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Richard L. Wahl, MD, discusses the approval of lutetium Lu 177 vipivotide tetraxetan for patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer.

Lu 177 Vipivotide Tetraxetan Approved for PSMA-Positive mCRPC

ASH 2024 Preview for Community Oncologists: The Show and After Show

The American Society of Hematology (ASH) Annual Meeting and Exposition aims to educate oncology providers across an array of hematologic malignancies, with a focus on novel agents, drugs across the FDA pipeline, and more.

, co-hosts Kristie L. Kahl and Andrew Svonavec offer a glimpse at some of the presentations guaranteed to spark one’s curiosity, spur debate, and enhance the field even further. Some key highlights include:

 Continued advancements in CAR T-cell therapy are expected to revolutionize the treatment of hematologic malignancies.

 Bispecific antibodies, such as Epcoritamab (Epkinly), offer a novel approach to target multiple antigens on cancer cells.

 The assessment of MRD is becoming increasingly important in predicting treatment response and overall survival.

Advances in Acute Lymphoblastic Leukemia (ALL)

Blinatumomab (Blincyto) in pediatric ALL:

 The addition of blinatumomab to chemotherapy has shown promise in improving disease-free survival in high-risk pediatric ALL. This combination therapy may offer a more effective treatment option for young patients.

Acalabrutinib (Calquence) in mantle cell lymphoma (MCL):

 The FDA is set to review the approval of acalabrutinib with bendamustine or rituximab (Rituxan) for previously untreated MCL, based on data from the phase 3 ECHO trial (NCT02972840).

Asciminib (Scemblix) in chronic phase chronic myelogenous leukemia (CML-CP):

 The FDA recently granted accelerated approval to asciminib for newly diagnosed CML-CP. This tyrosine kinase inhibitor has shown favorable safety and tolerability profiles.

 isn't just about data, as the duo also offers food recommendations, tourist attractions and fun activities to partake in, as well as interesting facts about San Diego.

This is just a taste of the wealth of information and inspiration waiting at the 2024 ASH Annual Meeting. Check back for future meeting previews with 

Targeted Oncology co-hosts Kristie L. Kahl and Andrew Svonavec highlight abstracts for community oncologists to look out for at the upcoming ASH Annual Meeting in San Diego, with some additional tidbits to round out the main event.

News

The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in a press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

The FDA has accepted a new supplemental biologics license application (sBLA) for pembrolizumab (Keytruda), an anti-PD-1 therapy, as a single agent for the treatment of patients with advanced endometrial carcinoma that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have diseased progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation, according to a press release by Merck.

The sBLA is based on the results of cohorts D and K of the KEYNOTE-158 trial (NCT02628067), which evaluated pembrolizumab monotherapy in participants with advanced solid tumors. The phase 2 parallel assignment, non-randomized, interventional study had an estimated enrollment of 1595 participants with an estimated completion date of June 2026. The primary end point of the study is objective response rate (ORR). Secondary end points include duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

During the ongoing study, patients receive either 200 mg or 400 mg of pembrolizumab. Solid tumors included in the study include advanced cancer, anal carcinoma, anal cancer, biliary cancer, cholangiocarcinoma, bile duct cancer, neuroendocrine tumor, carcinoid tumor, endometrial carcinoma, endometrial cancer, cervical carcinoma, cervical cancer, vulvar carcinoma, vulvar cancer small cell lung carcinoma, small cell lung cancer, mesothelioma, thyroid cancer, salivary gland carcinoma, salivary gland cancer, salivary cancer, parotid gland cancer, advanced solid tumors, and colorectal carcinoma.

In order to participate in the study, patients must have progressed or are intolerant to therapies with known clinical benefit, have radiologically measurable disease, have an ECOG status of 0 or 1, a life expectancy of at least 3 months, adequate organ function, and must be willing to provide adequate contraception. Patients with a diagnosed immunodeficiency, autoimmune disease, treatment with an anti-cancer monoclonal antibody within 4 weeks prior to study day 1, active infections, or known active central nervous system metastases are not eligible to participate. 

