Tony Berberabe

As investigators have developed a greater understanding of treating hematologic malignancies, they have been faced with increasingly complex challenges, especially when classifying and treating these cancers. A lot has changed, according to Jorge E. Cortes, MD, director at the Georgia Cancer Center at Augusta University. Cortes shared his insights in an interview with Targeted Therapies in Oncology™ prior to the 26th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma. The conference, hosted by Physicians’ Education Resource®, LLC (PER®), will be held in Miami Beach, Florida, in February 2022.

“There are many more challenges in classifying and understanding the biology,” said Cortes, who is a cochair of the conference. “There isn’t 1 type of AML [acute myeloid leukemia], there isn’t 1 type of CML [chronic myeloid leukemia], and there isn’t 1 type of myeloproliferative syndrome.”


Classifying and analyzing hematologic malignancies now involves morphology, cell surface markers, immunohistochemistry, and cytogenetic abnormalities. Further complicating the clinical picture is the identification of novel subclasses that have distinct molecular profiles and clinical behaviors, Cortes said.

Historically, AML was treated in the first-line setting using induction therapy with cytarabine and daunorubicin. Treating CML involved interferon, and myeloproliferative neoplasms were treated with hydroxyurea. Effective therapies were limited, and these were relatively simple to give.

Although now there are many more treatments available, that poses another challenge that involves treatment choice, treatment sequence, and timing of treatments. “How does the oncologist choose when there are 3 or 4 options for a given scenario?” Cortes asked. In addition, the speed at which the treatment landscape evolves is rapid and ever changing, making sharing of information more important than ever. These challenges and more will be addressed at the conference through case scenarios, question-and-answer sessions, and presentations by world-renowned experts.

The role of chimeric antigen receptor (CAR) T cells and other immune-based therapies will have expanded coverage during the conference. A full afternoon session will be dedicated to addressing advances in CAR T-cell therapy for hematologic malignancies and other immune-based therapies and strategies to overcome treatment resistance. Other sessions will focus on applying state-of- the-art treatment strategies in the clinical practice setting.

“Treatment with CAR T cells is a rapidly emerging field. They play a big role in pediatric acute lymphoblastic leukemia, but their role will expand beyond the pediatric setting,” Cortes said.

Molecular screening and information to help clinicians decide which screening panels to consider will be a topic of discussion, Cortes said.

“That’s a topic that inevitably comes up because there are so many approaches. They range from homegrown panels to commercial panels. These panels can offer identification of a few genes to some panels with hundreds of genes,” Cortes said. The clinician is challenged to make sense of this information and sometimes is given more information than what’s asked for. “How does the clinician know what’s valuable and what’s not? What’s valuable therapeutically? What’s valuable from a prognostic perspective? These are questions that will be addressed during the conference,” Cortes said.

Cortes anticipates that one area for important discussion will be research that evaluated venetoclax (Venclexta) in AML from the initial phase 1, phase 2, and randomized phase 3 studies, which established the agent as the standard of care in a short amount of time.

The FDA approved the agent in October 2020 in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC) for the treatment of newly diagnosed acute myeloid leukemia in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

 Venetoclax was previously granted provisional approval under the FDA’s accelerated approval program in November 2018.

The approval is primarily based on the results of 2 phase 3 studies, VIALE-A (NCT02993523) and VIALE-C. (NCT03069352) Results of the VIALE-A study, which were published in the 

 in August 2020, showed venetoclax plus azacitidine significantly reduced the risk of death by 34% (overall survival; OS) compared with azacitidine alone (median OS, 14.7 months vs 9.6 months; HR, 0.66; 95% CI, 0.52-0.85; 

Patients treated with venetoclax plus azacitidine had significantly higher rates of complete remission (CR), 37% (95% CI, 31%- 43%) compared with 18% (95% CI, 12%-25%) in patients treated with azacitidine alone (

 < .001). The venetoclax plus azacitidine combination also led to higher rates of CR and CR with partial hematologic recovery (CR + CRh), with the combination showing a CR + CRh of 65% compared with 23% with azacitidine alone (

The most frequent serious adverse reactions (≥ 5%), reported in 83% of patients treated with venetoclax plus azacitidine, were low white blood cell count with fever (30%), pneumonia (22%), blood infection (excluding fungal; 19%), and bleeding (6%).

 the approval was based on the rate and duration of CR. Twenty-seven percent (95% CI, 20%-35%) of patients treated with venetoclax plus low-dose cytarabine (LDAC) achieved a CR (median duration of CR [DOCR], 11.1 months) vs 7.4% (95% CI: 2.4%-16%) of patients treated with LDAC alone (median DOCR, 8.3 months).

The median OS for patients treated with venetoclax plus LDAC was 7.2 months vs 4.1 months (HR, 0.75; 95% CI, 0.52-1.07; 

 = .114) for patients treated with LDAC alone. These OS results were not statistically significant.

