University of Illinois College of Pharmacy Clinical Oncology Pharmacist at
UI Healthcare, Chicago, IL

Can you briefly describe margetuximab’s mechanism of action?

A: The mechanism of action of margetuximab [Margenza] is exciting; we’re now moving into this new era of monoclonal antibody technology. We’ve been using monoclonal antibodies since the 1990s, and the way I teach [about] them in school is [that there are] naked monoclonal antibodies, the first ones at least; now, we’ve advanced to antibody-drug conjugates, where we’re tacking on a cytotoxic component, and bispecific monoclonal antibodies [that] have dual binding. When we talk about the mechanism of action of margetuximab, it’s a bispecific monoclonal antibody, and it has 2 binding sites. It has one binding that targets the HER2 receptor. It’s been genetically modified and engineered to bind to the natural killer [NK] cell. What’s exciting about this mechanism of action is that we’re building on this technology with this dual binding, so we’re enhancing this basic monoclonal antibody that we’ve been using, at least with trastuzumab [Herceptin], since the 1990s.

More specifically, the mechanism of action of margetuximab is that it targets the HER2 receptor, the extracellular domain, and the FC [fragment crystallizable] component of that monoclonal antibody has been genetically engineered to target and bind to the NK cell. When it binds to the NK cell, the idea is that you’re enhancing the antibody-dependent cellular cytotoxicity. Margetuximab has the same binding, as well as binding affinity, to the HER2 receptor as trastuzumab. We have 2 monoclonal antibodies, trastuzumab and margetuximab, binding to the same site with a similar binding affinity to that receptor, which is different from pertuzumab [Perjeta].

What are some of the concerns with margetuximab’s toxicity profile? Have any new safety concerns become more apparent with its use in the real-world treatment setting?

A: Margetuximab is an antibody that targets HER2. Two things are really important to highlight about the safety profile of margetuximab that were observed in the SOPHIA trial [NCT02492711]. First, the infusion-related reactions: About 13% of patients in SOPHIA experienced infusion-related reactions, primarily grade 1 and grade 2 [in severity]. When compared with trastuzumab in that study, only about 3% experienced infusion-related reaction.

In the real world, we really don’t see infusion-related reactions with trastuzumab. It’s not very common with trastuzumab, and we don’t premedicate [for it] with trastuzumab. However, I’m not really surprised by that in the sense that in the nomenclature of these drugs, we know that there is a difference. Trastuzumab is a humanized monoclonal antibody, as indicated by the “

” in the nomenclature. Margetuximab is a chimeric monoclonal antibody, as indicated by “

” in the nomenclature. Infusion-related reactions are more commonly seen with chimeric monoclonal antibodies because of that murine base compared with humanized monoclonal antibodies. This can partially explain the difference in higher incidence of infusion-related reactions with margetuximab compared with trastuzumab. Another possible reason for increased infusion-related reactions may be related to its mechanism of action with an enhanced immune response.

Infusion-related reactions in the SOPHIA trial primarily happened in cycle 1 and with subsequent cycles if [disease was] low grade 1 or grade 2. To manage those, we were able to add premedications [such as] antihistamines, antipyretics, and corticosteroids. Another recommendation is slowing the infusion.

It’s important that we all think about cardiotoxicity with any HER2-directed monoclonal antibody. We associate cardiotoxicity with any monoclonal antibody that targets HER2; we see that with trastuzumab or pertuzumab. What does that cardiotoxicity look like with margetuximab? Does this FC-engineered component add or worsen cardiotoxicity? What we’ve seen and what’s been published [show that] it does not appear that it has any more cardiotoxicity than trastuzumab. In the clinical trials, about 3% of patients experience a decline in the ejection fraction, which was similar to trastuzumab.

This agent was approved in December 2020, and no additional safety pharmacovigilance reports that I’m aware of say that there’s more cardiotoxicity than what was observed in the clinical trial. Also, it had similar cardiotoxicity in terms of lower ejection fraction [and] it was reversible, like what we see with trastuzumab and other HER2[-targeted] monoclonal antibodies. In the clinical trials, it is primarily asymptomatic. These declines in ejection fraction were observed via monitoring, not because the patient was symptomatic.

Q: What are some of the risks of left ventricular dysfunction associated with this agent?

A: [Speaking specifically about] left ventricular dysfunction, just knowing the mechanism of action [of this agent and] that it targets the HER2 receptor, we know that there will be, just from the mechanistic perspective, some level of cardiotoxicity, given our [experience with] previous agents. Again, margetuximab had about 3% of cardiotoxicity, primarily manifesting as decrease in ejection fraction, [which was] asymptomatic and reversible. The management is [similar to what] we do with trastuzumab. If it’s greater than or equal to a 16% drop from pretreatment ejection fractions, you’re going to hold [the drug] and at that point, you should consult a cardio-oncologist. Once it recovers, you can restart.

Q: Are dosing modifications common with the use

A: Because margetuximab is a monoclonal antibody, the dosing adjustments are primarily centered around [ejection fraction]. The recommendation is to get a baseline [echocardiogram] or ejection fraction and to continue monitoring that every 3 months. If you do see a decline in the ejection fraction greater than or equal to 16%, you’re going to hold and wait for it to recover. In terms of dosing adjustments, it’s pretty much like all monoclonal antibodies: Either give or you don’t give. When you hold, it’s because of a decrease or a significant increase in ejection fraction or for more severe infusion-related reactions. There are no hepatic or renal adjustments. This was given in combination with chemotherapy. If a patient experiences neutropenia or diarrhea, it’s likely because of the chemotherapy component vs margetuximab. This agent has a very similar [adverse] effect profile to trastuzumab, with the exception of the infusion-related reactions; we’re seeing those be a little bit more enhanced with margetuximab.