“The FDA’s acceptance of our application adds to our momentum of advancing new treatment options to address the most challenging cancers facing women,” said Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, in a press release. “Keytruda monotherapy is already playing a role for the treatment of certain patients with advanced endometrial carcinoma through the tumor-agnostic MSI-H indication which received accelerated approval four years ago. We look forward to sharing the latest results from KEYNOTE-158, including updated data for Keytruda in certain types of MSI-H/dMMR advanced endometrial carcinoma, at the ESMO Congress in September.”

 in combination with lenvatinib (Lenvima). The combination led to a median OS of 17.4 months in patients with MMR proficient (pMMR) disease versus 12 months with chemotherapy. Among all patients, the median OS was 18.3 months for the combination compared to 11.4 months with chemotherapy.

The median PFS for the combination was 6.6 months in patients with pMMR and 7.2 months in the overall population. For patients who received the chemotherapy, the median PFS was 3.8 months for those with pMMR disease and 3.8 months in the general population. The ORR for the combination in patients with pMMR disease was 30.3% versus 15.1% for those who received the combination. The rate of complete responses was 5.2% in the combination cohort versus 2.6% in the chemotherapy cohort. 

1.FDA accepts application for Merck’s KEYTRUDA® (pembrolizumab) as single agent for certain patients with MSI-H/dMMR advanced endometrial carcinoma. News release. Merck. August 10, 2021. Accessed August 10, 2021. 

2. Study of pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-158/KEYNOTE-158). ClinicalTrials.gov. Accessed August 10, 2021.

The FDA has accepted a new supplemental biologics license application for pembrolizumab, an anti-PD-1 therapy, as a single agent for the treatment of patients with advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, who have diseased progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. 

FDA Accepts sBLA for Pembrolizumab Monotherapy for Endometrial Cancer

The FDA has granted approval to pembrolizumab (Keytruda) in combination with chemotherapy and with or without bevacizumab (Avastin), for the treatment of patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 with a combined positive score (CPS) ≥1, as determined by an FDA-approved test, according to an FDA issued press release.

A regular approval was simultaneously granted by the FDA to single-agent pembrolizumab, for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This approval follows an accelerated approval for this indication granted in June 2018 with the companion diagnostic PD-L1 IHC 22C3 pharmDx.

Results from the phase 3 multicenter, randomized, double-blind, placebo-controlled trial (KEYNOTE-826; NCT03635567) support the FDA approval of pembrolizumab/chemotherapy and pembrolizumab alone for patients with recurrent or metastatic cervical cancer with PD-L1 expression. Results from the study were recently presented during the European Society of Medical Oncology Congress 2021.

KEYNOTE-826 showed that adding pembrolizumab to chemotherapy with or without bevacizumab led to a statistically significant and clinically meaningful improvement in overall survival (OS), and progression-free survival (PFS) in women with persistent, recurrent, or metastatic cervical cancer.

The study included 617 patients with persistent, recurrent, or metastatic cervical cancer not amenable to curative treatment who did not receive prior systemic chemotherapy and had an ECOG performance status of 0 or 1. Patients were randomized 1:1 to either pembrolizumab 200 mg given intravenously (IV) every 3 weeks (Q3W) for up to 35 cycles in combination with paclitaxel plus cisplatin or carboplatin iv Q3W for up to 6 cycles, and with or without bevacizumab 15 mg/kg IV Q3W. In the control arm, patients received matching placebo, paclitaxel, cisplatin, carboplatin, and in some cases, bevacizumab.

The coprimary end points of KEYNOTE-826 were OS and PFS per RECIST v1.1 and by investigator assessment. The secondary end points included objective response rate (ORR), duration of response (DOR), 12-month PFS rate, and safety. The study also looked at the exploratory end point of patient-reported outcomes.

Patients were stratified by presence of absence of metastases, high versus low PD-L1 expression, and whether or not they receive bevacizumab.

