Kristie L. Kahl

A novel prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical for positron emission tomography (PET) known as 

F-DCFPyL, may help to identify occult prostate cancer and more accurately characterize disease burden, according to a subanalysis of the OSPREY trial presented at the 2021 Genitourinary Cancers Symposium.

F-DCFPyL-PET/CT identified M1 disease in the majority of patients examined who otherwise had locoregional disease,” the researchers wrote. “These data suggest that 

F-DCFPyL-PET/CT may be a useful tool in properly staging men with both metastatic and nonmetastatic relapsed disease, which could lead to superior treatment paradigms than currently exist using conventional imaging.”

In the poster presentation, Jeremy C. Durack, MD, MS, interventional radiologist, Memorial Sloan Kettering Cancer Center, noted that previous topline results demonstrated the following:

F-DCFPyL helped to identify recurrent/metastatic prostate cancer, with a positive predictive value (PPV) of 82% and sensitivity of 96%.

F-DCFPyL demonstrated a 40% sensitivity rate, compared to 40% with conventional imaging, as well as a high PPC (87%), an 83% net present value, and 98% specificity in men at high risk for metastatic prostate cancer.

18F-DCFPyL facilitated initial therapy for patients.

In the prospective phase 2/3 study OSPREY study (NCT02981368), conducted across 10 sites in the US and Canada, Durack and colleagues evaluated 

F-DCFPyL in 385 patients broken into 2 cohorts: cohort A (men with high-risk prostate cancer per National Comprehensive Cancer Network guidelines) and cohort B (men with presumptive recurrent or metastatic prostate cancer based on radiologic findings).

F-DCFPyL was administered at 9 mCI (333 MBq), with imaging beginning 1 to 2 hours after administration.

F-DCFPyL detection rates were systematically analyzed. The prospective analysis included 3 blinded, independent 

F-DCFPyL-PET/CT readers and 1 blinded conventional imaging reader.

In their poster presentation, the researchers reported on cohort B, in which 

F-DCFPyL-PET/CT was evaluated in 117 men with radiologic evidence of local recurrence or metastatic disease on baseline anatomical imaging, including a CT scan or MRI, or whole-body bone scintigraphy and in whom at least 1 lesion was deemed amenable to biopsy.

Key efficacy end points from cohort B included sensitivity of 

F-DCFPyL imaging within metastatic lesions relative to histopathology, positive predictive value (PPV) within metastatic lesions, and detection rates between 18F-DCFPyL and conventional imaging.

At baseline, 82 patients (71%) had radiographic M1 stage disease, including 14 patients with M1a, 50 patients with M1b, 18 patients with M1c; 33 patients (29%) were M0 stage at baseline by central conventional imaging review; and 2 patients were unevaluable. In addition, 28% (n = 32) had PSA <2.0 ng/mL.

Of the 33 patients with M0 stage using conventional imaging, 18F-DCFPyL up-staged 19 (58%) men to M1 stage. Ten (91%) of 11 men underwent an extra-pelvic biopsy and were confirmed to have M1 disease by pathology, including 9 patients with M1b and 1 patient with M1a.

Of the 82 patients with M1 stage at baseline using conventional imaging, 

F-DCFPyL up-staged 10 men (12%) to a higher M1 sub-stage, including 4 patients from M1a to M1b or M1c and 6 patients from M1b to M1c. Moreover, 

F-DCFPyL down-staged 18 men (22%) to M0 in this group.

“Conventional imaging and bone scintigraphy are suboptimal modalities for identifying (prostate cancer),” the researchers wrote. “PSMA-based imaging is highly promising for (prostate cancer) detection. 

F-DCFPyL is a novel PSMA-targeted radiopharmaceutical for PET that may be useful in staging of (prostate cancer).”

Durack JC, Alva AS, Preston MA, et al. A prospective phase II/III study of PSMA-targeted 18F-DCFPyL-PET/CT in patients (pts) with prostate cancer (PCa) (OSPREY): A subanalysis of disease staging changes in PCa pts with recurrence or metastases on conventional imaging. Presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021; Virtual. Abstract 32.

Articles

A novel prostate-specific membrane antigen–targeted radiopharmaceutical for positron emission tomography known as 18F-DCFPyL, may help to identify occult prostate cancer and more accurately characterize disease burden, according to a subanalysis of the OSPREY trial presented during the 2021 Genitourinary Cancers Symposium.