Q: Are there any major drug interactions with margetuximab that clinicians should

A: Margetuximab skips the cytochrome P450 pathway. The important drug interactions are with other cardiotoxic drugs. In the breast cancer world, the primary drug interaction here would be doxorubicin. You would not want to give this drug concomitantly with doxorubicin. I would say it’s contraindicated, similar [to] trastuzumab. No anthracycline would be recommended concomitantly with margetuximab because of the additional additive cardiotoxic toxicity.

Q: Have any barriers to administration or receipt by the patient emerged since this agent’s approval, such as common reimbursement issues or logistical challenges to obtaining the medication?

A: Margetuximab was approved in December 2020, and [so far], in terms of access or administration, we have observed no real challenges or barriers with access or administration. We are just on the lookout for those infusion-related reactions in the 13% of patients who get them. When we were building our EPIC protocol, that was a question: “Do we automatically just give some premedications? Or do we watch and wait?” But no, there are no major barriers or access issues with this agent. It’s a welcome addition to patients in the third-line and beyond setting [with] metastatic HER2-positive breast cancer.n

 The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Rugo HS, Im SA, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. 

 2021;7(4):573-584. doi:10.1001/jamaoncol.2020.7932

Margetuximab. Prescribing information. Macrogenics; 2020. Accessed August 23, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761150s000lbl.pdf

Articles

In an interview with ONCOLOGY®, Sandra Cuellar, PharmD, BCOP, FASHP, offers a comprehensive review of real-world treatment considerations of margetuximab as therapy for adult patients with metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2 regimens with at least 1 being for metastatic disease. 

Margetuximab for HER2-Positive Breast Cancer

Accelerated approval has been granted to tisotumab vedotin-tftc (Tivdak) for the treatment of patients with recurrent or metastatic cervical cancer following disease progression on or after chemotherapy, according the companies responsible for developing the agent, Seagen Inc. and Genmab A/S.

The decision from the agency is supported by data from the single-arm phase 2 innovaTV 204 trial (NCT03438396) of tisotumab vedotin which resulted in a 24% (95% CI, 15.9%-33.3%) confirmed overall response rate by independent review committee in previously treated, recurrent or metastatic cervical cancer.

“Tivdak’s approval as a monotherapy in the U.S. is an important milestone for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, as they are in need of a new treatment option and we look forward to making it available to them,” Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement. “The journey towards the approval of Tivdak started nearly 2 decades ago with innovative research by scientists at Genmab and Seagen and reflects on our purpose of making an impact in the lives of [patients with] cancer and their families. Today’s announcement marks Genmab’s evolution into a fully integrated biotechnology company and we would like to thank patients, caregivers, investigators, and our collaborators for their participation in our clinical studies.”

Results from the trial that were previously presented

 at the European Society for Medical Oncology 2020 Virtual Congress highlighted a 7% complete response rate and a 17% partial response rate, as well as a median duration of response (DOR) was 8.3 months (95% CI, 4.2–not reached).

The biologics license application for tisotumab vedotin-tftc in this indication was submitted in February 2021 and 

. Continuous approval may be contingent upon verification from additional clinical data. The phase 3 innovaTV 301 trial (NCT04697628) comparing tisotumab vedotin-tftc vs investigators choice of chemotherapy in patients with recurrent or metastatic cervical cancer is currently ongoing.

Seagen and Genmab announce FDA accelerated approval for TIVDAK™ (tisotumab vedotin-tftv) in previously treated recurrent or metastatic cervical cancer. News release. Seagen Inc. and Genmab A/S. September 20, 2021. Accessed September 20, 2021. https://bwnews.pr/2XJLowv

Tisotumab vedotin may now be used to treat patients with recurrent or metastatic cervical cancer after the FDA's decision to grant the agent an accelerated approval.

FDA Grants Accelerated Approval to Tisotumab Vedotin in Recurrent Or Metastatic Cervical Cancer

Baseline immunogenicity could potentially have an association with factors such as higher pathologic complete response (pCR) rates, 

 early stage breast cancer when examining outcomes following de-escalat

 neoadjuvant ado-trastuzumab Emtansine (T-DM1; Kadcyla) with or without endocrine therapy compared with trastuzumab (Herceptin)

endocrine therapy, according to findings from the phase 2 WSG ADAPT TP trial (NCT01779206) which were presented at the 

2021 European Society of Medical Oncology Congress

 mutations are in 16% of all of our tumors, and was correlated with poor outcome, even after T-DM1, which was, of course, followed by standard chemotherapy and trastuzumab in all non pCR,” Nadia Harbeck, MD, PhD, head, Breast Center, and chair, conservative oncology, Department of OB&GYN, University of Munich, Germany, said during a presentation at the Congress. “The majority of pCR patients with luminal A subtype have the best outcome despite comparatively low pCR rates after HER2-directed therapy.”

In her presentation at the Congress, Harbeck discussed the translational research from the trial, focusing on biomarkers analyzed in the baseline biopsy, immune biomarkers, 

 mutation status, and molecular subtypes.

The researchers found that baseline IHC expression of CD8 (hazard ratio, 0.61; range, 0.36-1.01; 

 = .052), of PD-L1ic (hazard ratio, 0.32; range, 0.10-1.07; 

 = .065), and CD8 expression by mRNA (hazard ratio, 0.66; range, 0.47-0.92; 

 = .015) were associated with a decreased invasive disease-free survival risk. TILs were not associated with a decreased risk.

 mutation was significantly associated with increased iDFS risk in the T-DM1 arms (hazard ratio, 3.66; 95% CI, 1.33-10.06; 

 = .012). The 5-year iDFS rate for those with 

-mutated disease was 68.4% (95% CI, 42.8-84.4), and 90.2% (95% CI, 82.5-94.6) in those with wild type disease.

