The addition of tucatinib (Tukysa) to trastuzumab (Herceptin) and capecitabine has continued to demonstrate an overall survival (OS) benefit compared with trastuzumab/capecitabine alone in patients with HER2-positive metastatic breast cancer who have stable or active brain metastases, according to updated results from the pivotal phase 2 HER2CLIMB trial (NCT02614794).

Updated data, which were presented during the 2021 San Antonio Breast Cancer Symposium, showed that after a median follow-up of 29.6 months, the tucatinib triplet demonstrated a median OS of 21.6 months (95% CI, 18.1-28.5) vs 12.5 months (95% CI, 11.2-16.9) with trastuzumab and capecitabine alone in patients with active and stable brain metastases (n = 291; HR, 0.60; 95% CI, 0.44-0.81).

Among patients with active brain metastases (n = 174), the addition of tucatinib resulted in a median OS of 21.4 months (95% CI, 18.1-28.9) vs 11.8 months (95% CI, 10.3-15.2) with trastuzumab and capecitabine alone (HR, 0.52; 95% CI, 0.36-0.77). Additionally, in those with stable brain metastases (n = 117) a median OS of 21.6 months (95% CI, 15.3-42.4) was experienced by those in the tucatinib arm vs 16.4 months (95% CI, 10.6-21.6) by those in the placebo arm (HR, 0.70; 95% CI, 0.42-1.16).

“The risk of breast cancer spreading to the brain is more pronounced for patients with aggressive subtypes of breast cancer, including HER2-positive breast cancer,” Nancy U. Lin, MD, director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, stated in a press release. “These analyses provide a hopeful outcome for patients with HER2-positive metastatic breast cancer when cancer has spread to the brain, as they show that the tucatinib regimen not only helped patients live longer but also slowed disease progression in the brain.”

Tucatinib is an oral TKI of the HER2 protein. In vitro, the agent has been shown to inhibit phosphorylation of HER2 and HER3, which has led to the inhibition of downstream MAPK and AKT signaling and cell growth. The agent has also demonstrated antitumor activity in HER2-expressing tumor cells. Tucatinib has also been found to inhibit the growth of HER2-expressing tumors in vivo. When paired with trastuzumab, the regimen increased antitumor activity in vitro, as well as in vivo vs either agent alone.

Currently, tucatinib is approved for use in 36 countries. In April 2020, the 

FDA gave the green light to tucatinib for use in combination with trastuzumab and capecitabine

 in the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, following at least 1 previous anti-HER2­­­–based regimen in the metastatic setting.3 The regulatory decision was supported by data from HER2CLIMB.

The multinational, randomized, double-blind, placebo-controlled, active comparator, pivotal clinical trial randomized 612 patients 2:1 to receive either oral tucatinib at a twice-daily dose of 300 mg plus intravenous trastuzumab at a loading dose of 8 mg/kg on day 1 of cycle 1 followed by 6 mg/kg every 3 weeks and oral capecitabine at a twice-daily dose of 1000 mg/m2 on days 1 through 14 of each 21-day cycle (n = 410), or placebo plus trastuzumab/capecitabine (n = 202).

To be eligible for enrollment, patients needed to have unresectable, locally advanced or metastatic HER2-positive breast cancer and have previously been treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). Patients needed to have an ECOG performance status of 0 or 1 and a brain MRI at baseline.

Notably, patients with treated, stable brain metastases, untreated metastases that did not require immediate treatment, previously treated progressing metastases that do not require immediate therapy, and those with no evidence of brain metastases were all eligible to participate.

The primary end point of the trial was progression-free survival (PFS) per RECIST v1.1 criteria and blinded independent central review (BICR). Secondary end points included OS and PFS in patients with metastases and confirmed OS in those with measurable disease.

Additional updated data indicated that those with stable and active brain metastases who received the addition of tucatinib experienced an improvement in median central nervous system (CNS)-PFS compared with trastuzumab/capecitabine alone, at 9.9 months (95% CI, 8.4-11.7) and 4.2 months (95% CI, 3.6-5.7), respectively (HR. 0.39; 95% CI, 0.27-0.56).

Moreover, the median CNS-PFS for those with active brain metastases was 9.6 months (95% CI, 7.6-11.1) vs 4.0 months (95% CI, 2.9-5.6) in the tucatinib and placebo arms, respectively (HR, 0.34; 95% CI, 0.22-0.54). Furthermore, those with stable brain metastases experienced a median CNS-PFS of 13.9 months (95% CI, 9.7-24.9) with the tucatinib triplet vs 5.6 months (95% CI, 3.0–not evaluable) with trastuzumab/capecitabine (HR, 0.41; 95% CI, 0.19-0.85).

In terms of safety, serious adverse effects (AEs) occurred in 26% of patients in the tucatinib arm. Serious AEs that experienced by 2% or more of patients who received tucatinib included diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal AEs were reported in 2% of patients who received tucatinib, and included sudden death, sepsis, dehydration, and cardiogenic shock.

Furthermore, AEs led to treatment discontinuation in 6% of patients on the tucatinib arm. Those that occurred in 1% or more patients were hepatotoxicity (1.5%) and diarrhea (1%). AEs that required dose reductions were reported in 21% of patients treated with the agent and included hepatotoxicity (8%) and diarrhea (6%).