Staging of Nonmetastatic Relapsed Prostate Cancer May Be Aided by PSMA-Directed PET Tracer

Findings presented on patients with hematologic malignancies at the 2021 Transplantation and Cellular Therapy Meetings of ASTCT and CIBMTR show that patients who had undergone a hematopoietic stem cell transplantation (HSCT) may accumulate effective immunity against SARS-CoV2 infection and non-SARS human coronaviruses (hCoVs). These findings imply protective memory.

“Our findings have implications for the rational use of the upcoming vaccines and for development of broader cross-reactive anti-hCoV T-cell–based immunotherapy approaches for these highly vulnerable group of patients,” the investigators wrote in their poster presentation.

The coronavirus disease 2019 (COVID-19) has affected individuals with comorbidities—including those with cancer, in particular—and causes severe respiratory infections among immunocompromised patients and HSCT recipients. As a result, closely related non-SARS hCoVs 229E, OC43, NL63, and HKU1 may also lead to similar complications.

“Emerging evidence points to the central role of T cells in post-infection immunity against SARS-CoV2 that might be long-lasting, unlike relatively short-lived humoral responses,” the investigators explained. “It is unclear if patients with immune deficiency can generate sufficient immunological memory allowing for future protection.”

Therefore, investigators from Columbia University Irving Medical Center in New York City aimed to understand the development of T-cell responses against SARS-CoV2 in HSCT recipients and patients with hematological malignancies who survived COVID-19; explored T-cell immunity against hCoVs that commonly affect HSCT recipients; and demonstrated the potential of developing universal, cross-reactive immunotherapies for coronaviruses including SARS-CoV2 and hCoVs.

They conducted a comprehensive analysis of T-cell responses against SARS CoV2 and hCoVs in peripheral blood samples from 12 patients after HSCT or with a blood cancer and documented COVID-19 history (COVID-positive, n = 8; COVID-negative, n = 4) as compared with 33 healthy donors with and without documented history of infection (COVID-positive, n = 11; COVID-negative, n = 22).

Of the 12 patients who were immunocompromised, 1 underwent chemotherapy for multiple myeloma, 1 for prostate cancer, and 10 patients had allogenic HSCT.

To gauge the immunocompetence, microculture priming and 14-day expansion strategy was used to stimulate peripheral blood mononuclear cells (PBMC) with overlapping peptide libraries (pepmixes) derived from spike 1 and 2, membrane and nucleocapsid from SARS-CoV2 and their counterparts from all 4 hCoVs. Expanded T cells were re-challenged with the pepmixes and tested for specific cytokine release by FACS, according to the poster.

The investigators saw discernable T-cell activity against SARS CoV2 antigens in healthy COVID-19 survivors, predominantly within the CD4-positive T-cell compartment. On the other hand, unexposed subjects who displayed good reactivity against hCoVs had significantly lower, more variable responses.

Of note, in the vulnerable population of patients, the investigators saw the same T-cell activity against the majority of SARS CoV2 antigens, “indicating that those subjects were highly capable of generating T-cell memory,” the investigators wrote.

“Furthermore, all tested patients also displayed potent responses against multiple antigens from common hCoVs. Marked cross-reactivity between hCoV antigens and their counterparts from SARS CoV2 was seen, especially [versus] previously unexplored membrane and nucleocapsid hCoV antigens.”

Moreover, COVID-19–positive individuals demonstrated a higher frequency of polyfunctional CD4-positive T cells and a higher presence of CD4-positive T-effector memory, or TEM, cells which also supports the ability to generate T-cell memory.

Lastly, hCoV-specific CD4-positive T-cells from both COVID-negative and -positive individuals responded against antigens from other hCoVs, and SARS CoV2, “suggesting that the generation of polyreactive CD4[-positive] T cells might be possible,” the researchers said.

Migliori E, Soni M, Assal A, et al. Robust T Cell Immunity Against SARS-CoV2 and Common Human Coronaviruses Emerges in Stem Cell Transplant Recipients and Patients with Hematological Malignancies Who Survived COVID-19. Presented at: 2021 Transplantation and Cellular Therapy Meeting. February 8-12, 2021; Virtual. Abstract LBA11.

Finding presented on patients with hematologic malignancies at the 2021 Transplantation and Cellular Therapy Meetings of ASTCT and CIBMTR show that patients who had undergone a hematopoietic stem cell transplantation can accumulate effective immunity against SARS-CoV2 infection and non-SARS human coronaviruses.