“This is an interesting finding. We already know from the neoadjuvant setting that 

 mutation is associated with poor outcome, particularly in the hormone receptor-positive/HER2-positive tumors. But so far, at least in the metastatic breast cancer setting, T-DM1 efficacy did not seem to be affected by 

In total, 55% of patients were luminal A, and had improved 5-year iDFS, compared with others (96% vs 83%, respectively; hazard ratio, 0.50; 95% CI, 0.23-1.08; 

 = .079). Moreover, in a multivariate analysis, clinical nodal burden was significantly associated with poor iDFS, while 

“So our conclusion would be for further treatment de-escalation strategy,” Harbeck said. “They need to be based on pCR rate and outcome in the luminal A subtype. [It is] promising as pCR-directed approaches in the HER2-enriched subtype. Survival data of ADAPT TP II, evaluating paclitaxel pus a dual blockade in the same setting are still pending and will help us to clarify whether the results from ADAPT are representative for the hormone receptor-positive subtype as a whole.”

The multicenter, prospective phase 2 WSG ADAPT TP trial, which is part of the ADAPT umbrella trial (NCT 01779206), evaluated 375 patients with HR+/HER2+ early-stage breast cancer who were randomized 1:1:1 to receive 12 weeks of either 3.6 mg/kg T-DM1, with (n = 127) or without (n = 119) endocrine therapy, or trastuzumab plus endocrine (n = 129).

Standard chemotherapy was recommended after surgery. Chemotherapy omission was allowed in all patients with pCR after study treatment.

The primary end point was pCR, while secondary end points included safety, 5-year iDFS, overall survival (OS), and translational research.

In 2017, the researchers observed pCR in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and endocrine therapy, and 15.1% with trastuzumab and endocrine therapy (

 < .001). Early responders (67% of patients with an assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio [OR], 2.2; 95% CI, 1.24-4.19).

At the 2020 ESMO Congress, the time to event analysis showed that a pCR was significantly associated with better DFS, with 5-year rates of 92.1% (95% CI, 77.5-97.4) versus 82.7% (95% CI, 77.0-87.1) among those without a pCR (

 = .014). Moreover, 5-year DFS rates were comparable between the study arms, at 88.9% for patients given T-DM1, 85.3% for those given T-DM1 plus endocrine therapy, and 84.6% for patients receiving trastuzumab plus endocrine therapy. Distant 5-year DFS were also similar at 91.6%, 92.3% and 88.9%, respectively, and there were corresponding 5-year OS rates of 97.2%, 96.4% and 96.3%.

1. Harbeck N, Nitz U, Christgen M, et al. Predictive impact of biomarkers on pCR and survival after de-escalated neoadjuvant T-DM1 with or without endocrine therapy (ET) vs. trastuzumab+ET in HER2+/HR+ early breast cancer: WSG ADAPT TP trial. 

. 2021;32(suppl_5):S1283-S1346. doi:10.1016/annonc/annonc741.

2. Harbeck N, Gluz O, Christgen M, et al. De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET. 

. 2017;35(26):3046-3054. doi:10.1200/JCO.2016.71.9815.

3. Harbeck N, Nitz U, Christgen M, et al. De-escalated neoadjuvant T-DM1 with or without endocrine therapy (ET) vs trastuzumab+ET in early HR+/HER2+ breast cancer (BC): ADAPT-TP survival results. 

. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325.

Investigators believe the use of biomarkers can determine the results of de-escalated neoadjuvant T-DM1 in HR-positive/HER2-positive early breast cancer.

Possible Association Noted Between Tumor Immunogenicity and Survival Outcomes in HR+, HER2+ Early Breast Cancer Following Neoadjuvent T-DM1 De-Escalation

–mutant non–small cell lung cancer (NSCLC) appear to achieve clinical benefit after being treated with adagrasib (Lumakras), according to positive topline findings from the phase 2 KRYSTAL-1 trial (NCT03785249).

The analysis, which was conducted in the intent-to-treat arm, showed that a 600 mg twice daily dose of adagrasib resulted in an objective response rate (ORR) of 43% and disease control rate of 80% based on central independent review. The median follow-up for the study was 9 months. Notably, 98.3% of patients were given adagrasib after being treated with chemotherapy or immunotherapy agents.

 mutation has historically been challenging to target, leaving patients with limited treatment options,” Charles M. Baum, MD, PhD, president and chief executive officer at Mirati Therapeutics, Inc., said in a press release. “These positive topline data further strengthen our belief in adagrasib as a potentially differentiated therapy for patients with non-small cell lung cancer harboring the 

G12C mutation. We look forward to submitting our New Drug Application to the U.S. Food and Drug Administration in the fourth quarter of 2021 and advancing our expanding adagrasib development program, which includes numerous monotherapy and combination studies in 

The nonrandomized KRYSTAL-1 trial had an estimated enrollment of 565 patients. The primary outcome measure of the study was to characterize the safety of the agent in patients with 

G12C–mutant advanced solid tumors, as well as evalute pharmacokinetics and efficacy. The secondary outcome measure included establishing the maximum-tolerated dose and characterizing the safety and tolerability.

To be enrolled on the study, patients were required to have a tumor with a histologically confirmed 

 G12C mutation. Additionally, unresectable or metastatic disease, being unavailable or unwilling to receive a standard treatment, and adequate organ function were also required.Those who had a history of intestinal lung disease, major gastric surgery, or an inability to swallow oral medications, as well as any other type of active cancer were all exclusion criteria for the study.

Additional findings from the phase 1/1b portion of the KRYSTAL-1 study highlighted an investigator-assessed ORR of 58%, 2 responses of which occurred after being on treatment for 10 months or more. The median follow-up for the analysis was 17.3 months. Additionally, the median treatment duration was 9.5 months and the median duration of response was 12.6 months.

Moreover, 64% of responders were still on treatment and continuing to experience a response. Investigators also reported a median progression-free survival of 8.3 months. The median overall survival was not reached.

In terms of safety, 26% of patients experienced a grade 3/4 treatment-related adverse effect (AE) and 1 patient experienced a grade 5 AE.