Overall, the most common AEs experienced by patients who received tucatinib were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Seagen announces updated results from pivotal HER2CLIMB trial evaluating TUKYSA® (tucatinib) in patients with HER2-positive breast cancer with brain metastases. News release. Seagen Inc; December 8, 2021. Accessed December 20, 2021. 

Lin NU, Murthy RK, Abramson V, et al. Tucatinib vs placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; virtual. Abstract 858.

FDA approves first new drug under international collaboration, a treatment option for patients with HER2-positive metastatic breast cancer. News release. FDA; April 17, 2020. Accessed December 20, 2021.

This article was originally published on OncLive as “Tucatinib Triplet Maintains OS Benefit in HER2+ Breast Cancer With Brain Metastases”

Articles

A triplet regimen of tucatinib, trastuzumab, and capecitabine helped patients with HER2-positive metastatic breast cancer and brain metastases live longer with reduced disease progression compared with trastuzumab and capecitabine alone. 

Patients With HER2+ Breast Cancer and Brain Metastases Achieve Better OS With Tucatinib Triplet Regimen

Patients with liver-only metastatic colorectal cancer (CRC) who received adjuvant chemotherapy with modified fluoropyrimidine, leucovorin, and oxaliplatin (mFOLFOX6) in addition to hepatectomy achieved superior rates of disease-free survival (DFS), according to updated results from a phase 2/3 trial (JCOG0603) published in the 

 However, more research is needed to determine how these findings will translate into overall survival outcomes.

At a median follow-up of 59.2 months (range, 26.5-95.3), the updated 5-year DFS rate was 49.8% (95% CI, 41.0%-58.0%) with mFOLFOX6 vs 38.7% (95% CI, 30.4%-46.8%) with hepatectomy alone (HR, 0.67; 95% CI, 0.50-0.92; 

 = .006). However, adjuvant mFOLFOX6 resulted in an updated 5-year OS rate of 71.2% (95% CI, 61.7% to 78.8%) vs 83.1% (95% CI, 74.9% to 88.9%) with hepatectomy alone.

“Adjuvant chemotherapy with mFOLFOX6 improves DFS compared with hepatectomy alone but causes severe adverse effects [AEs] in approximately half of the patients,” lead study author Yukihide Kanemitsu, MD, of the National Cancer Center, and colleagues, wrote. “Further follow-up and study are needed to determine whether improved DFS translates into improved OS. At this point, routine use of adjuvant FOLFOX is not universally recommended after hepatectomy for liver-only metastatic CRC.”

Hepatectomy is currently considered to be the most effective therapeutic approach for patients with liver-only metastatic CRC, as long-term survival is often unachievable with other treatment modalities. However, hepatectomy alone does not always result in complete cure. Moreover, relapse occurs in 70% to 80% of patients at 5 years—even after curative resection.

In prior studies, post-hepatectomy adjuvant chemotherapy was found to improve DFS, but determining the OS benefit derived from this approach continues to be controversial. The current recommendations for adjuvant regimens of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were extrapolated from the EORTC Intergroup trial 40983 (NCT00006479), which demonstrated that perioperative FOLFOX resulted in a progression-free survival benefit, but not an OS benefit.

In this trial, investigators sought to examine the safety and efficacy of post-hepatectomy, adjuvant FOLFOX compared with hepatectomy alone for patients with liver-only metastatic CRC.

The trial enrolled patients between the ages of 20 and 75 years who had histologically confirmed, liver-only metastatic CRC. To be eligible for participation, patients had to have an R0 resection for both the primary tumor and liver metastasis, an ECOG performance status of 0 or 1, and sufficient organ function.

Patients could not have extrahepatic metastasis or recurrence, nor could they have received prior chemotherapy with oxaliplatin or other chemotherapy or radiotherapy within 3 months of enrollment. Prior adjuvant therapy without oxaliplatin following primary resection was permitted if more than 3 months had passed since the last administration.

A total of 300 participants were randomly assigned in a 1:1 fashion to receive adjuvant chemotherapy (n = 151; eligible, n = 146) or hepatectomy alone (n = 149; eligible, n = 137) via a minimization method with a random component to balance the arms on the basis of liver metastatic status (synchronous vs metachronous), number of liver metastases (≤ 3 or ≥ 4), maximum liver metastatic lesion size (< 5 cm vs ≥ 5 cm), number of metastatic lymph nodes from the primary lesion (≤ 3 vs ≥ 4), and institution.

In the adjuvant chemotherapy arm, mFOLFOX6 was initiated 56 to 84 days following hepatectomy; this course was repeated every 2 weeks for 12 courses until progressive disease or intolerable toxicity.

Treatment was discontinued if recurrence was diagnosed clinically or based on imaging findings. Discontinuation was also elected if a serious AE occurred, if the treatment course was delayed for more than 28 days because of an AE, if a third dose reduction because of AEs was required, if the patient declined treatment, or if judged necessary by the attending physician for other reasons.

The primary end point of the trial was DFS, and the key secondary end points included OS, incidence of AEs, and patterns of recurrence.