Stem Cells Achieve Potent Immunity Against SARS-CoV2 and Common Human Coronaviruses In Patients

Five-year follow-up results from the phase 2/3 KEYNOTE-010 study show that pembrolizumab (Keytruda) continued to achieve a clinically meaningful improvement in overall (OS) and progression-free survival (PFS), compared with docetaxel, in patients with previously treated, PD-L1–positive advanced non-small cell lung cancer (NSCLC).

The results were presented by Roy S. Herbst, MD, PhD, ensign professor of medicine and professor of pharmacology, chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital, and associate cancer center director for translational research, Yale Cancer Center during the 2020 World Conference on Lung Cancer Singapore.

“We continue to see a clinically meaningful improvement in OS and PFS. Five-year rates more than doubled in the pembrolizumab-treated patients for overall survival, compared with those receiving docetaxel,” Herbst, said during a virtual presentation of the follow-up results.

“Patients who completed 35 cycles or 2 years of experienced durable responses,” he added. The second course of pembrolizumab provided meaningful disease control. Incidents of any grades 3-5 treatment effects were lower with pembrolizumab versus docetaxel. Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated, PD-L1–positive advanced non-small cell lung cancer.”

Five-year median OS rates were more than doubled with pembrolizumab, compared with docetaxel, in patients with PD-L1 TPS ≥ 50% (25.0% vs 8.2%, respectively) and ≥ 1% (15.6% vs 6.5%). Median OS was superior with pembrolizumab, compared with docetaxel, in patients with PD-L1 TPS ≥ 50% (16.9 months [95% CI, 12.3-21.4] vs 8.2 months [95% CI, 6.4-9.8], respectively; HR, 0.55; 95% CI, 0.44-0.69) and ≥ 1% (11.8 months [95% CI, 10.4-13.1] vs 8.4 months [7.6-9.5]; HR, 0.70; 95% CI, 0.61-0.80).

Median PFS rates were also superior for those with PD-L1 TPS ≥ 50% (5.3 months [95% CI, 4.2-6.5] vs 4.2 months [95% CI, 3.8-5.1]; HR, 0.57; 95% CI, 0.46-0.71) and ≥ 1% (4.0 months [95% CI, 3.1-4.1] vs 4.1 months [95% CI, 3.8-4.5]; HR, 0.84; 95% CI, 0.73-0.96).

In addition, patients who completed 35 cycles or 2 years of treatment with pembrolizumab demonstrated durable clinical benefit, with an overall response rate (ORR) of 98.7%, including 15 complete responses (CRs) and 63 partial responses (PRs). In total, 61 patients (77.2%) were alive at the data cutoff, including 38 patients who were alive without progressive disease (PD). The 3-year OS rate after completing 35 cycles or 2 years was 83.0%.

Twenty-one patients received second-course pembrolizumab. Among those patients, 15 (71.4%) were alive at data cutoff. ORR after starting second-course pembrolizumab was 52.4%, including 1 CR, 10 PRS, and 6 patients with stable disease (SD). Eight patients with a CR, PR, or SD after starting second-course pembrolizumab subsequently had PD.

As of April 8, 2020, the median time from randomization to data cutoff was 67.4 months (range, 60.0-77.9).

In this follow-up analysis, treatment with pembrolizumab continued for 35 cycles (approximately 2 years) or until disease progression or unacceptable toxicity. The analysis included patients who completed pembrolizumab treatment or stopped pembrolizumab after achieving CR. Patients who received ≥6 months of treatment could receive a second course of pembrolizumab for up to 17 cycles (1 year) following disease progression after stopping pembrolizumab. Responses were assessed every 9 weeks, while survival was assessed every 2 months after treatment ended.

The primary end points of the follow-up study were OS and PFS in patients with PD-L1 TPS ≥50% and in those with PD-L1 TPS ≥1%. In the analysis, the pembrolizumab dose groups were pooled.

Previously reported results from the KEYNOTE-010 study (NCT01905657) showed that docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1% demonstrated a median OS of 10.4 months with 2 mg/kg pembrolizumab and 12.7 months with 10 mg/kg pembrolizumab, compared with 8.5 months with docetaxel.

OS was significantly longer in patients treated with 2 mg/kg, compared with docetaxel (HR, 0.71; 95% CI, 0.58-0.88), and in those treated with 10 mg/kg (HR, 0.61; 95% CI, 0.49-0.75; 

Those treated with 2 mg/kg and 10 mg/kg pembrolizumab showed a median PFS of 3.9 months and 4.0 months, respectively, compared with 4.0 months with docetaxel.