The most frequent serious adverse reactions (≥ 10%), reported in 65% of patients treated with venetoclax plus LDAC, were pneumonia (17%), low white blood cell count with fever (16%), and blood infection (excluding fungal; 12%).

Another topic of discussion will be trials that look at elective treatment discontinuation or trials that focus on the effects of limiting chemotherapy, especially in CML. Discussions about connecting patients with optimal therapy also will garner much interest. “These are some of the important findings from clinical research that have been presented over the past year,” Cortes said.

The 4-day conference will take place at the Eden Roc Miami Beach hotel in Florida.

1. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. News release. Accessed October 21, 2020. https://bit.ly/3ptyC0G

2.DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. 

. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971

3. Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. 

. 2020;135(24):2137-2145. doi:10.1182/blood.2020004856

Articles

Complex challenges have arisen with classifying and treating hematologic malignancies in recent years, according to Jorge E. Cortes, MD.

Conference Will Highlight Strategic Treatment Delineation in AML, CML

Investigators determined the feasibility, safety, and tolerability of new combinations of tisotumab vedotin (Tivdak; TV) and bevacizumab (Avastin) or pembrolizumab (Keytruda) or carboplatin in a 2-part multicohort, phase 1b/2 trial (ENGOT-cx8/GOG-3024/innovaTV 205; NCT03786081). TV is an investigational antibody- drug conjugate directed at tissue factor, which is highly expressed in many solid tumors, particularly cervical cancer. The 3 combination agents have nonoverlapping mechanisms of action and are known to be active in cervical cancer.

The primary objective of the study was to determine the maximum tolerated dose, as well as recommend a phase 2 dose (RP2D) for TV combined with bevacizumab, pembrolizumab, or carboplatin. Secondary objectives were to evaluate the safety and tolerability, antitumor activity, and durability of tumor response of the TV combinations.

Bradley Monk, MD, FACOG, FACS, presented the dose-binding portion of the study, which led to the recommended RP2D, during the International Gynecologic Cancer Society 2021 Annual Global Meeting.

“Baseline demographics were representative of the patient mix as seen in the clinic,” Monk, medical director of gynecologic oncology research at The US Oncology Network, and professor, clinical scholar track, University of Arizona College of Medicine in Phoenix, said. “The majority of patients had either failed first-line or second-line treatment for metastatic disease,” he continued.

At data cutoff on March 1, 2021, the median duration of follow-up was 8.6 months (range, 5-20) for the TV plus bevacizumab arm, 16.0 months (range, 0-22) for the TV plus pembrolizumab arm, and 12.5 months (range, 0-20) for the TV plus carboplatin arm. Monk noted that disease progression was the most common reason for discontinuation of study treatment for all patients in the TV plus bevacizumab arm. In both the TV plus pembrolizumab and TV plus carboplatin arms, 61.5% of patients discontinued because of disease progression, reported investigators. Discontinuation of treatment due to adverse events (AEs) was rare, with no patients in the TV plus bevacizumab arm and 15.4% of patients for both the pembrolizumab and carboplatin arms.

“There were no instances of dose-limiting toxicities in any of the cohorts based on review by the data monitoring committee,” Monk said. “We never reached a maximum tolerated dose. [This means] that it’s possible to combine full-dose TV with full-dose bevacizumab, pembrolizumab, or carboplatin,” Monk continued.

The maximum planned dose level was determined to be the RP2D in each study arm, which was TV 2 mg/kg plus bevacizumab at 15 mg/kg, carboplatin area under the curve 5, or pembrolizumab 200 mg once every 3 weeks. No fatal AEs related to TV were reported, and common grade 3 or higher AEs related to TV included anemia (30.8%) and thrombocytopenia (15.4%) in the TV plus carboplatin arm and peripheral sensory neuropathy (15.4%) in the TV plus pembrolizumab arm (

). Prespecified AEs of interest included ocular AEs, bleeding, and peripheral neuropathy, but these were mostly grade 1 or 2.

For all combinations, the majority of patients demonstrated a decrease in tumor burden from baseline, with more than half of the patients showing greater than 30% reduction at the respective RP2Ds for each arm.

“Five patients in the TD plus bevacizumab arm had a confirmed objective response, and that included 1 complete response and 4 partial responses,” Monk said. “In the other arms, 2 of 11 patients in the pembrolizumab arm and 4 of 12 patients in the carboplatin arm had partial responses,” he said.

Monk noted that a previous pivotal phase 2 single-arm study2 showed that single-agent TV had durable and clinically meaningful activity with a 24% response rate (95% CI, 15.9%-33.3%) and 7% complete response rate in patients with metastatic or recurrent cervical cancer. Additionally, 49% of patients had stable disease.

These findings led to the FDA approval of TV monotherapy for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TV is the first and only approved antibody-drug conjugate for this indication.