Patient characteristics were well balanced between the treatment arms. The median age of the hepatectomy-alone group was 65 years (range, 58-69) compared with 63 years (range, 56-69) in the mFOLFOX6 group. In the investigative and control arms, 83% and 81% of patients, respectively, had 0 to 3 metastatic lymph nodes from the primary tumor and 17% and 19% of patients, respectively, had 4 or more nodes.

Regarding the number of liver metastases, 91% of patients in the hepatectomy-alone arm had 1 to 3, as did 90% of those in the chemotherapy arm; 9% and 10% of patients, respectively, had 4 or more. Moreover, in the control and investigative arms, 55% and 56% of patients, respectively, had synchronous liver metastasis, and 45% and 44% of patients, respectively, had metachronous liver metastasis. The maximum liver metastatic lesion size was less than 5 cm in 87% and 85% of patients, respectively; it was 5 cm or larger in 13% and 15% of patients, respectively.

In the chemotherapy arm, 85 patients (56%) completed the 9 courses of mFOLFOX6, and 67 (44%) completed the planned 12 courses. Additionally, 10 patients (7%) did not start treatment and were excluded from the safety analysis.

Additional data showed that the 3-year DFS rates with chemotherapy and hepatectomy-alone were 52.7% (95% CI, 44.0%-60.7%) and 42.6% (95% CI, 34.3%-50.6%), respectively. The 3-year OS rates in the investigative and control arms were 87.2% (95% CI, 80.2%-91.9%) and 91.8% (95% CI, 85.7%-95.4%), respectively.

DFS subgroup analyses revealed an advantage with chemotherapy over hepatectomy alone except primary site and prior treatment received. In contrast, OS subgroup analyses indicated that no subsets derived benefit from chemotherapy. Another observation was that those who received adjuvant chemotherapy without oxaliplatin following primary resection experienced poorer prognosis than those who did not have prior treatment.

“There was a tendency for an interaction between primary site and treatment for DFS and between prior treatment and treatment for OS,” the study authors noted.

Additionally, more patients who received hepatectomy alone experienced disease recurrence vs those who received chemotherapy, at 56% and 45%, respectively. Recurrence in the remnant liver proved to be more prevalent in the control arm vs the investigative arm, at 51% and 37%, respectively. However, recurrence in the lungs and other distant metastasis proved to be more prevalent in the investigative arm vs the control arm, at 63% and 48%, respectively.

In terms of safety, the most common grade 3 or higher severe AEs in the chemotherapy arm (n = 141) were neutropenia (50%), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after receiving 3 courses of mFOLFOX6.

“A future prospective randomized study is needed to investigate the role of biomarkers in determining subgroups that might benefit from chemotherapy after hepatectomy for liver-only metastatic CRC,” the study authors concluded.

Kanemitsu Y, Shimizu Y, Mizusawa J, et al. Hepatectomy followed by mFOLFOX6 versus hepatectomy alone for liver-only metastatic colorectal cancer (JCOG0603): a phase II or III randomized controlled trial. 

. 2021;39(34):3789-3799. doi:10.1200/JCO.21.01032

Kemeny N. The management of resectable and unresectable liver metastases from colorectal cancer. 

. 2010;22(4):364-73. doi:10.1097/CCO.0b013e32833a6c8a

Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. 

. 2013;14(12):1208-1215. doi:10.1016/S1470-2045(13)70447-9

Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. 

. 2008;371(9617):1007-1016. doi:10.1016/S0140-6736(08)60455-9

This article was originally published on OncLive as “Hepatectomy Plus Adjuvant mFOLFOX6 Improves DFS in Liver-Only Metastatic CRC”

Disease-free survival in liver-only metastatic CRC was significantly improved by introducing adjuvant mFOLFOX6 chemotherapy to hepatectomy

Adjuvant mFOLFOX6 Increases Hepatectomy Efficacy, Improves DFS in Liver-Only Metastatic CRC

Patients with platinum-resistant epithelial ovarian cancer experienced elevated responses to pembrolizumab (Keytruda) following the addition of a short-term, flat dose of bevacizumab (Avastin) to the anti–PD-1 therapy, according to results from the phase 1 PEMBOV trial (NCT03596281) that were presented during the 2021 SITC Annual Meeting.

Results from the study showed that among the 19 patients enrolled, the combination yielded an overall response rate (ORR) of 26%; this was comprised of 1 complete response (CR; 5%) and 4 partial responses (PRs; 21%). Additionally, the disease control rate (DCR) with the doublet was 79%.

For patients with platinum-resistant ovarian cancer, there is an unmet medical need for more efficacious treatment options.

Previously, the phase 3 AURELIA trial (NCT00976911) examined the combination of chemotherapy and bevacizumab in platinum-resistant patients who were bevacizumab naïve and had received a maximum of 2 prior treatment regimens. Results showed that the median progression-free survival (PFS) was 3.4 months in those treated with chemotherapy vs 6.7 months in those who received the combination. Moreover, the ORRs reported in each group were 11.8% and 27.3%, respectively.

Bevacizumab monotherapy has been shown to induce a median PFS of 4.4 months and an ORR of 15.9% in this patient population.

 Anti–PD-1/PD-L1 monotherapies have been shown to elicit ORRs ranging from 3.7% to 15.0%, and a median PFS ranging from 1.9 months to 3.5 months. The addition of chemotherapy to these agents appears to slightly improve outcomes, with ORRs ranging from 13.3% to 23.0%, and a median PFS ranging from 3.7 months to 8.1 months.