In patients with PD-L1 TPS ≥50%, OS was significantly longer with 2 mg/kg pembrolizumab, compared with docetaxel (14.9 months vs 8.2 months; HR, 0.54; 95% CI, 0.38-0.77; 

 = .0002) and with 10 mg/kg pembrolizumab (17.3 months vs 8.2 months; HR, 0.50; 0.36-0.70; 

 < .0001). PFS was also improved with 2 mg/kg (5.0 months vs 4.1 months; HR, 0.59; 95% CI, 0.44-0.78; 

 = .0001) and 10 mg/kg pembrolizumab (5.2 months vs 4.1 months; HR, 0.59; 95% CI, 0,45-0.78; 

Grade 3-5 treatment-related adverse events were less common with 2 mg/kg (13%) and 10 mg/kg (16%) pembrolizumab than with docetaxel (35%).

In the trial, patients with previously treated advanced NSCLC with PD-L1 TPS ≥1% and were randomized 1:1:1 to receive 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks (n = 690), or 75 mg/m2 docetaxel every 3 weeks (n = 343).

1. Herbst R, Garon E, Kim D, et al. 5-Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel in Previously Treated, PD-L1–Positive Advanced NSCLC. Presented at: 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract FP13.01.

2. Herbst R, Baas P, Kim D, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2015;387:10027. doi:10.10

Five years of follow-up in KEYNOTE-010 reveals that pembrolizumab can maintain improvement in survival over docetaxel in a non–small cell lung subgroup. 

Pembrolizumab Maintains Survival Improvement After 5 Years in PD-L1+ Advanced NSCLC

The use of pembrolizumab (Keytruda) monotherapy upfront demonstrated benefit with long-term outcomes compared with chemotherapy regimens in patients with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC), according to an updated analysis of the pivotal phase 3 KEYNOTE-177 trial.

In a presentation at the 2021 ASCO Gastrointestinal Cancers Symposium, Kai-Keen Shiu, FRCP, PhD, reported that pembrolizumab induced superior progression-free survival (PFS)2 and improved health-related quality of life (HRQoL) over chemotherapy with or without bevacizumab (Avastin) or cetuximab (Erbitux).

Pembrolizumab reduced the risk for progression on next-line therapy by 37% (HR, 0.63; 95% CI). Moreover, in the pembrolizumab arm, median PFS2 was not reached, compared with 23.5 months (range, 16.6-32.6) with chemotherapy. The 12- and 24-month PFS2 rates with pembrolizumab were 76% and 65%, respectively, compared with 67% and 50% with chemotherapy.

Patients treated with pembrolizumab monotherapy also experienced better HRQoL, including improvements in global health status/QOL, physical functioning, role functioning, emotional functioning, and social functioning, as well as improvements in symptoms like fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.

“[Data from this trial] support pembrolizumab as a new standard of care for first-line therapy in patients with MSI-high, mismatch repair deficient metastatic colorectal cancer,” Shiu, University College London Hospital and NHS Foundation Trust, said during a virtual presentation of the data. “We also look forward to upcoming studies both in the neoadjuvant and adjuvant setting.”

In the KEYNOTE-177 trial (NCT02563002), investigators randomized patients 1:1 to receive either 200 mg pembrolizumab every 3 weeks for up to 2 years (n = 153) or investigator’s choice of mFOLFOX6 (5-Fluorouracil, leucovorin, and oxaliplatin [Eloxatin]) or FOLFIRI (folinic acid, fluorouracil, and irinotecan) every 2 weeks, with or without bevacizumab or cetuximab (n = 154). Patients were treated until progression, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles with pembrolizumab only.

Patients in the chemotherapy arm could crossover to pembrolizumab treatment for up to 35 cycles after confirmed progressive disease.

Primary end points included PFS per RECIST v1.1, per blinded independent central review (BICR), and overall survival (OS). Secondary end points were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Duration of response (DOR) per RECIST v1.1 by BICR, PFS2, and HRQoL served as exploratory end points. In addition, tumor response per RECIST v1.1 by BICR was assessed at week 9 and every 9 weeks thereafter.

Data cutoff was February 19, 2020 and included 307 patients with locally-determined MSI-H/dMMR mCRC and an ECOG performance score of 0 or 1.