Monk said the findings from innovaTV 205 show that the maximum planned dose of TV and the combination agents were feasible and considered to be the RP2D. “All combinations showed some promising but preliminary antitumor activity. I think we’d all agree that these data are encouraging. We’re excited for dose-expansion cohorts,” he concluded.

1. Monk BJ, Van Gorp T, Lorusso D, et al. Tisotumab vedotin + bevacizumab or pembrolizumab or carboplatin in recurrent/metastatic cervical cancer: phase 1b/2 ENGOT-Cx8/GOG-3024/innovaTV 205 study dose escalation results. Presented at: International Gynecologic Cancer Society 2021 Annual Global Meeting; August 30-September 2, 2021; virtual.

2. Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. 

. 2021;22(5):609- 619. doi:10.1016/S1470-2045(21)00056-5

3. Seagen and Genmab announce FDA accelerated approval for Tivdak™ (tisotumab vedotin-tftv) in previously treated recurrent or metastatic cervical cancer. News release. Seagen, Inc. September 20, 2021. Accessed September 20, 2021. https://bwnews.pr/3hSbILN

Tisotumab Vedotin Combos Are Tolerable, Feasible in Recurrent Metastatic Cervical Cancer

The combination of pembrolizumab (Keytruda) plus trastuzumab (Herceptin) and chemotherapy continued to demonstrate deeper and durable responses compared with trastuzumab and chemotherapy in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer in an interim analysis of KEYNOTE-811 (NCT03615326).1

Investigators reported an overall response rate (ORR) of 74.4% in the treatment arm, which was a statistically significant difference of 22.7% compared with the placebo arm (95% CI, 11.2-33.7; 

 = .00006). Findings from the phase 3 global trial were presented during the European Society for Medical Oncology 2021 World Congress on Gastrointestinal Cancer.

The interim analysis resulted in an accelerated approval of the immune checkpoint inhibitor combination for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.2

In KEYNOTE-811, 692 patients with HER2-positive disease and an ECOG performance status 0 or 1 were randomized to receive pembrolizumab at 200 mg every 3 weeks and trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for up to 35 cycles vs placebo and trastuzumab plus chemotherapy. Dual primary end points were overall (OS) and progression-free survival (PFS). Key secondary end points were ORR and duration of response (DOR) per RECIST v1.1.

“These were relatively well patients with excellent functional status and organ function,” lead author Yelena Y. Janjigian, MD, chief, gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center, said during presentation of the data. “It's important to note that patients were permitted to enroll regardless of PD-L1 status.”

Janjigian noted that the data presented was from the protocol-specified first interim analysis.

After the first 260 patients enrolled with ≥ 8.5 months of follow-up, investigators evaluated if adding pembrolizumab to trastuzumab and chemotherapy improved ORR based on the one-sided superiority boundary of 

 = .002. At the data cutoff of June 17, 2020, 434 patients had enrolled with the first 264 patients evaluated for efficacy. All patients who had received ≥ 1 dose of study medication were evaluated for safety.

In the efficacy population, after a median follow-up of 12.0 months (range, 8.5-19.4), 41% of patients were still enrolled and were continuing with therapy compared with 28% of patients continuing in the placebo arm. In patients undergoing treatment, 5% discontinued because of adverse events (AEs) compared with 8% in the placebo arm.

In the intent-to-treat population, with a median follow-up of 9.9 months (range, 0.1-19.4), similar dispositions were observed. In the treatment arm, 59% of patients continued, compared with 48% in the placebo arm. Treatment discontinuation rates were similar as well: 41% in the treatment arm and 52% in the placebo arm, respectively.

Overall, baseline patient characteristics were relatively well matched between the 2 arms in the efficacy and intent-to-treat populations, Janjigian said.

In the efficacy population, 97% of patients in the treatment arm demonstrated any decrease in size of tumor from baseline; further, 32% of patients demonstrated a decrease in tumor size of ≥ 80%. In the placebo arm, 90% of patients had any decrease in tumor size and 15% of patients had a decrease of ≥ 80%.

“We observed much more deeper responses and more meaningful responses [in the treatment arm] compared with the placebo arm, in which 15% of the population had deep responses of ≥ 80%,” Janjigian said.

The confirmed response rate in the efficacy population also favored the treatment arm. Investigators reported a disease control rate of 96% in the treatment arm vs 89.3% in the placebo arm. Median duration of response in the treatment arm was 10.6 months vs 9.5 months in the placebo arm, with patients in the treatment arm reporting a ≥ 6-month duration at rates of 70% vs 61% in the placebo arm. Nine-month DOR rates were 58% in the treatment arm vs 51% in the placebo arm.

“What is also notable is that in the pembrolizumab arm, in addition to this depth of response and overall response rate of 74%, 11% of patients had complete responses, which is quite remarkable for this combination and is not what we would typically expect in metastatic gastric cancer,” Janjigian said.

There were no new signals observed and the regimen was relatively well tolerated, Janjigian said. The most common AEs reported were chemotherapy-related events. In the treatment and placebo arms, these included diarrhea (53% vs 44%, respectively), nausea (49% vs 44%), and anemia (41% vs 44%).