Mirati Therapeutics announces positive phase 2 topline results for investigational adagrasib in patients with KRAS G12C-mutated advanced non-small cell lung cancer. News release. Mirati Therapeutics, Inc. September 20, 2021. Accessed September 20, 2021. https://bit.ly/3zoRpLZ

Topline findings from the phase 2 KRYSTAL-1 study indicated that adagrasib may hold promise in patients with KRAS G12C–mutant non–small cell lung cancer.

Adagrasib Demonstrates Promising Activity in KRAS G12C+ Advanced NSCLC

Treatment with adjuvant atezolizumab (Tecentriq) vs best supportive care (BSC) resulted in improved disease-free survival (DFS) and time to locoregional and distant relapse in those with stage II to IIIA PD-L1–positive non–small cell lung cancer (NSCLC), according to an exploratory analysis from the phase 3 IMpower010 trial (NCT02486718) presented during the 

, showed that atezolizumab extended the DFS benefit in patients in the all-randomized stage II to IIIA population with PD-L1 expression on at least 50% of tumor cells (TC), including those with 

 aberrations (n = 1005; HR, 0.43; 95% CI, 0.27-0.68) and without (HR, 0.43; 95% CI, 0.26-0.71).

Furthermore, in a post-hoc descriptive analysis, investigators studied the time from randomization to relapse. In those with PD-L1 expression on 1% or higher of TC, the median time to any relapse was 17.6 months (95% CI, 0.7-42.3) with atezolizumab vs 10.9 months (range, 1.3-37.3) with BSC, appearing to delay recurrence in this subset with the PD-L1 inhibitor.

“The greatest magnitude of disease-free survival benefit was observed in those patients with PD-L1 in at least 50% of tumor cells,” lead study author Enriqueta Felip, MD, head of the Thoracic and Head and Neck Cancer Unit of Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, in Barcelona, Spain, reported in a virtual presentation. “At this DFS interim analysis, similar patterns of relapse were seen between the study arms, and time to relapse appeared to favor atezolizumab vs best supportive care in the group of patients with stage II to IIA, PD-L1–positive tumors.”

Up to 60% of patients with stage I to III NSCLC experience relapse even following curative intent treatment, creating a clear unmet need. In August 2021, the FDA granted a priority review designation to atezolizumab as an adjuvant treatment following surgery plus platinum-based chemotherapy in patients with NSCLC whose tumors harbor PD-L1 expression of 1% or higher per an FDA-approved test.

The decision is supported by the IMpower010 data, which previously showed that adjuvant atezolizumab induced a 34% reduction in the risk of disease recurrence or death vs (HR, 0.66; 95% CI, 0.50-0.88; 

= .004) in patients with stage II to IIIA disease and a PD-L1 tumor expression of 1% or higher.

In the phase 3 trial, 1280 patients with completely resected stage IB to IIA NSCLC per Union for International Cancer Control/American Joint Committee on Cancer version 7 received cisplatin plus pemetrexed, gemcitabine, docetaxel, or vinorelbine for 1 to 4 cycles. Then, 1005 patients were randomized 1:1 to receive either 1200 mg of atezolizumab every 21 days or BSC.

Patients had to have an ECOG performance status of 0 or 1, must have undergone a lobectomy or pneumonectomy, and had tumor tissue available for PD-L1 analysis. Stage IB tumors had to be at least 4 cm in size.

Stratification factors included sex (male vs female), disease stage (IB vs II vs IIIA), PD-L1 tumor expression status (TC2/3 and any immune cell [IC] vs TC0/1 and IC2/3 vs TC0/1 and IC0/1).

The primary end points were investigator-assessed DFS tested hierarchically in patients with a PD-L1 tumor cell expression of at least 1% or higher, all randomized patients with stage II to IIIA disease, and the intent-to-treat (ITT) population of patients who have stage IB to IIIA disease. Secondary outcome measures included OS in the ITT population, DFS in those with PD-L1 TC expression of 50% or higher and stage II to IIIA disease, as well as 3- and 5-year DFS rates in all 3 patient populations.

The median patient age was 62 years (range, 26-84), and 38.0% were at least 65 years old. A total 66.9% of patients were male, 73.4% were White, and 55.3% had an ECOG performance status of 0; 65.6% of patients had nonsquamous histology. Additionally, 12.2% of patients had stage IB disease, and 54.6% had a PD-L1 tumor cell expression of 1% or higher.

In the data presented at the 2021 ASCO Annual Meeting, at a median follow-up of 32.2 months (range, 0.57-5), the median DFS in the all-randomized stage II to IIIA population in the investigative and control arms was 42.3 months (95% CI, 36.0–not estimable [NE]) vs 35.3 months (95% CI, 30.4-46.4), respectively (HR, 0.79; 95% CI, 0.64-0.96; 

In the ITT population, the median DFS with atezolizumab (n = 507) was NE (95% CI, 36.1–NE) vs 37.2 months (95% CI, 31.6–NE) with BSC (HR, 0.81; 95% CI, 0.67-0.99; 

The findings presented at the 2021 ESMO Congress focused on time to relapse and subsequent treatment in these patient populations.

Additional DFS results by PD-L1 status showed that, for patients in the all-randomized stage II to IIIA population (n = 882) with PD-L1–positive tumors (TC 1%-49%), including those with 

 abnormalities (n = 247), the benefit with atezolizumab was smaller (HR, 0.87; 95% CI, 0.60-1.26). DFS outcomes with atezolizumab were similar in the patient subgroup who did not have 

 abnormalities (HR, 0.82; 95% CI, 0.54-1.25). The 

excluded group (n = 743) was part of a post-hoc exploratory analysis, Felip explained.

“Now we know that probably these patients [PD-L1 TC 1%-49%] are benefitting less from immunotherapy as monotherapy,” she said.

