Kristie L. Kahl

Neoadjuvant nivolumab (Opdivo) added to chemotherapy lead to an improvement in pathological complete responses (pCR), compared with chemotherapy alone, as treatment of patients with resectable non-small cell lung cancer (NSCLC), according to data from the phase 3 CheckMate-816 trial presented at week 1 of the virtual AACR Annual Meeting 2021.

Moreover, the regimen did not decrease the ability to perform surgery. With this, the CheckMate-816 study (NCT02998528) is the first positive phase 3 trial demonstrating a significant improvement in pathologic response with neoadjuvant immunotherapy plus chemotherapy in resectable NSCLC.

“CheckMate-816 is the first phase 3 trial to show a benefit of neoadjuvant chemotherapy plus chemo and this has the potential to represent a new neoadjuvant treatment option for patients with early-stage, resectable non-small cell lung cancer,” Patrick Forde, MBBCh, associate professor, Sidney Kimmel Comprehensive Cancer Center and Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, said during a press conference held ahead of the meeting.

In the intent-to-treat (ITT) population, nivolumab plus chemotherapy increased the pCR rate to 24%, compared with 2.2% with chemotherapy alone (odds ratio [OR], 13.94; 99% CI, 3.49-55.75; 

 < .0001). Among patients with resection, patients treated with the combination regimen demonstrated a pCR rate of 30.5%, compared with 3.2% in patients who received chemotherapy only. Similarly, in patients with a primary tumor only among the ITT population, showed improved pCR with the combination treatment versus chemotherapy alone (25.7% vs 2.8%, respectively). In an exploratory analysis of the ITT population, the pCR rate with nivoumab plus chemotherapy was 20.4% (95% CI, 13.4-29.0).

Moreover, this improvement in pCR was consistent across subgroups, including disease stage (IB/II, 26.2% vs 4.8%, respectively; ≥IIIA, 23.0% vs 0.9%), NSCLC subtype, PD-L1 status (<1%, 16.7% vs 2.6%; ≥1%, 32.6% vs 2.2%), tumor mutational burden status (low, 22.4% vs 1.9%; high, 30.8% vs 2.7%), and gender.

Patients treated with nivolumab plus chemotherapy were also more likely to have circulating tumor DNA clearance (56% vs 34%, respectively), compared with chemotherapy alone, in particular between cycle 1 and cycle 3 of neoadjuvant therapy. “And indeed, those patients who did have ctDNA clearance appear to be more likely to have a pathological complete response at the time of surgery,” Forde added.

In addition, the combination regimen increased the major pathological response rate, defined as 10% or less viable tumor in the lung and lymph nodes, to 36.9%, compared with 8.9% in the chemotherapy alone arm. Pre-surgery objective response rate on imaging in the combination arm was 53.6%, compared with 37.4% in the chemotherapy arm, and radiographic down-staging rates were 30.7%, compared with 23.5%, respectively.

Lastly, 83.2% of patients who received nivolumab in addition to chemotherapy went on to receive definitive surgery, compared with 75.4% of patients in the chemotherapy arm.

Surgery was cancelled due to adverse events (AEs) in 2 patients in each arm (1% each) and due to disease progression in 12 patients (7%) in the combination arm and 17 patients (9%) in the chemotherapy alone arm. Grade 3 to 4 treatment-related AEs occurred in 33.5% vs 36.9%, respectively, and surgery-related AEs in 11.4% vs 14.8%.

“We know that neoadjuvant adjuvant chemotherapy is recommended for patients with resectable non-small cell lung cancer. However, the 5-year overall survival gain is only 5%,” explained Forde, adding that previous phase 2 studies demonstrated that neoadjuvant therapy with nivolumab, either as monotherapy or in combination with chemotherapy, demonstrated encouraging pCR rates.

Therefore, in the randomized, open-label phase 3 CheckMate-816 trial, investigators randomly assigned patients 1:1 to receive treatment with either 360 mg nivolumab every 3 weeks plus platinum-doublet chemotherapy (n = 179) every 3 weeks for 3 cycles or chemotherapy alone (n = 179) every 3 weeks for 3 cycles. Both regimens were followed by surgery within 6 weeks after treatment.

The primary end points were pCR, defined as no residual viable tumor in both the resected lung specimen and the sampled lymph nodes after surgery, by blinded independent pathological review (BIPR) and event-free survival (EFS) by blinded independent central review (BICR). Overall survival, major pathological response per BIPR, and time to death or distant metastases served as secondary end points. Key exploratory endpoints were objective response rate per BICR, and potential predictive biomarkers including PD-L1 and tumor mutational burden.

To be eligible, patients had to have clinical stage IB (≥ 4 cm) to IIIA resectable NSCLC, ECOG PS 0-1, and no known 

Forde noted that the study continues to mature for data from the EFS co-primary end point.

Forde PM, Spicer J, Lu S, et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial. Presented at: AACR Annual Meeting; April 10-15, 2021; Virtual. Abstract CT003.

Articles

Neoadjuvant nivolumab added to chemotherapy lead to an improvement in pathological complete responses, compared with chemotherapy alone, as treatment of patients with resectable non-small cell lung cancer.

Nivolumab/Chemotherapy Improves PCR as Neoadjuvant Treatment of Resectable NSCLC

No statistically significant difference was seen with the combination of olaparib (Lynparza) and cediranib compared to cediranib alone in patients with recurrent, metastatic or persistent endometrial cancer, according to data from the phase 2 NRG-GY012 trial presented at the 2021 SGO Virtual Annual Meeting on Women’s Cancer. 