The incidence of immune-mediated AEs and infusion reactions was higher in the treatment arm compared with the placebo arm (18% vs 13%, respectively), as were the incidence of pneumonitis (5% vs 1%), colitis (5% vs 2%), and hypothyroidism (5% vs 3%). Overall, AEs were similar between the arms of the study.

“An analysis of OS and PFS will be performed in the future, according to the analysis plan. We are already using this [regimen] in the clinic, and it’s well tolerated,” Janjigian concluded.

Janjigian YY, Kawazoe A, Yanez P, et al. Initial data from the phase 3 KEYNOTE-811 study of trastuzumab and chemotherapy with or without pembrolizumab for HER2-positive metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Presented at: 2021 World Congress on Gastrointestinal Cancer; June 30-July 3, 2021; Virtual. Abstract LBA-4.

FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. Accessed July 3, 2021. 

“We observed much more deeper responses and more meaningful responses [in the treatment arm] compared with the placebo arm, in which 15% of the population had deep responses of ≥ 80%."


Deep, Durable Responses Continue With Pembrolizumab and Trastuzumab in Gastric/GEJ Cancer

demonstrated positive clinical activity in an ongoing phase 1a trial (NCT03544905) at the European Society for Medical Oncology Targeted Anticancer Therapies Virtual Congress 2021 by lead investigator Xiao-Li Wei, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China.

“Objective tumor responses were observed in 5 patients, including 1 complete response (CR) in 1 patient with ovarian cancer and 4 partial responses (PRs), 1 each in patients with colorectal cancer, breast cancer, ovarian cancer, and gastric cancer,” Wei said, during a virtual presentation of the findings.

The study was composed of 2 stages—a dose-escalation phase and a dose-expansion phase. In the dose-escalation phase, patients received 1 mg, 5, mg, 10 mg, 20 mg, 40 mg, and 60 mg of the agent. Dose expansion occurred at 20 mg, 30 mg, and 40 mg. Patients with or without 

mutations were eligible for dose escalation, but only patients with 

mutations were eligible for dose expansion.

The trial’s primary end points were safety, tolerability, and maximum tolerated dose of the oral monotherapy. The secondary end points were preliminary efficacy and pharmacokinetics, objective response rate (ORR), progression-free survival, duration of response, disease control rate, and the clinical benefit rate.

Thirty-nine patients, about evenly divided between male and female, were enrolled between July 2018 and November 2020.

Their median age was 54 years, and 21 (53.8%) harbored a 

mutation. Twenty-one patients (53.8%) had an ECOG performance status of 1, and the majority (71.8%) of patients had received 2 or more lines of prior therapy. 

The most common treatment-related adverse effect (TRAE) was any-grade hyperglycemia, affecting 84.6% of patients. Grade 3 hyperglycemia affected 51.3% of patients.

“Hyperglycemia was manageable and reversible, effectively controlled by antihyperglycemic medication or insulin,” said Wei.

Subsequent any-grade TRAEs observed were decreased appetite (33.3%), nausea (33.3%), and diarrhea (28.2%), on-target effects that were expected, Wei noted. Peripheral and facial edema each affected 15.4% of patients, which clinicians should keep in mind, added Wei. She said that no grade 4 or 5 TRAEs were reported.

Investigators reported that 3 patients had experienced dose-limiting toxicity: grade 3 hyperglycemia at the 40-mg and 60-mg dose level, and grade 3 nausea at the 60-mg dose level. Ultimately, the 40-mg dose was deemed to be the recommended phase 2 dose. 

Overall, 17 of 33 patients whose tumors harbored 

mutations were identified, and the ORR in this subpopulation was 23.5%. There were 4 patients on treatment as of the data cutoff date of November 15, 2020, Wei said.

“The main reason for stopping treatment was disease progression [56.4%] or subject withdrawal [17.9%],” Wei said. In patients with disease control, the median treatment duration was 16.4 weeks and the longest treatment duration time was 51 weeks in 1 patient with ovarian cancer.

In the dose-escalation phase, investigators reported 1 CR, 4 PRs, and 11 patients with stable disease. At the 40-mg dose, the overall ORR was 25.0%, and in the 

A total of 4 PI3K inhibitors have been approved by the FDA: idelalisib (Zydelig), copanlisib (Aliqopa), and duvelisib (Copiktra), all in hematologic malignancies; and alpelisib (Piqray), approved for hormone receptor–positive, HER2-negative breast cancer.

Studies involving CYH33 as monotherapy and in combination with other antitumor agents are ongoing to further explore the safety and efficacy in larger populations, concluded Wei.

Wei X-L, Liu J-H, Zhao H, et al. 33O: A phase I study to evaluate safety, pharmacokinetics (PK), and preliminary efficacy of CYH33, a phosphatidylinositol 3-kinase α (PI3Kα) inhibitor, in patients (pts) with advanced solid tumours. 