Prior phase 2 trials have also examined the combination of anti­–PD-L1 therapy and PARP inhibitors, a regimen that has been shown to elicit an ORR of 14.0% and a median PFS of 3.9 months,

 as well as anti­–PD-L1 therapy, PARP inhibition, and bevacizumab, a triplet which yielded an ORR of 28.0% and a median PFS of 4.1 months.

Additionally, phase 1b/2 trials have previously examined pembrolizumab in combination with bevacizumab and chemotherapy. When pembrolizumab and bevacizumab were paired with pegylated liposomal doxorubicin (PLD), the regimen yielded an ORR of 32.0%.

 When the 2 agents were combined with cyclophosphamide, the regimen induced an ORR of 43.3% and a median PFS of 7.6 months.

Prior phase 2 clinical trials have investigated the combination of an anti–PD-1 blockade plus an anti–CTLA-4 blockade. Results from these trials have showed that this approach can produce an ORR of 31.4% and a median PFS of 3.9 months.

The PEMBOV study enrolled patients with platinum-resistant epithelial ovarian cancer. There was no limit to the number of previous treatments patients could have received, and prior treatment with bevacizumab was permitted.

The study was comprised of 2 cohorts. Patients in cohort A received pembrolizumab plus PLD, and those in cohort B were given pembrolizumab plus bevacizumab. Here, investigators reported data from cohort B of the study.

Patients enrolled to cohort B received 200 mg of pembrolizumab once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent, and 400 mg of bevacizumab every 3 weeks for 6 cycles.

The primary end point of the study was best overall response (BOR) per RECIST v1.1 criteria, and duration of response (DOR). Secondary end points included safety and tolerability, and key exploratory objectives were to examine PD-L1 status and the pharmacokinetics of bevacizumab.

Among the 19 patients enrolled, the median age was 70 years (range, 38-76), and most had an ECOG performance status of 0 (52.6%) with the ovary as their primary tumor location (79%). Additionally, most patients had serous high-grade disease (95%) and had received prior antiangiogenic therapy (68%). Sixteen percent of patients had a 

 mutation, and 47% had received prior treatment with PARP inhibitors. Moreover, 95% of patients had received 2 or more prior chemotherapy regimens.

The median follow-up time was 7.6 months (95% CI, 6.7-19.5), with a minimum of 2.9 months and a maximum of 29.0 months. Time to progression (TTP) was not reached for 26.0% of patients (n = 5/19), and 42.0% of patients (n= 8/18) had a TTP that was 24 weeks or more.

For patients who had a PD-L1 combined positive score (CPS) of 10% or higher (n = 4), the ORR with the regimen was 50%; this was comprised of 2 PRs, and 1 patient had stable disease. Among those with a PD-L1 CPS of 1% or higher (n = 10), the ORR was 30%, which was comprised of 3 PRs and 4 patients achieved stable disease. For patients with a PD-L1 CPS of 1% or lower (n = 8), the ORR was 25%, and this was comprised of 1 CR, 1 PR, and 6 patients with stable disease.

In terms of safety, grade 3/4 treatment-related adverse effects (TRAEs) were reported in 20% of patients. The most common grade 3/4 TRAEs were cerebral ischemia (5%), sepsis (5%), bowel proliferation (5%), and proteinuria (5%).

No new safety signals were observed on the study, and correlative studies are ongoing.

Michels J, Frenel J-S, Genestie C, et al. Pembrolizumab and bevacizumab in platinum resistant epithelial ovarian cancer patients. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 355.

Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. 

. 2014;32(13):1302-1308. doi:10.1200/JCO.2013.51.4489

Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. 

. 2007;25(33):5180-6. doi:10.1200/JCO.2007.12.0782

Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. 

. 2015;33(34):4015-4022. doi:10.1200/JCO.2015.62.3397

Disis ML, Taylor MH, Kelly K, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial. 

. 2019;5(3):393-401. doi:10.1001/jamaoncol.2018.6258

Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. 

. 2019;30(7):1080-1087. doi:10.1093/annonc/mdz135

Pujade-Lauraine E, Fujiwarab K, Ledermannc JA, et al. Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: Primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial. Presented at: 50th Annual Meeting of the Society of Gynecologic Oncology; March 16-19, 2019. Honolulu, HI.

Lee EK, Xiong N, Cheng S-C, et al. Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: a phase 2 clinical trial. 

. 2020;159(1):72-78. doi:10.1016/j.ygyno.2020.07.028

Lampert EJ, Zimmer A, Padget M, et al. Combination of PARP inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian cancer: a proof-of-concept phase II study. 

. 2020;26(16):4268-4279. doi:10.1158/1078-0432.CCR-20-0056

Freyer G, Floquet A, Tredan O, et al. 733P Bevacizumab (bev), olaparib (ola) and durvalumab (durva) in patients with recurrent advanced ovarian cancer (AOC): the GINECO BOLD study. 

. 2021;32(5):S734-S735. Doi:10.1016/j.annonc.2021.08.1176

Michels J, Ghiringhelli F, Frenel J-S, et al. Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer. 

