotein which can be labeled with positron-emitting tomographic (PET) tracers like fluorine-18, gallium-68, or copper-64 and can be labeled with beta emitters like lutetium-177 to treat patients with metastatic castration-resistant prostate cancer (mCRPC). PSMA PET/CT has been shown to be superior to computer tomography (CT) and bone scintigraphy in accuracy, sensitivity, and specificity in the evaluation of metastatic tumor sites and may change treatment management. However, outcome studies showing an improvement in progression-free survival (PFS) and/or overall survival (OS) after management change is missing. PSMA PET/CT is highly recommended in prostate cancer patients with biochemical recurrence (PSA > 0.2 ng/ml). Patients presenting with high PSMA expression in PSMA PET/CT may be favorably treated with 177lutetium-617. In the TheraP study, a multicenter phase 2 trial, patients with mCRPC were randomly assigned to receive either 177lutetium-617 or cabazitaxel. The results indicate fewer treatment-related adverse events in patients treated with 177lutetium-617, an improvement in PSA response, but no improvement in OS after 36 months follow-up. In the VISION trial, a phase 3 international study, patients with mCRPC were randomly assigned to receive either 177lutetium-617 and standard of care (SOC) or SOC alone. At 12 months, radiographic PFS or PSA-PFS was 18% in patients treated with 177lutetium-617 and 3% in patients treated with SOC alone. The real status of 177lutetium-617 in the sequel of treatment regimens remains unclear and additional studies are therefore warranted.

Is 18F-FDG PET Needed to Assess 177Lu-PSMA Therapy Eligibility? A VISION-like, Single-Center Analysis.

18F-FDG and prostate-specific membrane antigen (PSMA) PET have been used to assess eligibility for PSMA-targeted therapy by some centers. However, it remains unclear whether both examinations are needed as a part of workup in the clinical practice or whether PSMA PET alone, as was done in the positive phase 3 VISION trial, is sufficient to identify suitable candidates. The aim was to reanalyze all patients who underwent both 18F-FDG and PSMA PET for PSMA-targeted therapy eligibility assessment using the VISION trial criteria. Methods: Eighty-nine men with metastatic castration-resistant prostate cancer referred to 177Lu-PSMA therapy from June 2019 to October 2021 who underwent both 18F-FDG and PSMA PET (using either 68Ga-PSMA-11 or 18F-PSMA-1007) examinations within 2 wk were included in this analysis. Eligibility status was determined in accordance with either knowledge of both 18F-FDG and PSMA PET (clinical routine) or VISION criteria with PSMA PET-only (study reassessment, done twice with liver only for PSMA-11 and liver/spleen as reference for PSMA-1007). A metastasis seen on 18F-FDG PET or CT but not on PSMA PET was denoted as a mismatch finding and led to exclusion from 177Lu-PSMA therapy. On the basis of clinical assessment, 52 patients received 177Lu-PSMA therapy, and 37 did not; all patients were reassessed. Results: Patients treated with 177Lu-PSMA therapy had significantly longer overall survival than those not treated (12.4 vs. 6.8 mo, P < 0.01). PSMA-only analysis (spleen/liver reference) and 18F-FDG/PSMA mismatch reads had substantial agreement (Cohen κ = 0.73). Eighteen percent (n = 16/89) of patients had a mismatch finding based on 18F-FDG/PSMA PET. With the liver/spleen reference, a minor fraction of patients who had no mismatch finding (and were therefore treated) would have been withheld from therapy by PSMA-only analysis (3%). Three percent (n = 3) of all patients had an 18F-FDG/PSMA mismatch finding not detected by PSMA PET-only (VISION-like) analysis. For patients not receiving PSMA therapy, the overall survival was not statistically significantly different comparing 18F-FDG/PSMA mismatch versus nonmismatch (P = 0.61) patients. Conclusion: 18F-FDG and PSMA PET provide complementary information, yet less than 5% of patients had mismatch findings not detected using PSMA PET-only. Based on our data, 18F-FDG/PSMA mismatch examination and PSMA-only analysis have a substantial level of agreement.