. 2021;32(suppl 1):S14. doi:10.1016/annonc/j.annonc.2021.01.048

A PI3Kα inhibitor, CYH33, demonstrated positive clinical activity in an ongoing phase 1a trial  at the European Society for Medical Oncology Targeted Anticancer Therapies Virtual Congress 2021.









Promising Efficacy, Manageable Safety Are Observed for CYH33 in Solid Tumors

Prostate-specific antigen (PSA) changes were observed 6 weeks after the administration of 

Lu-PSMA in men with metastatic castration-resistant prostate cancer (mCRPC), suggesting a prognostic value for long-term clinical benefit, according to a single center retrospective analysis presented at the Society of Nuclear Medicine and MolecularImaging 2020 Annual Meeting–Virtual Edition, held from July 11 to 14.

Lead author Andrei Gafi ta, MD, of the Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich in Germany, and colleagues wrote in their poster that the earlier response observed in this study could help clinicians decide if a change in treatment is required in the absence of a response. Further, the investigators noted that PSA responses at 6 weeks post treatment could indicate a long-term benefi t for overall survival (OS) and imaging-based progression- free survival (PFS). 

A total of 115 men had PSA levels measured at baseline, after 6 weeks of treatment, and at 12 weeks after

Lu-PSMA initiation. The percentage change from baseline at 6 and 12 weeks were categorized as a response, progression, and stable. Coprimary end points were OS and PFS. Secondary end points were PSA changes at 12 weeks and PSA flare-up, defined as an increase of at least 25% at 6 weeks followed by a decline below baseline levels at 12 weeks.

The investigators reported that median OS was 13.4 months (95% CI, 11.1-15.6) and the median PFS was 3.3 months (95% CI, 2.0-4.6). Overall, they noted that 50 patients (40%) experienced a PSA decline of greater than 30% at 6 weeks, whereas 30 patients (23%) had a PSA decline of greater than 50%. In the progression group, 3% of patients (1 of 36) had a PSA decline below baseline levels at 12 weeks, suggesting that minimal flare-up was experienced by patients.

Regarding changes to PSA, the investigators noted an association between PSA changes at 6 weeks and 12 weeks, and signifi cance between the percentage changes of those 2 time points (

 < .001). Ninety-four percent of 31 patients who exhibited progression at 6 weeks had PSA measurements at 12 weeks (

Gafita and colleagues reported that the PSA decline of 30% or greater at 6 weeks was associated with longer OS (median, 16.7 months) compared with both stable PSA (median, 11.8 months; 

 = .007) and PSA progression (median, 6.5 months; 

 < .001). PSA decline of 50% or greater at 6 weeks (median, 19.4 months) was not signifi cantly associated with longer OS compared with stable PSA (median, 12.6 months; 

 = .05), and in contrast to PSA progression (median, 6.5 months; 

The investigators observed that a PSA decline of 30% or greater at 6 weeks was associated with longer PFS (median, 7.1 months) compared with stable PSA (median, 2.0 months; 

 = .01) and PSA progression (median, 1.2 months; 

 <.001). A PSA decline of 50% or greater at 6 weeks was not statistically associated with longer PFS (median, 7.1 months) compared with stable PSA (median, 3.6 months; 

 = .30), in contrast to PSA progression (median, 1.2 months; 

The investigators reported that patients with a PSA response at 6 weeks also had a reduced risk of radiographic progression compared with those with stable PSA (HR, 0.60; 95% CI, 0.38-0.94; 

 = .02), whereas patients with PSA progression had a higher risk of radiographic progression compared with those showing stable PSA (HR, 3.18; 95% CI, 1.95-5.21; 

The investigators concluded that “PSA measurements as early as 6 weeks after 

LuPSMA initiation are associated with the clinical outcome and should be further investigated as a surrogate end point for clinical trials. Patient [treatment] decisions and…PSA flare-up during 

Gafi ta A, Heck M, Rauscher I, et al. Early prostate-specifi c antigen changes and clinical outcome following 177Lu-PSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer. 

d. 2020:61(suppl 1):591. doi:10.2967/jnumed.119.240242

Prostate-specific antigen changes were observed 6 weeks after the administration of 177Lu-PSMA in men with metastatic castration-resistant prostate cancer, suggesting a prognostic value for long-term clinical benefit, according to a single center retrospective analysis.

Early Responses Observed With Lu-PSMA Administration May Provide Prognostic Outlook in mCRPC

The HER2 receptor represents a prototypical molecular abnormality that is detectable in several common solid tumors including breast, ovarian, endometrial, colon, non–small cell lung, prostate, and cervical cancer. HER2 is an established target in breast cancer, but success in other solid tumors, remains elusive. Anti-HER2 agents in breast cancer have helped inform further development of agents in other tumor types moving forward.