. 2021;39(15):5522. Doi:10.1200/JCO.2021.39.15_suppl.5522

Zsiros E, Lynam S, Attwood K, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial

. 2021;7(1):78-85. Doi:10.1001/jamaoncol.2020.5945

Zamarin D, Burger RA, Sill MW, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG oncology study. 

. 2020;38(16):1814-1823. Doi:10.1200/JCO.19.02059

Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with ovarian cancer (PEMBOV). ClinicalTrials.gov. Updated July 22, 2021. Accessed November 17, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03596281

This article was originally published on OncLive as “Addition of Bevacizumab to Pembrolizumab Improves Responses in Epithelial Ovarian Cancer.”

The addition of bevacizumab was found to boost responses in patients with epithelial ovarian cancer receiving pembrolizumab. 

Adding Bevacizumab to Pembrolizumab Enhances Response Rates in Epithelial Ovarian Cancer

Patients with soft tissue sarcoma who received NBTXR3 in addition to radiotherapy did not experience negatively affected quality of life (QOL) or long-term morbidity. Moreover, the drug’s efficacy, along with its manageable safety profile, point to a favorable risk-benefit ratio for patients with soft tissue sarcoma, explained Sylvie Bonvalot, MD, PhD, HDR.

Results from a long-term safety analysis of the phase 2/3 Act.In.Sarc trial (NCT02379845), which examined NBTXR3 plus radiotherapy vs radiotherapy alone in patients with soft tissue sarcoma, showed that the rate of serious adverse effects [AEs] were similar among the 2 cohorts.

 Among those receiving the combination, 40.4% of patients reported a serious AE of any grade vs 35.8% in those receiving radiotherapy alone. Additionally, 12.4% of patients reported a serious AE related to treatment with NBTXR3.

“The qualityoflife, which was [assessed] by 5 different quality-of-life skills, was the same, with no differences [among the study groups],” Bonvalot said. “Altogether, it is interesting because it is very important that treatment is efficient, [but also that we can] show that with long-term follow-up, we do not have more morbidity or worse quality of life.”

, Bonvalot, the head of sarcoma surgery at Institut Curie, in Paris, France, discussed the long-term safety results from the phase 2/3 Act.In.Sarc trial with NBTXR3 and radiotherapy in patients with soft tissue sarcoma.

: Could you discuss the rationale for this study?

: NBTXR3 is a hafnium oxide nanoparticle, and it is activated by radiotherapy and administered by a one-time direct intratumoral injection. It was used for the first time in sarcoma, and sarcoma is the first cancer subtype to achieve a phase 2/3 [trial with this agent]. The interaction of radiotherapy with hafnium generates [approximately 9 times more] electrons than with water. [Moreover], these electrons increase the toxicity on the tumor cells, and there is more [tumor cell death] when radiotherapy interacts with hafnium.

What previous data have been seen to support the use of this strategy?

 showing the] initial results of the primary end point of a phase 2/3, randomized study comparing radiotherapy alone vs radiotherapy plus nanoparticles of hafnium NBTXR3. NBTXR3 was injected the day before starting radiotherapy, directly into the tumor. The radiotherapy was applied 50 Gy, and the patient was operated on 6 weeks later. The primary end point was pathologic complete response [pCR]. It is difficult to appreciate pathological response for soft tissue sarcoma because the tumor may decrease in size, however, this was done according to EORTC guidelines.

The main objective was pCR, and in the group of patients [who received] the nanoparticles and radiotherapy, the CR rate was 16%. In the group who had radiotherapy alone, the pCR rate was 9.9%, so…the primary end point was achieved. Another end point was the R0 resection rate, and there was a 77% [R0 rate in the group with NBTXR3 vs 64% in the group with radiotherapy alone]. It was significant, and in fact, the quality of the resection was better in the group with nanoparticles.

The [data] we presented this year at ASCO is the long-term safety of this study. It is very important because it is very promising to have nanoparticles, which increase the rate of pCR, but it is important to show that there is not an increase of toxicity.

Could you highlight the design of the study?

The morbidity of the surgery was quantified during the 6 months following, and the quality of life was quantified according to 5 different [parameters]. As these nanoparticles are now used in other cancer types, especially [in those where] radiotherapy is used alone, it is important to be sure that the safety is okay and that there is not [increased] morbidity. [This is] especially important when [these drugs are] used in tissue that are fragile, like the pancreas or liver.

What were the key takeaways from the trial?

The [rates of] serious adverse effects [AEs] related to radiotherapy were similar in both groups, with 11% in the group with nanoparticles and 13% in the group of patients treated with radiotherapy alone. In terms of hospitalization due to serious AE related to the surgery, in the group with the nanoparticles, 15.7% of the patients were re-hospitalized, [compared with 24% in] the group with radiotherapy alone. This is interesting because in previous studies, grade 3 morbidity, hospitalization, or reoperation due to radiotherapy is approximately 30%. [Here], it is a little bit less. Of course, it is a trial, and the patients were selected, but is less than previously [reported]. [Additionally] there was a little bit less in the group with nanoparticles.

Bonvalot S, Rutowski P, Thariat J, et al. Long-term evaluation of the novel radioenhancer NBTXR3 plus radiotherapy in patients with locally advanced soft tissue sarcoma treated in the phase II/III Act.In.Sarc trial. 