An exploratory analysis evaluated the incidence of disease relapse, with disease recurrence as the sole event for DFS. In the PD-L1 TC 1% or higher group, the disease relapse rates were 29.4% (n = 73/248) and 44.7% (n = 102/228) with atezolizumab and BSC, respectively. In all-randomized patients with stage II to IIIA disease, the atezolizumab arm had a 33.3% (n = 147/442) disease relapse rate compared with 43.0% (n = 189/440) in the BSC arm. Finally, in the ITT population of stage IB to IIIA disease, the disease relapse rates were 30.8% and 40.8% with atezolizumab (n = 156/507) and BSC (n = 203/498), respectively.

Overall, there were no clear differences in relapse patterns between the PD-L1 TC 1% or higher stage II to IIIA, all-randomized stage II to IIIA, and ITT stage IB to IIIA populations. Locoregional-only relapse occurred in 47.9% (n = 35/73) and 41.2% (n = 42/102) of atezolizumab- and BSC-treated patients, respectively, with PD-L1 TC 1% or higher stage II to IIIA disease. In comparison, those rates were 39.5% (n = 58/147) and 38.1% (n = 72/189), respectively, in the all-randomized stage II to IIIA population. In the ITT stage IB to IIIA population, these rates were 37.8% (n = 59/156) and 36.9% (n = 75/203), respectively.

Distant-only relapse rates were 38.4% and 39.2% with atezolizumab (n = 28/73) and BSC (n = 40/102), respectively, in the PD-L1 TC 1% or higher group. In the all-randomized stage II to IIIA subset, distant relapse occurred in 42.2% (n = 62/147) of atezolizumab-treated patients and 40.7% (n = 77/189) of BSC-treated patients; these rates were 42.9% with atezolizumab (n = 67/156) and 40.4% with BSC (n = 82/203) in the ITT stage IB to IIIA group.

“Please be aware that only 29% to 33% of the patients in the atezolizumab arm relapse vs 41% to 44% in the best supportive care arm,” said Felip.

When evaluating sites of relapse in the ITT stage IB to IIIA population, 17.3% of patients on atezolizumab (n = 156) experienced locoregional and distant relapse vs 18.7% of those on BSC. Felip noted that the overall patterns of the relapse sites in the PD-L1 TC 1% or higher stage II to IIIA and all-randomized stage II to IIIA populations were consistent with the ITT population.

In the post-hoc descriptive analysis of time to relapse, the delay was shorter in the all-randomized stage II to IIIA group vs the PD-L1–positive group, at a median 12.4 months (95% CI, 0.7-42.3) and 11.1 months (95% CI, 0.8-42.1) with atezolizumab and BSC, respectively. Similarly, in the ITT stage IB to IIIA subgroup, the median time to relapse was 12.3 months (95% CI, 0.7-42.3) with atezolizumab compared with 12.0 months (95% CI, 0.8-42.1) with BSC.

A closer examination of these rates in the PD-L1 TC 1% or higher group showed that the median time to locoregional and distant relapse was 24.0 months (range, 2.3-42.3; n = 9) with atezolizumab vs 5.3 months (range, 1.3-34.2; n = 17) with BSC. Central nervous system–only relapse occurred at a median 18.2 months (range, 0.7-35.5; n = 8) and 10.6 months (range, 4.0-24.1; n = 12) with atezolizumab and BSC, respectively.

“Please be aware of the small sample size of these analyses,” Felip cautioned. “There are no clear differences in the median time to relapse between the 2 treatment arms in the all-randomized stage II to IIIA population, and in the intent-to-treat population, including patients with stage IB disease.”

Systemic non-protocol anti-cancer treatment following relapse was also explored, which was found to be well balanced across the 3 arms of patients who received chemotherapy, TKI treatment, and targeted monoclonal antibody.

“As expected, more patients received immunotherapy in the best supportive care arm; approximately 32% of patients when compared to the atezolizumab arm, in which approximately 12% of the patients received immunotherapy at disease recurrence,” Felip added.

Furthermore, no differences were noted in the use of radiation or surgery as post-relapse treatments between the 2 treatment arms and across the 3 patient subgroups.

Longer follow-up is needed and may reveal differences in relapse patterns and treatment options in these patient populations, Felip concluded.

Felip E, et al. IMpower010: Patterns of relapse and subsequent therapy from a Phase III study of atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy (chemo) in stage IB-IIIA non-small cell lung cancer (NSCLC). Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA9.

Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. 

. Published online September 20, 2021. doi:10.1016/S0140-6736(21)02098-5

US FDA grants priority to Roche’s Tecentriq as adjuvant treatment for certain people with early non-small cell lung cancer. News release. Roche. August 3, 2021. Accessed August 3, 2021. https://bit.ly/3jj5TXN

Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). 

. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500

Patients with stage II to IIIA non–small cell lung cancer experienced an improvement in disease-free survival and time to locoregional and distant relapse after being treated with adjuvant atezolizumab.

Treatment With Adjuvant Atezolizumab Yields Improved Outcomes in Stage II-IIIA PD-L1–Positive NSCLC

The FDA has granted a fast track designation to the investigational potent humanized immunoglobulin G1 monoclonal antibody ficlatuzumab (previously AV-299) for patients with relapsed or recurrent head and neck squamous cell carcinoma (HNSCC), according to a press release from drug developer AVEO Oncology.

The safety and efficacy of the EGFR-targeted antibody was examined in a phase 2 study (NCT03422536) with or with cetuximab (Erbitux) in a population of patients with metastatic HNSCC who were refractory to previous treatment with immunotherapy, chemotherapy, and cetuximab.

 Although the single-agent arm was stopped due to futility with a median progression-free survival (PFS) of 1.8 months (90% CI, 1.7) and an overall response rate (ORR) of 4% including 1 partial response (PR), the combination cohort met its primary end point. Patients who received ficlatuzumab and cetuximab experienced a median PFS of 3.6 months (lower bound 90% CI, 2.3; 

 = .04) and an ORR of 19%, including 2 complete responses and 4 PRs.