 At the recent 2020 American Society of Clinical Oncology Virtual Scientific Program (2020 ASCO), key research evaluating the use of anti-HER2 agents were highlighted across multiple solid tumors, including gastric or gastroesophageal junction (GEJ) adenocarcinoma, colorectal cancer (CRC), and non–small cell lung cancer (NSCLC).

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor.

In the DESTINY-Breast01 trial (NCT03248492), which evaluated patients with HER2-positive metastatic breast cancer who had previously been treated with ado-trastuzumab emtansine (T-DM1; Kadcyla), T-DXd demonstrated strong efficacy, with an objective response rate (ORR) of 60.9% and median progression-free survival (PFS) of 16.4 months.2 These data were simultaneously published in the 

Further analysis of the DESTINY-Breast01 trial was presented during 2020 ASCO. Investigators explored the association between 15 clinical predictor variables and efficacy using logistic regression models and Cox proportional hazard models. Efficacy was demonstrated in all clinical subgroups analyzed; subgroups had ORRs ranging from 46.4% to 74.5% and PFS values ranging from 12.3 to 18.1 months, similar to the results reported for the overall cohort. Variables associated with improved efficacy included hormone receptor–positive status, fewer previous treatments, pertuzumab (Perjeta) given in the first or second line, and normal renal and hepatic function.

Additional DESTINY trials were presented during 2020 ASCO, as well as stand-alone trials with other HER2-directed therapies that are summarized herein.

Gastric cancer is proving to be an important setting for the use of anti-HER2 therapies in general and for T-DXd specifically, demonstrated by positive results from the DESTINY-Gastric01 trial (NCT03329690). Results from the primary analyses in patients with HER2-positive status were presented. HER2-positive status was determined by an immunohistochemistry (IHC) score of 3+. In cases with a borderline IHC result (score of 2+), a positive in situ hybridization (ISH) result confirming 

gene amplification could also indicate HER2-positive status.

“Chemotherapy plus trastuzumab [Herceptin] is a standard treatment for HER2-positive gastric cancer,” Kohei Shitara, MD, staff physician in the Department of Experimental Therapeutics and Gastrointestinal Oncology, National Cancer Center Hospital East, in Kashiwa, Japan, said during a recorded presentation of the poster. “However, several phase 3 studies with other HER2- targeting agents have failed to show survival benefit. Therefore, there is still an unmet need for patients with HER2-positive gastric cancer.”

This phase 2 study enrolled 187 patients with HER2-expressing advanced gastric cancer (AGC) or GEJ adenocarcinoma at 66 sites: 48 in Japan and 18 in South Korea. Patients had progressed on 2 or more prior regimens. The primary cohort was randomized to receive 6.4 mg/kg of T-DXd every 3 weeks (n = 125) or physician’s choice of chemotherapy (n = 62; irinotecan or paclitaxel). The primary end point was ORR determined by independent central review using RECIST version 1.1, and secondary end points were overall survival (OS), duration of response, PFS, disease control rate (DCR), and safety.

Shitara said the study met its primary end point, with ORR for patients treated with T-DXd (51.3%) over patients in the physician’s choice arm (14.3%; 

<.0001). Median duration of response was 11.3 months (95% CI, 5.6-not estimable) for T-DXd versus 3.9 months (95% CI, 3.0-4.9) with physician’s choice.

The investigators reported a significant improvement in median OS that favored the T-DXd arm (12.5 months) compared with 8.4 months for the physician’s choice arm (HR, 0.59; 95% CI, 0.39-0.88; 

= .0097) (TABLE 1).4 Additionally, the OS 

value crossed the prespecified boundary of .0202. OS rates at 6 and 12 months also favored T-DXd versus physician’s choice, at 80.3% versus 66.4% and 52.1% versus 28.9%, respectively.

Forty-eight percent of patients in the T-DXd arm received poststudy treatment, with 31.2% receiving a PD-1/PD-L1 inhibitor, versus 74.2% of patients in the physician’s choice arm, with 45.2% receiving a PD-1/PD-L1 inhibitor.

“Interestingly, more patients were on treatment at the time of data cutoff in the T-DXd arm than in the physician’s choice arm [22.4% vs 4.8%],” Shitara said.

Median PFS was 5.6 months (95% CI, 4.3-6.9) with T-DXd versus 3.5 months (95% CI, 2.0-4.3) with physician’s choice (HR, 0.47; 95% CI, 0.31- 0.71; 

= .0003). In subgroup analyses, ORRs also favored T-DXd and were consistent within each treatment arm across subgroups.

Regarding safety, the most common grade 3 or greater treatment-emergent adverse effects (TEAEs) were decreased neutrophil count, observed in 51.2% of patients who received T-DXd and 24.2% of patients who received physician’s choice, followed by anemia (37.6% vs 22.6%), decreased white blood cell count (20.8% vs 11.3%), and decreased appetite (16.8% vs 12.9%). Among patients in the T-DXd arm, 9.6% developed interstitial lung disease (ILD)/pneumonitis, with a median time to onset of 84.5 days (range, 36-638 days). Most cases were grade 1 or 2 in severity, although there were 2 patients with grade 3 and 1 patient with grade 4.