“The progression-free survival observed in the ‘reference arm’ of cediranib was consistent with GOG 229 J and no new safety signals were identified. Olaparib was well tolerated but did not meet the primary end point. Based on the interim analysis the data monitoring committee recommended termination of this study arm,” B.J. Rimel, MD, assistant professor, obstetrics and gynecology, Cedars-Sinai Medical Center, said during a virtual presentation of the data.

In the randomized phase 2 NRG-GY012 trial, investigators randomized 109 women with recurrent endometrial cancer 1:1:1 to receive either oral cediranib monotherapy (30 mg daily; n = 34), oral olaparib monotherapy (300 mg twice daily; n = 39), or the combination of olaparib (300 mg twice daily) and cediranib (20 mg daily; n = 26) until disease progression.

Eligible patients had received at least 1 prior platinum-containing chemotherapy but no more than 2 prior lines of chemotherapy, had an ECOG PS of 2 or more; had well controlled blood pressure (≤ 140/90mmHg); and had no history of bowel obstruction in the last 3 months and were able to take oral medication. Prior treatment with biologic, hormonal, or immunotherapy was allowed. Moreover, patients were stratified by histology: serous versus endometrioid.

The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, and safety and toxicity.

Across the cediranib monotherapy, olaparib monotherapy, and combination arms, median age was 64.5 years (range, 41-79), 69 years (range, 58-86), and 65 years (range, 41-86), respectively. In total, 47 women (39.2%) had serous histology, 62 (51.7%) had endometrioid, and 8 (6.7%) had mixed histology. Rimel also noted that 12% of patients were non-White, most patients had only 1 prior chemotherapy, only about 10% of patients had prior immunotherapy, “but that reflects the time of the study conduct no doubt. And it should be noted that 50% of patients had prior radiation,” she said.

Median follow-up was 18.3 months. Patients underwent a median of 3 cediranib monotherapy cycles, 2 olaparib monotherapy cycles, and 3.5 cycles of the combination regimen.

Kaplan Meir estimated median PFS was 3.8 months for cediranib monotherapy, 2.0 months for olaparib monotherapy, and 5.5 months for the combination. When comparing cediranib versus olaparib, the one-sided 

 value stratified log rank test was 0.935 (HR, 1.45; 95% CI, 0.91-2.30). When comparing cediranib monotherapy with the combination regimen, it was 0.064 (HR, 0.7; (95% CI, 0.43- 1.14).

Across the cediranib monotherapy, olaparib monotherapy, and combination arms, progression was the reason for treatment discontinuation for 22 (55%), 33 (82.5%), and 17 (42.5%) patients, respectively, while adverse events led to discontinuation in 10 (25%), 5 (12.5%), and 10 (25%) patients.

No new safety signals were reported. The most common adverse events (AEs) across the cediranib monotherapy, olaparib monotherapy, and combination arms were hypertension (35.9% vs. 2.5% vs. 33.3%, respectively), diarrhea (17.9% vs. 0% vs. 2.6%), fatigue (10.3% vs. 0% vs. 20.5%), nausea (2.6% vs 0% vs. 5.1%), endocrine (2.6% vs. 0% vs. 5.1%), VTE (2.6% vs. 10% vs. 5.1%), anemia (2.6% vs. 12.5% vs. 2.6%), and febrile neutropenia (0% vs. 2.5% vs. 0%).

"Cediranib had more adverse events as anticipated and more withdrawals [from the trial],” Rimel said. “The data on withdrawals did not show a clear pattern with some patients withdrawing [because of] secondary social [issues] as well as quality of life issues.”

Four patients were still receiving the combination regimen at data cut-off.

Response rates to second-line chemotherapy for women with endometrial cancer is approximately 10% to 15%, Rimel noted, with an approximate PFS of 3 months. However, she added common genomic events like histology have suggested that targeting DNA repair could be an effective therapeutic strategy.

Cediranib, an oral multi-tyrosine kinase inhibitor, has previously demonstrated modest efficacy in patients with endometrial cancer, while olaparib, an oral PARP inhibitor, is approved in multiple settings for gynecologic malignancies.

“Potential synergy between these 2 agents and prior data suggests the combination may be active and tolerable in the treatment of endometrial cancer,” Rimel said.

She added that integrated biomarker analysis is in progress for the trial, which has been amended to include an additional 4 arms of study: retaining cediranib as the reference arm, olaparib plus capivasertib, olaparib plus durvalumab, and cediranib plus durvalumab.

Rimel BJ. A Randomized, Phase II Study Comparing Single-Agent Olaparib, Single Agent Cediranib, and the Combination of Cediranib/Olaparib in Women with Recurrent, Persistent or Metastatic Endometrial Cancer. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 21, 2021; Virtual. Abstract 11636.

No statistically significant difference was seen with the combination of olaparib and cediranib compared to cediranib alone in patients with recurrent, metastatic or persistent endometrial cancer.

Superior Efficacy Not Induced by the Addition of Olaparib to Cediranib in Advanced Endometrial Cancer

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.

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.

Kristie L. Kahl | Authors

Articles

Nivolumab/Chemotherapy Improves PCR as Neoadjuvant Treatment of Resectable NSCLC

Superior Efficacy Not Induced by the Addition of Olaparib to Cediranib in Advanced Endometrial Cancer

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