Cost-Effectiveness of Tepotinib Versus Capmatinib for the Treatment of Adult Patients With Metastatic Non–Small Cell Lung Cancer Harboring Mesenchymal–Epithelial Transition Exon 14 Skipping

ObjectivesFrom the US Medicare perspective, this study compared the cost-effectiveness of tepotinib and capmatinib for treating metastatic non–small cell lung cancer with tumors harboring mesenchymal–epithelial transition factor gene exon 14 skipping. MethodsA 3-state partitioned survival model assessed outcomes over a lifetime horizon. Parametric survival analysis of the phase 2 VISION trial informed clinical inputs for tepotinib. Capmatinib inputs were captured using hazard ratios derived from an unanchored matching-adjusted indirect comparison study and published literature. National cost databases, trial data, and literature furnished drug, treatment monitoring, and disease/adverse event management expenditures (2021 US dollars) and utility inputs. Outcomes were discounted at 3% annually. ResultsIn the base case, tepotinib dominated capmatinib in frontline settings (incremental discounted quality-adjusted life-years [QALYs] and costs of 0.2127 and −$47 756, respectively) while realizing an incremental cost-effectiveness ratio of $274 514/QALY in subsequent lines (incremental QALYs and costs of 0.3330 and $91 401, respectively). In a line agnostic context, tepotinib produced an incremental cost-effectiveness ratio of $105 383/QALY (incremental QALYs and costs of 0.2794 and $29 447, respectively). Sensitivity and scenarios analyses for individual lines typically supported the base case, whereas those for the line agnostic setting suggested sensitivity to drug acquisition costs and efficacy inputs. ConclusionsTepotinib could be cost-effective versus capmatinib in frontline and line agnostic contexts, considering the range of willingness-to-pay thresholds recommended by the Institute for Clinical and Economic Review ($100 000-$150 000/QALY). Tepotinib could be cost-effective in subsequent lines at higher willingness-to-pay levels. These results are to be interpreted cautiously, considering uncertainty in key model inputs.

PCR153 A Comparison of Utility Values Generated Using Different Methods From the Phase II Vision Trial of Tepotinib for Patients With Non-Small Cell Lung Cancer (NSCLC) Harboring MET Exon 14 (METex14) Skipping

Health-related quality of life (HRQoL) data are routinely used to generate utilities for health technology assessment, with a range of methods available to calculate health state utility values (HSUVs). Values may depend on the questionnaire, value set, and statistical analysis performed. The Phase II VISION study (NCT02864992) of tepotinib in patients with NSCLC harboring METex14 skipping captured both EQ-5D-5L and EORTC QLQ-C30 responses. This study compares alternative HSUVs generated from VISION.

Lutetium Lu 177 vipivotide tetraxetan for metastatic castration-resistant prostate cancer

ABSTRACT Introduction 177Lu-vipivotide tetraxetan is a radiopharmaceutical that selectively targets prostate-specific membrane antigen (PSMA) and delivers beta-radiations to kill prostate cancer cells. Areas covered Extensive experience outside the United States as well as randomized phase II and phase III data demonstrate that 177Lu-vipivotide tetraxetan is a safe, generally well tolerated, and effective therapy for men with mCRPC. 177Lu-vipivotide tetraxetan was approved by the FDA in March 2022 for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition and taxane-based chemotherapy based on the results of the VISION trial. Expert opinion This review discusses the development and studies leading to the approval of 177Lu-vipivotide tetraxetan. In all, 177Lu-vipivotide tetraxetan is an exciting new tool in the arsenal for men with mCRPC after novel androgen pathway inhibitors and at least one taxane chemotherapy. Optimal selection of patients, sequencing of 177Lu-vipivotide tetraxetan with the other agents available to treat mCRPC, and the use of dosimetry are current areas of interest with great potential and opportunities for further individual patient optimization using the tools of theranostics.

Eligibility for 177Lu-PSMA Therapy Depends on the Choice of Companion Diagnostic Tracer: A Comparison of 68Ga-PSMA-11 and 99mTc-MIP-1404 in Metastatic Castration-Resistant Prostate Cancer.