At a median follow-up of 22.0 months (range, 15.1-29.4), the 12-month PFS rate in in patients with a PD-L1 CPS ≥ 1 was 45.5% (95% CI, 39.2%-51.5%) with the pembrolizumab combination compared with 34.1% (95% CI, 28.3%-40.0%) with the placebo combination (HR, 0.62; 95% CI, 0.50-0.77; 

 <.001). Those with a PD-L1 CPS of ≥10 had a 12-month PFS rate of 44.6% (95% CI, 36.3%-52.5%) with pembrolizumab/chemotherapy compared with 33.5% (95% CI, 25.9%-41.2%) with the control combination (HR, 0.58; 95% CI, 0.44-0.77; 

The 24-month OS rate in the low PD-L1 CPS group treated with pembrolizumab plus chemotherapy was 53.0% (95% CI, 46.0%-59.4%) compared with 41.7% (95% CI, 34.9%-48.2%) with the control (HR, 0.64; 95% CI, 0.50-0.81; 

 <.001. Among patients with ahigh PD-L1 CPS, the 24-month OS rate was 50.4% (95% CI, 43.8%-56.6%) with the experimental combination compared with 40.4% (95% CI, 34.0%-46.6%) with the control (HR, 0.67; 95% CI, 0.54-0.84; 

The ORR observed with the pembrolizumab combination was in patients with a PD-L1 cPS ≥ 1 was 68.1% (95% CI, 62.2%-73.6%) compared with 50.2% (95% CI, 44.1%-56.2%) among patients treated with the placebo and chemotherapy. The median DOR was 18.0 months (range, 1.3+ to 24.2+) in the pembrolizumab arm compared with only 10.4 months (range, 1.5+ to 22.0+) in the placebo/chemotherapy arm. In patients with a PD-L1 CPS ≥ 10, the ORR rate in the pembrolizumab arm was 65.5% (95% CI, 61.8%-76.7%) compared with 49.1% (95% CI, 41.1%-57.1%). The median DOR was 21.1 months (range 1.3+ to 24.2+) with pembrolizumab/chemotherapy compared with 9.4 months (range 2.1+ to 21.5+) with placebo/chemotherapy. 

According to the FDA, peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite are the most common adverse event observed with the combination of pembrolizumab, chemotherapy, and bevacizumab. The FDA recommends that pembrolizumab be dosed at 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.

1. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. News release. FDA. October 13, 2021. Accessed October 13, 2021. 

2. Colombo N Dubot C, Lorusso D, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: Randomized, double-blind, phase III KEYNOTE-826 study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA2_PR.

Pembrolizumab is now FDA approved in combination with chemotherapy and with or without bevacizumab, for the treatment of patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1. 




FDA Approves Pembrolizumab With Chemotherapy for PD-L1+ Recurrent or Metastatic Cervical Cancer

A 48-year-old woman with T1N1 triple-negative breast cancer (TNBC) received adjuvant dose-dense doxorubicin, dose-dense cyclophosphamide, and paclitaxel, which she tolerated well. Eight months after completion of adjuvant therapy, she reports worsening fatigue. ​

Labratory results: alanine aminotransferase 1.5x upper limit of normal, aspartate transaminase 1.5x upper limit of normal

CT showed 1 liver and 2 left lung lesions​.

Biopsy of the liver lesion confirmed recurrent metastatic TNBC ​(mTNBC).

Brain MRI: negative for brain metastasis ​

Genetic panel testing: negative for detectable mutations​

PD-L1 on immune cells (IHC 22C3 pharmDx): 0%​

No significant comorbidities; otherwise healthy​

: What was the FDA indication for sacituzumab govitecan-hziy (Trodelvy) leading to its approval for use in patients with breast cancer?

 For patients with mTNBC, they must have received 2 or more prior systemic therapies, and at least 1 of the therapies [must have been] for metastatic disease.

 Patients can be on second-line treatment, had 1 in the metastatic setting, and the second one could have been in the adjuvant setting.

It’s tricky because I would love to give this particular patient sacituzumab up front. Technically that’s not really the way the indication is from the FDA label because you must have had at least 1 line of therapy in the metastatic setting. Although, I think that many people may argue that, if someone is recurring so soon after capecitabine, they probably had metastatic disease while receiving the capecitabine. But that’s not the way the label is written. If you decided to use sacituzumab in that particular case, you would have to see if insurance would approve it, and how savvy they would be about the nuances of the label.

Microtubule inhibitor (eribulin, vinorelbine)

Initially sacituzumab got an accelerated approval based on their phase 1 basket data.

During a live virtual event, Sara Tolaney, MD, discussed the results of the ASCENT trial of sacituzumab govitecan in patients with triple-negative breast cancer.

Richard L. Wahl, MD

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