Patients with human papillomavirus (HPV)–negative disease, a subgroup known to be associated with poorer outcomes, experienced superior ORR and median PFS when administered the combination therapy.

“The FDA’s decision to grant FTD underscores the potential for ficlatuzumab to address a serious unmet need and serve as a meaningful therapeutic option for patients with metastatic HNSCC,” Michael Bailey, president and chief executive officer of AVEO, said in a press release. “We are committed to unlocking the full potential of ficlatuzumab in patients with HNSCC and look forward to working closely with the FDA to determine next steps for the program.”

The randomized, non-comparative study included an intent-to-treat population of patients who received 1 or more doses of the treatment. To be eligible for enrollment, patients were required to have an ECOG performance status of 0 or 1 and needed to be resistant or ineligible to platinum chemotherapy and cetuximab. Additionally, patients needed to have undergone treatment with or been ineligible for anti–PD-1 therapy and have no significant medical comorbidities.

Those who met the study’s criteria were enrolled and randomized to receive either 20 mg/kg of ficlatuzumab intravenously every 2 weeks or 20 mg/kg of ficlatuzumab and 500 mg/m2 of cetuximab every 2 weeks.

The primary end point of the study was median PFS, with key secondary end points including ORR, overall survival, toxicity, and median PFS in HPV-stratified populations.

The study included 60 patients, 27 of whom received single-agent ficlatuzumab and 33 of whom were treated with the combination regimen. A majority of patients in the monotherapy arm (78%) and the combination arm (91%) were male with median ages of 65 (range, 37-83) and 63 (range, 46-75) years, respectively.

Additional findings from the study indicated that patients whose disease was HPV negative had an ORR of 38% (

 = .02), as well as a median PFS of 2.9 months (

In the single-agent cohort, the most common grade 1/2 toxicities included hypoalbuminemia (30%), peripheral (15%) and facial/head and neck (8%) edema, and fatigue (8%). Additionally, grade 3/4 adverse effects (AEs) included pneumonitis (8%), maculopapular rash (4%), and facial/head and neck edema (4%). Moreover, the most common grade 1/2 AEs in the combination arm included acneiform rash (44%), hypoalbuminemia (31%), and peripheral edema (16%). The most common grade 3/4 AEs in this cohort was acneiform rash (19%).

AVEO Oncology announces ficlatuzumab granted fast track designation by the U.S. FDA for the treatment of relapsed or recurrent head and neck squamous cell carcinoma. News release. AVEO Oncology. September 20, 2021. Accessed September 20, 2021. 

Baunan JE, Roe D, Saba NF, et al. Randomized, phase II study of ficlatuzumab with or without cetuximab in patients with pan-refractory, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). 

. Published online May 25, 2020;38(Supple 15). doi:10.1200/JCO.2020.38.15_suppl.TPS6594

Ficlatuzumab, which received a fast track designation from the FDA, may provide benefit to patients with relapsed or recurrent head and neck cancer.

FDA Grants Fast Track Designation to Ficlatuzumab for Relapsed or Recurrent Head and Neck Cancer

Improved efficacy was seen among patients with malignant pheochromocytoma and paraganglioma (MPPGL) treated with sunitinib (Sutent), according to results from the FIRSTMAPPP trial presented at the 2021 ESMO Congress.

MPPGL, a very rare cancer with an annual incidence < 1 per million, are highly vascularized tumors that arise from the adrenal medulla and paraganglia, with strong expression of VEGF, PDGF, and VEGFR-1/2, according to Eric Baudin, MD, PhD. At the Congress, he reported on the first academic randomized, double-blind phase 2 FIRSTMAPPP study results assessing sunitinib efficacy compared to placebo in patients with MPPGL.

“Together with a team of experts and also both of translational researchers, we elected sunitinib as the first drug to investigate in [MPPHLs]. The design and clinical method [were created based on] extreme toxicities to this cancer, compatibility of hormone- and drug-related hypertension, behavior of the group of tumors, and absence of standard,” explained Baudin, Department of Endocrine Oncology, Gustave Roussy.

Patients with malignant, non-resectable progressive PPGL were randomized 1:1, stratified by SDHB status and line of treatment, to receive either 37.5 mg sunitinib per day with continuous dosing or placebo.

Main inclusion criteria were metastatic disease, pre-treatment, inherited disease, evaluable RECIST 1.1 criteria, and progressive disease within 18 months, according to RECIST. Exclusion criteria was comprised of hypertension that could not be controlled, abnormal cardiac function, and treatment with prior tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors.

Patients were evaluated every 12 weeks. At time of progression, crossover was allowed.

The primary end point of the trial was progression-free survival (PFS) at 12 months, according to real-time central review. Secondary end points included overall survival (OS), PFS, time to progression, duration of response, and safety. Exploratory objectives of the study were predictors and surrogates (symptoms, genetic status, FDG-PET, conventional imaging, hormones, quality of life, safety), hormone response, and cardiovascular management.

In 8 years, 78 patients were enrolled in the trial. In total, 32% had a 

 mutation, 40% were receiving first-line treatment, 40% had hypertension, and 60% had bone metastases.

Of the 39 patients treated with sunitinib, 14 (35.9%) had no progression at 1 year, compared with 18.9% in the placebo arm, meeting the trial’s primary endpoint.

Those treated with sunitinib demonstrated a media PFS of 8.9 months (95% CI, 5.5-12.7), compared with 3.6 months (95% CI, 3.1-6.1) in the placebo group.

Median sunitinib treatment duration was 11 months (range, 0-37), compared with 4 months in the placebo arm (range, 0-35), of which 87% crossed over to treatment with sunitinib.

-positive mutations, 6 had a partial response (50%), 4 had stable disease (33%) and 2 had progressive disease (17%) following treatment with sunitinib.