. 2021;39(15):11544. doi:10.1200/JCO.2021.39.15_suppl.11544

This article was originally published on OncLive as “NBTXR3 Plus Radiotherapy Maintains Safety, Quality of Life in Soft Tissue Sarcoma”

An expert from the Institut Curie discusses the risk-benefit ratio associated with NBTXR3 plus radiotherapy for the treatment of patients with soft tissue sarcoma.

NBTXR3 Plus Radiotherapy Does Not Negatively Affect Quality of Life in Soft Tissue Sarcoma

The mRNA COVID-19 vaccines may be less effective in patients with lymphoid malignancies, especially patients who have received anti-CD20 antibody therapies. Therefore, this patient population is advised to continue to take precautionary measures against COVID-19 infection, regardless of vaccination status, according to results from a study published in 

Results showed that among 6 patients who had received anti-CD20 antibody therapy within 12 months of vaccination, none mounted an antibody response to COVID-19 following both doses of the mRNA vaccines.

“Our findings suggest that patients with lymphoid cancers who have been vaccinated for COVID-19 should not assume they have immunity against the disease,” lead study author Jennifer Crombie, MD, a physician at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, stated in a press release. “Patients should continue to be vigilant against becoming infected.”

Patients with lymphoid malignancies are not only at increased risk for developing COVID-19, but also at higher risk for experiencing poor outcomes. Additionally, in prior studies examining patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), recent anti-CD20 antibody therapy was associated with decreased humoral responses to the mRNA COVID-19 vaccines. Moreover, although patients on these studies who were treatment naïve were more likely to develop a humoral response to the vaccines, rates of humoral responses were still significantly lower in these patients compared with healthy controls.

In the prospective study by Crombie and colleagues, investigators sought to evaluate serologic response following vaccination with both the Pfizer-BioNTech COVID-19 vaccine (previously referred to as BNT152b2; Comirnaty), as well as the mRNA-1273 vaccine, in patients with key lymphoid malignancies.

Patients with lymphoid malignancies who planned to receive 1 of the mRNA COVID-19 vaccines were eligible to enroll on the study. Patients who had received prior chimeric antigen receptor T-cell therapy or autologous stem cell transplant received their vaccine at least 3 months after completing the cellular therapy. All other patients were vaccinated based on their own preference or that of their provider.

Healthy controls for the study were adult healthcare workers from Brigham and Women’s Hospital who had no prior history of COVID-19 infection.

Investigators collected blood samples at 3 time points: before first dose of the vaccine, at the time of second dose, and then 28 days after second vaccine dose. Overall, 23 patients on the study received both dose of the vaccine and 21 completed all planned blood draws at the 3 time points.

Of the 23 patients enrolled, 14 had CLL (61%), 3 had diffuse large B-cell lymphoma (13%), 3 had mantle cell lymphoma (13%), 1 had follicular lymphoma (4%), 1 had marginal zone lymphoma (4%), and 1 had Hodgkin lymphoma (4%). The median age for patients enrolled on the study was 69 years (range, 30-82) compared with 24 years (range, 22-56) for the control group. Fifty-seven percent of participants in both groups were female and 70% of patients received the Pfizer-BioNTech vaccine.

Eleven patients were actively receiving treatment (48%), 6 had received prior treatment (26%), and 6 were treatment naïve (26%). Moreover, the median number of prior treatments received by patients was 1 (range, 0-3).

Fifteen patients had received prior treatment with an anti-CD20 antibody therapy (65%), 6 of whom had received this treatment within the previous 12 months and 9 of whom received it more than 12 months prior. Eight patients had received no prior anti-CD20 antibody therapy.

At baseline, no patients had detectable anti-nucleocapsid immunoglobulin G, which implied no prior infection with COVID-19. Additionally, although anti-spike immunoglobulin G titers were similar among patients with lymphoid malignancies and healthy volunteers at baseline (

 = .66), the magnitude was lower at the time of the second vaccine dose (

 = .0001) and 28 days after vaccination (

 = .001) among the lymphoid malignancy cohort.

Additional data showed that 2 patients who underwent prior anti-CD20 antibody therapy within 12 months were able to develop anti-spike immunoglobulin G titers above the study’s predetermined threshold. However, both of those patients had also received the therapy more than 12 months before vaccination as well.

Moreover, all treatment-naïve patients enrolled on the study (n = 6) had developed anti-spike immunoglobulin G titers by the 28 days threshold after vaccination.

“Patients with lymphoid malignancies should not be assumed to be protected from vaccination and should remain maximally prudent to avoid infection,” study authors wrote. “Conversely, our findings suggest that humoral response can be seen following cytotoxic chemotherapy, in patients receiving anti-CD19–directed cellular therapy, and among patients who have not received prior therapy, even with CLL.”

Crombie JL, Sherman AC, Cheng C, et al. Activity of mRNA COVID-19 vaccines in patients with lymphoid malignancies. 

. 2021;5(16):3062-3065. doi:10.1182/bloodadvances.2021005328

Study sounds note of caution on effectiveness of COVID-19 vaccines for patients with lymphoid malignancies. News release. Dana-Farber Cancer Institute. August 23, 2021. Accessed August 24, 2021. 

Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. 