“In summary, T-DXd demonstrated statistically significant and clinically meaningful improvements in objective response rate and overall survival compared with the standard chemotherapy in patients with HER2-positive gastric cancer, with separation [of the Kaplan-Meier curves] and [with] intestinal lung disease as notable toxicity,” Shitara said. “Based on these findings, T-DXd may be an effective treatment option for patients with advanced HER2-positive gastric/GEJ adenocarcinoma who have progressed after trastuzumab.”

Further research in the gastric setting is examining combination therapies. The following phase 1 and 2 trials often combine anti-HER2 agents with immunotherapies.

Significant tumor shrinkage was observed in the phase 1b/2 PANTHERA trial (NCT02901301) of the triplet combination of pembrolizumab (Keytruda), trastuzumab, and chemotherapy as first-line therapy for HER2-positive AGC.

Investigators from Yonsei Cancer Center of Yonsei University College of Medicine in Seoul, South Korea, reported tumor shrinkage of 95.3%, a median depth of response of 54.6%, and an ORR of 76.7% (TABLE 2).5 Further analysis revealed that the ORR consisted of 16.3% complete responses (CRs) and 60.5% partial responses (PRs), and the DCR was 97.7%. Median PFS was 8.6 months (95% CI, 7.2-22.0), and median OS was 18.4 months (95% CI, 17.9-not available).

Results of the open-label, phase 1b Ni-HIGH study to determine the safety and tolerability of adding an anti–PD-1 antibody to trastuzumab in patients with HER2-positive AGC were also presented at 2020 ASCO. The trial consisted of a safety portion and an expansion portion.

 Eligible patients had histopathologically confirmed HER2-positive AGC and measurable lesions.

In the safety portion, patients were randomized to receive nivolumab (Opdivo; 360 mg), trastuzumab (course 1, 8 mg/kg; course ≥2, 6 mg/kg), and oxaliplatin (130 mg/m2) once every 3 weeks plus either S-1 (a prodrug of 5-fluorouracil at 40 mg/m2 twice per day) or capecitabine (1000 mg/m2 twice per day) for 14 days of every 3-week cycle until disease progression or unacceptable toxicity.

Both the S-1– and capecitabine-containing regimens were shown to be well tolerated. The investigators reported that this ongoing study demonstrates favorable efficacy for these combinations.

Another trial evaluated pembrolizumab with trastuzumab, fluoropyrimidine, and platinum chemotherapy in HER2-positive metastatic esophagogastric cancer using plasma and tumor-based biomarker analysis.

The objectives were to evaluate circulating tumor DNA (ctDNA) as a possible early predictor of therapeutic response and resistance and to identify genomic mutations leading to resistance. Tumor biopsies and serial blood samples were collected from patients. To be eligible for this first-line regimen, patients had to have a diagnosis of stage IV, HER2-positive metastatic esophagogastric cancer.

Tumor-matched ctDNA was detected at baseline in 84% of patients. Median PFS was longer in patients who cleared ctDNA at 9 weeks (12.3 months; 95% CI, 7.44-not available) than in those who did not (3.9 months; 95% CI, 2.01-not available). Activating 

alterations were found in 10 patients upon progression.

Loss of HER2 overexpression/amplification was noted in 44% of patients with postprogression samples, as determined by IHC or fluorescence ISH. The reappearance of ctDNA preceded radiographic progression in 56% of patients with serial ctDNA. The investigators concluded that reappearance of ctDNA may serve as an early predictor of progression.

The open-label, phase 2 DESTINY-CRC01 study (NCT03384940) evaluated T-DXd in patients with HER2-expressing, unresectable, and/or metastatic CRC. Eligible patients had progressed on 2 or more lines of therapy and had wild-type 

“Importantly, patients who received prior anti-HER2 therapies were allowed to enroll, [whereas] patients with a history of or suspected interstitial lung disease were excluded,” lead investigator Salvatore Siena, MD, a professor of medical oncology at Università degli Studi di Milano in Italy, said during a recorded presentation of the data.

Three cohorts were evaluated. Cohort A comprised 53 patients with HER2-positive tumors, defined as IHC 3+ or IHC 2+/ISH positive. Siena said that futility monitoring was conducted after at least 20 patients in cohort A had undergone 12 weeks of follow-up to inform the opening of cohorts B and C, which both had low HER2 expression. Cohort B comprised 7 patients whose tumors were HER2 IHC 2+ and ISH negative. Cohort C contained 18 patients who had HER2 IHC 1+ tumors.

The primary end point was confirmed ORR by independent central review in cohort A. In the overall study population, the median age was 58.5 years. The median sum of target lesions was 8.4 cm in cohort A and 8.8 cm for all patients. The primary tumor site was the left intestine in almost 90% of patients, both in cohort A (88.7%) and in the overall study population (89.7%). About 80% of patients had microsatellite-stable tumors; the remainder had unknown status.