177Lu-prostate-specific membrane antigen-617 (177Lu-PSMA-617) is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC), with evidence of improved survival over standard care. The VISION trial inclusion criteria required a metastatic lesion-to-liver ratio of greater than 1 on 68Ga-PSMA-11 PET scans. We aimed to determine whether an equivalent ratio is suitable for a SPECT tracer, 99mTc-MIP-1404, and to compare lesion and lesion-to-normal-organ ratios between the 2 radiotracers. Methods: Two cohorts of patients with mCRPC matched for age, prostate-specific antigen level, and total Gleason score, with either 99mTc-MIP-1404 SPECT/CT (n = 25) or 68Ga-PSMA-11 PET/CT (n = 25) scans, were included for analysis. Up to 3 lesions in each site (prostate/prostate bed, lymph nodes, bone and soft-tissue metastases) as well as normal liver, parotid gland, spleen, and mediastinal blood-pool SUVmax were measured. Results: 99mTc-MIP-1404 SPECT lesion SUVmax was not significantly different from 68Ga-PSMA-11 PET (median, 18.2 vs. 17.3; P = 0.93). However, 99mTc-MIP-1404 liver SUVmax was higher (median, 8.5 vs. 5.8; P = 0.002) and lesion-to-liver ratios were lower (median, 2.7 vs. 3.5; P = 0.009). There was no significant difference in parotid gland or splenic SUVmax or lesion-to-parotid gland ratios between the 2 tracers although there was a small difference in lesion-to-spleen ratios (P = 0.034). Conclusion: There are differences in biodistribution and, in particular, liver activity, between 68Ga-PSMA-11 and 99mTc-MIP-1404. Therefore, if 99mTc-MIP-1404 is used to assess eligibility for 177Lu-PSMA-617 therapy, a lower adjusted lesion-to-liver ratio should be used.

Tepotinib: Management of Adverse Events in Patients With MET Exon 14 Skipping Non-Small Cell Lung Cancer.

Tepotinib, a highly selective, oral, once-daily MET inhibitor, has been approved for treatment of metastatic MET exon 14 skipping non-small cell lung cancer. This article provides nurse-specific recommendations for identification and management of tepotinib adverse events (AEs). Guidance on monitoring and proactive/reactive AE management was developed based on published literature and real-world nursing experience. Case studies of VISION trial participants were summarized to illustrate key principles. Tepotinib AEs are generally mild to moderate and manageable, and can include peripheral edema, hypoalbuminemia, nausea, diarrhea, and creatinine increase. Alongside supportive care, tepotinib interruption and dose reduction is recommended for grade 3 AEs. For peripheral edema, proactive monitoring is crucial, and treatment interruption (including frequent, short treatment holidays) should be considered early. Nursing management of tepotinib AEs includes proactive monitoring, patient education, and interprofessional team coordination.

1372P Association between prostate-specific antigen decline and clinical outcomes in patients with metastatic castration-resistant prostate cancer in the VISION trial

In the phase 3 VISION trial, lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to protocol-permitted standard of care (SoC) in patients with progressive, PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). The proportion of patients with confirmed decline from baseline in prostate-specific antigen (PSA) level ≥ 50% was higher with 177Lu-PSMA-617 plus SoC treatment than with SoC alone.

1374P Radiographic progression-free survival correlation with time-to-event endpoints: A post hoc analysis of the VISION trial

Earlier time-to-event (TTE) endpoints than overall survival (OS) are needed to accelerate drug development and regulatory approval in metastatic castration-resistant prostate cancer (mCRPC). In the phase 3 VISION trial, [177Lu]Lu-PSMA-617 (lutetium (177Lu) vipivotide tetraxetan) plus SoC prolonged PCWG3-defined radiographic progression-free survival (rPFS) and OS, and delayed time to first symptomatic skeletal event (SSE) or death in patients with mCRPC. This post hoc analysis aimed to estimate correlations between these TTE endpoints and provide further evidence for rPFS as an early endpoint for regulatory approval, in the context of radioligand therapy (RLT).

Exposure–response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations

PurposeTepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes.MethodsExposure–efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure–safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30–1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia’s method (QTcF).ResultsTepotinib exhibited flat exposure–efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure–safety relationships for all endpoints within the exposure range observed with 30–1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses.ConclusionsThese analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations.Registration NumbersNCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.