. 2021;137(23):3165-3173. doi:10.1182/blood.2021011568

This article was originally published on OncLive as “mRNA COVID-19 Vaccines May Decrease Efficacy in Lymphoid Malignancies”

Physicians urge patients with lymphoid malignancies to continue precautionary COVID-19 measures regardless of vaccination status. 

COVID-19 Vaccines May Be Less Effective in Patients with Lymphoid Malignancies

The driving force behind oncologist and hematologist burnout during the COVID-19 pandemic was the loss of in-person patient interaction, revealed data from a study presented at the 2021 ASCO Quality Care Symposium.

 Although income-related concerns also contributed to a decrease in professional satisfaction, this factor was ranked second in importance.

Results showed that among 259 community oncologists and hematologists surveyed, 46% attributed the loss of in-person patient interaction as factor contributing to their feelings of burnout compared with 42% citing practice financial loss. Moreover, 50% of those surveyed reported that they experienced more burnout at work since the COVID-19 pandemic began (36% agreed, 14% strongly agreed).

“Given the high baseline rate of burnout among these physicians, it remains critical to prevent, mitigate, and control additional risks [created by] pandemic-related factors,” lead study author Ajeet Gajra, MD, FACP, a clinical professor of medicine at Upstate Medical University, said in a presentation of the data.

About one-third (31%) of respondents neither agreed nor disagreed that they experienced more burnout at work since the COVID-19. Sixteen percent disagreed with the question, and 3% strongly disagreed.

The COVID-19 pandemic has had a significant impact on healthcare workers globally. Investigators have observed higher than normal rates of burnout have been reported, especially among frontline workers. Organizations such as ASCO have attempted to assess the impact of the pandemic on oncologists in the United States, but further research is needed to understand the full impact community oncologists and hematologists, as these groups experiences several unique challenges.

In this study, investigators sought to assess the impact of the pandemic among community oncologists and hematologists in the United States prior to widespread distribution of COVID-19 vaccines.

Investigators conducted a web-based survey from October 2020 to December 2020 that included questions regarding the impact of the pandemic on both the personal and professional lives of community oncologists and hematologists. Demographic and practice setting information were collected for participants, and all participants were compensated for completing the survey. Investigators then then analyzed the responses using descriptive statistics.

Respondents had a median of 18 (range, 1-42) years in practice. Most worked in academic settings. Practice setting for study participants were as follows:

Academic center or affiliated teaching hospital:

Community practice, owned by large entity:

Large, privately owned, community practice (with more than 10 physicians): 

Small, privately owned, community practice (2-5 physicians): 

Medium-sized, privately owned, community practice (6-10 physicians):

Thirty-six percent of participants were geographically located in the South, 22% in the West, 22% in the Midwest, and 20% in the Northeast. Furthermore, 51% of participants reported that their perception of the trend in COVID-19 cases in their local area was stable, 29% said it was increasing, and 20% reported that it was decreasing.

Additional data showed that 49% of participants reported that the pandemic had a moderate impact on their professional life, 33% reported a slight impact, 11% reported a severe impact, and 7% reported no impact at all. In term of their personal lives, 48% reported a moderate impact, 28% reported a slight impact, 17% reported a severe impact, and 7% reported no impact at all.

Factors that contributed to negative impacts on professional lives included, concerns over patients transmitting COVID-19 to themselves or their staff (52%), difficulty providing care to patients (45%), loss of income (41%), loss of patient volume (37%), inability to attend scientific meetings in person (35%), added expense to make the practice safe (32%), fear of litigation due to telemedicine visits and potential missed findings (8%), and other (2%).

Factors that contributed to negative impacts on personal lives included, concerns about safety of themselves and their families (84%), a sense of anxiety (50%), loss of family income (24%), a sense of depression or doom (22%), space limitations due to more family members working from home (11%), friction with family due to working from home (10%), and other (5%).

Additional factors that contributed to feelings of burnout among participants included reduced patient volume (35%), access to necessary supplies and/or medicine (29%), personal financial loss (27%), layoffs of other staff members (23%), increased patient volume (12%), and other (5%).

Finally, factors that impacted income among participants included the change from office-based to telemedicine visits (38%), pay cuts from their hospital or practice (33%), cancellation of elective services/procedures (31%), reassignment to other departments in need (6%), and other (6%). Moreover, 22% of participants reported that their income had not been impacted by the COVID-19 pandemic.

Gajra A, Jeune-Smith Y, Fortier S, et al. Impact of COVID-19 pandemic on oncologists’ professional and personal lives: A pre-vaccine study. 

. 2021;39(28): 45-45. doi:10.1200/JCO.2020.39.28_suppl.45

This article was originally published on OncLive as “Loss of In-Person Patient Interaction is Key Factor in Pandemic-Related Burnout Among Oncologists”

Data presented at the 2021 ASCO Quality Care Symposium demonstrated that in-person interactions had a bigger impact of professional satisfaction than financial stability.

Oncologists Attribute Pandemic-Related Burnout to Loss of In-Person Patient Interactions

Patients with neuroendocrine tumors (NETS) undergoing operation can safely discontinue prophylactic octreotide because stopping its use was not found to result in an elevated rate or duration of carcinoid crisis, according to data from a study presented during the 2021 NANETS Annual Symposium.