In total, 48 patients (61%) experienced a grade 3 or higher adverse event (AE)–28 (72%) in the sunitinib arm and 20 (51%) on the placebo arm–including asthenia-fatigue (18% vs 3%, respectively), hypertension (10% vs 6%), and bone pain (0% vs 10%). Drug decrease occurred in 59% vs 13%, respectively, in the sunitinib and placebo arms, and drug withdrawal from an AE occurred in 14% vs 0%. Three deaths occurred in the sunitinib arm (rectal bleeding-pelvic bone metastases, respiratory insufficiency, and peritoneal carcinomatosis); however, only 1 death was drug related (rectal bleeding). One death occurred in the placebo arm (ischemia cerebrovascular).

“This is the highest level of evidence ever reached in this very rare cancer,” Baudin concluded. “This is practice changing, if sunitinib becomes a therapeutic option, with the most robust evidence of anti-tumor activity in progressing metastatic pheochromocytoma and paraganglioma.”

Invited discussant, Rocio Garcia-Carbonero, MD, Gastrointestinal (GI) Tumor Unit, Hospital Universitario Doce de Octubre in Madrid, agreed that the data could be practice changing for this patient population moving forward.

“I think this is a positive trial; sunitinib is active in these patients. Efficacy is particularly relevant in but not restricted to 

-mutated tumors. Safety seems to be reasonable and manageable. So, this is the first and largest trial ever conducted in the field of metastatic PPGL,” she said.

“This is the highest level of evidence ever reached in this very rare cancer. It is in the range of all the systemic treatment options included in clinical guidelines. And I do agree with Dr. Baudin: It is practice changing. And sunitinib has become the therapeutic options with the most solid and robust evidence of anti-tumor activity that we have to date.”

Baudin E, Goichot B, Berruti A, et al. First International Randomized Study in Malignant Progressive Pheochromocytoma and Paragangliomas (FIRSTMAPPP): An academic double-blind trial investigating sunitinib. 

. 2021;32(suppl_5): S621-S625. doi:10.1016/annonc/annonc700.

Treatment with sunitinib resulted in improved efficacy results in the FIRSTMAPPP trial for patients with malignant pheochromocytoma and paraganglioma.

Sunitinib Treatment Improved Survival for Malignant Pheochromocytoma and Paraganglioma

, CancerNetwork® spoke with Fredrik Schjesvold, MD, PhD, founder and head of the Oslo Myeloma Center, about the rationale for the phase 3 OCEAN trial (NCT03151811), and why investigators decided to examine melflufen (Pepaxto) in combination with dexamethasone compared with pomalidomide (Pomalyst)/dexamethasone in patients with relapsed/refractory multiple myeloma.

The rationale [behind the] OCEAN trial was to take the drug melflufen that was already approved in the [United States] for patients who have received at least 4 previous lines of treatment. The next phase in the development of treatment was to compare this in an earlier line of treatment [with] the standard pomalidomide/dexamethasone in patients who are already lenalidomide [Revlimid] refractory and exposed to proteasome inhibitors. …The study was to show that [melflufen/dexamethasone is better than pomalidomide/dexamethasone.

Schjesvold F, Dimopoulos MA, Delimpasi S, et al. OCEAN (OP-103): a Phase 3, randomized, global, head-to-head comparison study of melflufen and dexamethasone (Dex) versus pomalidomide (Pom) and dex in relapsed refractory multiple myeloma (RRMM). Presented at: International Myeloma Workshop; September 8-11, 2021; Vienna, Austria. Accessed September 11, 2021.

Videos

Fredrik Schjesvold, MD, PhD, speaks about the FDA approval of melflufen in relapsed/refractory multiple myeloma and its next phase of development at the 2021 International Myeloma Workshop.

Fredrik Schjesvold, MD, PhD, Discusses the Rationale for the OCEAN Trial in Relapsed/Refractory Multiple Myeloma

Patients with previously untreated esophageal squamous cell carcinoma experienced an improvement in survival after being treated with pembrolizumab (Keytruda) and chemotherapy compared with placebo plus chemotherapy, according to the results of the phase 3 KEYNOTE-590 trial (NCT03189719) published in in 

Patients with esophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more who received the combination achieved a median overall survival (OS) of 13.9 months compared with 8.8 months in the placebo arm (HR, 0.57; 95% CI, 0.43-0.75; 

< .0001). Patients in the pembrolizumab arm experienced a median progression-free survival (PFS) of 6.3 months compared with 5.8 months among those in the placebo arm (HR, 0.65; 95% CI, 0.54-0.78; 

“To our knowledge, this is the first study to show a significant survival benefit with immunotherapy plus chemotherapy in the first-line setting for esophageal cancer. These data support the recent US Food and Drug Administration approval of pembrolizumab plus chemo- therapy in first-line therapy for advanced or metastatic esophageal or gastroesophageal junction cancer,” investigators of the study wrote.

The study enrolled 749 patients, 373 of whom were randomized to the pembrolizumab group and 376 were randomized to the placebo group. In total, 73% (n = 548) of patients had esophageal squamous cell carcinoma, 52% (n = 286) of whom had a PD-L1 CPS of 10 or more. Additionally, 27% (n = 201) had adenocarcinoma, 12% (n = 91) of whom had Siewert type 1 gastroesophageal junction adenocarcinoma. Patients received 200 mg of pembrolizumab intravenously every 3 weeks along with standard of care. Patients in the placebo group received the placebo to pembrolizumab intravenously every 3 weeks along with standard of care.

The median duration of follow-up was 22.6 months. A total of 4% (n = 15) of patients in the pembrolizumab group and less than 1% (n = 1) in the placebo group completing the 35 treatment cycles. The mean exposure to treatment was 7.7 months in the pembrolizumab group and 5.8 months in the placebo group.