Patients treated with pembrolizumab monotherapy were a median age of 63 years (range, 24-93), and the majority were diagnosed with a right-sided tumor (n = 102) and had no prior systemic therapy (n = 115).

After a median follow-up of 32.4 months (range, 24.0-48.3), pembrolizumab demonstrated superior PFS (median, 16.5 months vs 8.2 months), compared with chemotherapy (HR, 0.60; 95% CI, 0.45-0.80; 

 = 0.0002). Moreover, the 12- and 24-month PFS rates were 55.3% and 48.3%, respectively, with frontline pembrolizumab monotherapy, compared with 37.3% and 18.6% with chemotherapy. By patient subgroup, PFS benefit with pembrolizumab was still seen regardless of age, gender, ECOG performance score, geographic region, stage, and tumor site.

Pembrolizumab also induced superior confirmed ORR ([43.8%; 95% CI, 35.8-52.0] vs [33.1%; 95% CI, 25.8-41.4]), compared with chemotherapy. With frontline pembrolizumab, 11.1% of patients experienced a complete response, 32.7% with a partial response, 20.9% with stable disease, and 29.4% with progressive disease, compared with 1.9%, 29.2%, 42.2%, and 12.3%, respectively, with chemotherapy.

DOR was not reached with pembrolizumab (median range, 2.3+ to 41.4+) versus 10.6 months (median range, 2.8 to 37.5+) with chemotherapy. The rates of response at 24 months or more were 83% and 35%, respectively, with pembrolizumab and chemotherapy. The median time to response was 2.2 months (range, 1.8-18.8) with pembrolizumab and 2.1 months (range, 1.7-24.9) with chemotherapy.

In total, 56 patients (36%) of those treated with chemotherapy crossed over to receive pembrolizumab after confirmed disease progression. In addition, 35 more patients in the chemotherapy arm received anti-PD-1/PD-L1 therapy outside of the study, inducing an effective crossover rate of 59% in the intent-to-treat population.

Fewer patients treated with pembrolizumab, compared with chemotherapy, experienced a grade 3 TRAE (22% vs 66%); however, 10% and 6%, respectively, discontinued treatment. TRAEs in the pembrolizumab and chemotherapy arms included diarrhea (25% vs 52%, respectively), fatigue (21% vs 44%), nausea (12% vs 55%), decreased appetite (8% vs 34%), stomatitis (5% vs 30%), alopecia (3% vs 20%), vomiting (3% vs 28%), decreased neutrophil count (1% vs 23%), neutropenia (0% vs 21%), and peripheral sensory neuropathy (0% vs 20%).

Grade 3 or higher immune-mediated AEs occurred in 9% of the pembrolizumab arm, compared with 2% in the chemotherapy arm. All grade immune-mediated AEs included hypothyroidism (12%), colitis (7%), hyperthyroidism (4%), pneumonitis (4%), adrenal insufficiency (3%), hepatitis (3%), infused reactions (2%), hypophysitis, myositis, nephritis, pancreatitis, severe skin reaction, thyroiditis, and Type 1 diabetes mellitus (1% each).

“We have a lot of work to do. We wait for the overall survival analysis of this trial eagerly later this year, because there's a lot of biomarker work we have to do. And I also think in a lot of upcoming trials, in the same setting, but also in the earlier setting, the agent will keep on giving us more answers. I think it's really important from a patient perspective looking at this data,” Shiu said in prerecorded commentary of the presentation.

“And then it's in our remit as clinicians to make sure that not only once they get access to therapy, we really think hard about making sure they get the best way and integrate that with the standard of care pathways and to make sure they get the best outcomes as demonstrated in this trial,” he added.

Shiu KK, Andre T, Kim TW, et al. KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium; January 15-17, 2021; Virtual. 

The use of pembrolizumab monotherapy upfront significantly improved progression-free survival while demonstrating superior safety, compared with chemotherapy, in patients with microsatellite-instability high/mismatch repair deficient metastatic colorectal cancer.

Kristie L. Kahl | Authors

Articles

Staging of Nonmetastatic Relapsed Prostate Cancer May Be Aided by PSMA-Directed PET Tracer

Stem Cells Achieve Potent Immunity Against SARS-CoV2 and Common Human Coronaviruses In Patients

Pembrolizumab Maintains Survival Improvement After 5 Years in PD-L1+ Advanced NSCLC

Long-Term Benefit of Pembrolizumab in MSI-H/dMMR mCRC Seen in PFS2, HRQoL