Results from the study showed that among 171 patients who underwent 195 operations without receiving perioperative octreotide, crisis was reported in 25% (n = 49) of operations, with a mean duration of 3 minutes. Additionally, it was found that carcinoid crisis was more likely to occur in patients with small bowel primary tumors (

 < .001). Furthermore, those who experienced crises were more likely to experience major postoperative complications (

“Based on the results of this prospective study, we conclude that use of prophylactic octreotide may be safely discontinued owing to inefficacy without concern for increased incidence of crisis,” lead study author Sarah M. Wonn, MD, of Oregon Health & Science University, and colleagues, wrote. “Similarly, treatment of crisis with octreotide should be replaced with intravenous fluids and vasopressors, which address the actual pathophysiology of crisis, without concern for increasing crisis duration or rates of major postoperative complications.”

Patients with neuroendocrine tumors are at increased risk for carcinoid crisis, which is described as a sudden event of hemodynamic instability that occurs in those undergoing invasive procedures. Because the nature of crisis is unpredictable, sudden, and life-threatening, these events have proven to be difficult to research. Moreover, an exact definition for carcinoid crisis has not been established. As such, investigators have created their own descriptions for these events, which makes comparability between studies particularly challenging.

In previous studies, the somatostatin analog octreotide was found to inhibit the release of vasoactive hormones, which serves to rapidly reverse a carcinoid crisis. As such, the drug has been used prophylactically to reduce crisis rates and treat crises that still occur. However, guidance regarding the optimal timing, dosage, route of administration, and duration of the agent have varied. Even with the routine use of octreotide, studies have demonstrated crisis rates still range from 24% to 35%.

To understand whether the use of perioperative octreotide should be recommended, investigators sought to study patients with NETs who underwent operations without the agent. The goal of the study was to determine whether the rate of carcinoid crisis was higher than what has been reported in previous studies, if the duration of crisis was longer, and if these patients experienced additional harm.

The study examined patients with NETs who had undergone a major abdominal operation under general anesthesia with a single surgeon at Oregon Health & Science University between January 2017 and May 2020. Those with pancreatic primary tumors were excluded. Notably, the preoperative use of long-acting somatostatin analogs for symptom and/or tumor control was permitted.

In this study, criteria for carcinoid crisis was defined as a sudden and significant change in hemodynamic parameters without another attributable cause like blood loss, compression of the inferior vena cava, or insufficient intravenous fluid resuscitation. Additionally, hemodynamic instability was considered to be significant if systolic blood pressure was less than 80 mm Hg or more than 180 mm Hg, heart rate was higher than 120 beats per minute, or if the patient exhibited physiology that could cause end organ dysfunction.

Moreover, both the surgeon and anesthesiologist had to agree that there was no other plausible cause to declare a carcinoid crisis. If declared, treatment was initiated immediately, and it could include intravenous fluids, bolus injections, or continuous intravenous infusions of vasopressors or vasodilators, per anesthesiologist discretion.

Duration of crisis was measured from the time of onset of hemodynamic instability to the time when systolic blood pressure was restored to more than 80 mm Hg and less than 180 mm Hg, heart rate was less than 120 beats per minute, and ventilatory pressures were normal.

A total of 195 operations done on 171 patients happened during the study period. Operations included hepatic metastases resection and bowel resection (n = 66), bowel resection with no hepatic metastases resected (n = 47), hepatic metastases resection with no bowel resected (n = 45), and other (n = 37). Of the carcinoid crises reported during 49 operations, 35 were hypertension alone, 11 were tachycardia and hypotension, 2 were hypotension and flushing, and 1 was tachycardia and flushing.

Forty-one patients had a single operation with crisis. “The remaining 8 crisis occurrences were observed in the following scenarios: in 1 patient who had 2 operations both with crisis, and 6 other patients with multiple operations, with at least 1 of whom had a crisis,” study authors wrote.

Additional data showed that patients with carcinoid crisis were less likely to have grade 1 primary tumor than those without crisis, at 59% vs 77%, respectively (

 = .015), and they were more likely to have a higher median age at operation, at 67 years vs 64 years, respectively (

 = .021). Those with crisis also had a longer median anesthesia time (333 minutes vs 245 minutes; 

 < .001), higher median estimated blood loss (400 mL vs 200 mL; 

 < .001), and a higher percentage of receiving at least 1 intraoperative transfusion (22% vs 6%; 

Furthermore, in the 49 operations where crises were observed, the median number of crises experienced during an operation was 2 (range, 1-14), the maximum number of crises observed in a single patient was 14, and the median duration of the first carcinoid crisis was 3 minutes (range, 2-4).

In those patients who experienced a second carcinoid crisis (n = 35), the median duration of that crisis was 2 minutes (range, 2-4). Similarly, for patients who had a third carcinoid crisis (n = 23), the median duration of crisis was also 2 minutes (range, 2-4). The median duration of crisis increased to 3 minutes (range, 2-4) in patients who had a fourth carcinoid crisis (n = 14). No crisis was documented to occur for longer than 10 minutes.

Those who experienced carcinoid crisis were more likely than those who did not to have post-operative complications (43% vs 26%; 

 = .034), as well as a longer median hospital stay (8 days vs 6 days; 

New research found that the discontinuation of prophylactic octreotide was not associated with an increased rate or duration of carcinoid crisis in patients with neuroendocrine tumors.

Courtney Marabella

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