The OS for patients with esophageal squamous cell carcinoma was 12.6 months in the pembrolizumab group and 8.8 months in the placebo groups (HR, 0.72; 95% CI, 0.60-0.88; 

 = .0006). The OS for those with PD-L1 CPS of 10 or more was 13.5 months in the pembrolizumab group and 9.4 months in the placebo group (HR, 0.62; 95% CI, 0.49-0.78; 

 < .0001), while the OS for all randomized patients was 12.4 months in the pembrolizumab group and 9.8 months in the placebo group (HR, 0.73; 95% CI, 0.62-0.86; 

The 24-month OS rate in the pembrolizumab group was 31% compared with 15% in the placebo group. Moreover, in patients with esophageal squamous cell carcinoma who had a PD-L1 CPS of 10 or more, the 24-month OS rate was 29% in the pembrolizumab group and 17% in the placebo group. Among those with esophageal squamous cell carcinoma, the rate was 31% in the pembrolizumab group vs 15% in the placebo group for those with a PD-L1 CPS of 10 or more. It was also reported that the 24-month OS rate was 28% in the pembrolizumab group compared with 16% in the placebo group for all randomized patients.

PFS for patients with PD-L1 CPS of 10 or more was 7.5 months (95% CI, 6.2-8.2) in the pembrolizumab group and 5.5 months (95% CI, 4.3-6.0) in the placebo group (HR, 0.51; 95% CI, 0.41-0.65; 

< .0001). Additionally, pembrolizumab yielded a median PFS of 6.3 months (95% CI, 6.2-6.9) compared with 5.8 months (95% CI, 5.0-6.0) in the placebo group (HR, 0.65; 95% CI, 0.55-0.76; 

< .0001) in the population of randomized patients.

The overall response rate in all randomized patients in the pembrolizumab group was 45.0% (95% CI, 39.9-50.2) compared with 29.3% (95% CI, 24.7-34.1) in the placebo group. The median duration of response in the pembrolizumab group was 8.3 months and 6.0 months in the placebo group. In total, 18% of patients in the pembrolizumab group had response durations lasting 24 months or longer compared with 6% of those in the placebo group.

All patients had adverse effects (AEs) in the pembrolizumab group vs 99% (n = 368) in the placebo group. AEs of grade 3 or higher occurred in 86% (n = 318) in the pembrolizumab group and 83% (n = 308) in the placebo group. The most notable AEs in the pembrolizumab and placebo cohorts, respectively, were decreased neutrophil count (24% vs 17%), anemia (17% vs 22%), and neutropenia (15% vs 16%).

A total of 24% (n = 90) of patients in the pembrolizumab group and 20% (n = 74) in the placebo group discontinued treatment due to of AEs. Eight percent (n = 28) of patients in the pembrolizumab arm and 10% (n = 38) in the placebo arm died due to of AEs.

Investigators reported that 98% (n = 364) of patients in the pembrolizumab group and 97% (n = 360) in the placebo group had treatment-related AEs (TRAEs). Additionally, 72% (n = 266) of patients in the pembrolizumab group and 68% (n = 250) in the placebo group had a grade 3 of higher TRAE. Two percent (n = 9) of patients in the pembrolizumab group and 1% (n = 5) in the placebo group died due to TRAEs.

Patients also experienced immune-mediated AEs and infusion reactions, including 26% (n = 95) in the pembrolizumab group and 12% (n = 43) in the placebo group. The most common immune-mediated AEs in the pembrolizumab and placebo groups, respectively, were hypothyroidism (11% vs 7%), pneumonitis (6% vs 1%), and hyperthyroidism (6% vs 1%). Grade 3 or higher immune-mediated AEs occurred in 7% (n = 26) of patients in the pembrolizumab group and 2% (n = 8) in the placebo group.

Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. 

. 2021;398(10302):759-771. doi:10.1016/S0140-6736(21)01234-4

Pembrolizumab plus chemotherapy compared with the placebo plus chemotherapy demonstrated an improvement in overall survival and progression-free survival for patients with esophageal squamous cell carcinoma. 

Pembrolizumab Plus Chemotherapy Combination Improves Survival in Esophageal Squamous Cell Carcinoma

The anti–PD-1/CTLA-4 inhibitor combination of balstilimab plus zalifrelimab (AGEN1884) elicited durable responses and notable overall survival (OS) in previously treated recurrent/metastatic cervical cancer, according to data from a single arm phase 2 trial (NCT03495882) presented at the 

2021 European Society for Medical Oncology Congress

Among the 125-patient efficacy evaluable population, the combination elicited an overall response rate (ORR) of 25.6%. Ten (8.8%) responders experienced a complete response (CR). Among the 67-patients with a positive PD-L1 status, the ORR was 32.8% compared with 9.1% in the PD-L1-negative subgroup (n = 33).

Notably, the median duration of response (DOR) was not reached (range, 9.3 months-not reached). The 6-month DOR rate was 86.4% and the 12-month rate was 66.7%.

“There remains a significant unmet medical need for patients with recurrent or metastatic cervical cancer who progress after platinum-containing chemotherapy,” explained David O'Malley, MD, the director of the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine in Columbus.

Results of a single-arm study indicate that patients with previously treated metastatic cervical cancer may derive benefit from treatment with balstilimab plus zalifrelimab.

ONCOLOGY Vol 35, Issue 8 | September 2021

Perspective

Evolving Role of Autologous Stem Cell Transplantation for Light Chain Amyloidosis in the Modern Era

Clinical Quandaries

Sjögren Syndrome Induced by Immune Checkpoint Inhibitors in a Patient with Advanced Renal Cell Carcinoma

Case Study

A 64-Year-Old Man With Germline BRCA2-Mutated Breast Cancer: Known and Unknown Aspects of Male Breast Cancer

Review Article

The Role of Autologous Stem Cell Transplantation in Amyloidosis

Interview

Lung Cancer Investigators Expand Upon Indications of Standard Therapeutic Agents

Editorial

The Unhappy Intersection of Cancer and COVID-19

Clinical Trials in Progress

Clinical Trials in Progress: ROADS Trial