Regarding previous treatments, 100% of patients in cohort A had received either panitumumab (Vectibix) or cetuximab (Erbitux), which are both anti-EGFR antibodies. About 30% of patients in cohort A had received anti-HER2 agents, such as pertuzumab, trastuzumab, T-DM1, lapatinib (Tykerb), or tucatinib (Tukysa).

The ORR in cohort A was 45.3% (24 of 53 patients) and consisted of 1 CR and 23 PRs. An additional 20 patients in cohort A had stable disease, resulting in a DCR of 83%.

“Interestingly, median duration of response was not reached,” Siena said. “There were no confirmed responses in cohorts B and C.”

The median treatment duration was 4.8 months (range, 1-11) in cohort A and 3.5 months (range, 1-11) in all patients.

Drug-related TEAEs of grade 3 or higher occurred in 50.9% of patients in cohort A and 48.7% of all patients. Serious drug-related TEAEs were reported in 22.6% of patients in cohort A and 17.9% of all patients. There were 2 deaths related to the study drug, including 1 death of pneumonitis and 1 caused by ILD; both occurred in cohort A.

“[ILD] was an adverse effect of special interest,” Siena said. “Among 78 patients treated with T-DXd, ILD occurred in 5 patients, with a median time to onset of 80 days, ranging from 22 to 132 days.” He added that ILD is an important risk that requires careful monitoring and proper intervention.

Interim results of DESTINY-Lung01 (NCT03505710) revealed a high response rate that was durable in 42 patients with 

- mutated NSCLC who were treated with T-DXd.9 Findings were presented in a prerecording by Egbert Smit, MD, PhD, professor of pulmonary medicine (pulmonary oncology) at the Netherlands Cancer Institute and in the Department of Pulmonary Diseases of Vrije Universiteit Medical Centre in Amsterdam, the Netherlands.

Eligible patients had unresectable, metastatic NSCLC that was relapsed or refractory to standard treatments. The primary end point was confirmed ORR by independent central review.

Cohort 1 enrolled patients with HER2-expressing tumors, defined as IHC 2+ or 3+. Cohort 2 consisted of patients whose tumors harbored an activating 

mutation. All patients were treated with T-DXd (6.4 mg/kg) every 3 weeks. The authors presented results for cohort 2 in this report.

The median age of patients at baseline was 63.0 years, and the majority (64.3%) were women. ECOG performance status was 0 (23.8%) or 1 (76.2%). Central nervous system metastases were present in 45.2%. Median prior lines of treatment was 2 and included platinum-based therapy (90.5%), a PD-1/PD-L1 inhibitor (54.8%), and docetaxel (19.0%).

The investigators reported that 45.2% of patients in cohort 2 remained on treatment at the data cutoff in November 2019. The other 54.8% discontinued treatment, with the primary reasons being progressive disease (21.4%) and adverse events (AEs; 21.4%).

The confirmed ORR by independent review was 61.9% (95% CI, 45.6%-76.4%). One patient (2.4%) had a CR, 59% had PRs, and 28.6% had stable disease as their best outcome.

Median PFS was 14.0 months (95% CI, 6.4- 14.0), and median OS was not reached (95% CI, 11.8-not evaluable).

- mutated NSCLC was generally consistent with what was previously reported, said Smit. Low-grade gastrointestinal and hematological AEs were most commonly observed. TEAEs that occurred in more than 15% of patients were mainly nausea, alopecia, anemia, decreased appetite, decreased neutrophil count, and vomiting. The majority of the TEAEs were either grade 1 or 2.

“Of note, the median duration of exposure of patients to the study drug was 7.8 months,” Smit said. The most common TEAEs associated with dose reduction were fatigue and nausea. The most common TEAEs associated with dose interruption were decreased neutrophil count and lung infection. Five patients with TEAEs died, but investigators noted that none of the deaths were considered to be related to the treatment.

“In this analysis, there were 5 patients [who] experienced grade 2 interstitial lung disease, but there were no patients [who] had interstitial lung disease of higher grades,” said Smit.

“However, ILD remains an important identified risk for patients treated with T-DXd and requires careful monitoring and management,” Smit said. “The study was expanded with an additional 50 patients to better characterize the risk-benefit ratio of T-DXd in patients with 

-mutated non–small cell lung cancer,” Smit concluded.

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6. Takahari D, Shoji H, Minashi K, et al. A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study): safety evaluation. 

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8. Siena S, Di Bartolomeo M, Raghav KPS, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. 

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At the recent 2020 American Society of Clinical Oncology Virtual Scientific Program, key research evaluating the use of anti-HER2 agents were highlighted across multiple solid tumors, including gastric or gastroesophageal junction adenocarcinoma, colorectal cancer, and non–small cell lung cancer.