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Melina E. Marmarelis, MD, reports the study design of the Chrysalis-2 trial and ongoing trials researching the combination of amivantamab and lazertinib in patients with EGFR-mutated advanced non–small cell lung cancer.

Ongoing Trials Investigate Amivantamab Combinations for EGFR+ NSCLC

Melina E. Marmarelis, MD, reports the rationale and key findings from the Chrysalis-2 trial of patients with EGFR-mutated advanced non–small cell lung cancer.

Amivantamab Combination Shows Efficacy Post-Osimertinib in EGFR+ NSCLC

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

In practice, what is the most difficult disease feature to manage in primary myelofibrosis? Is it thrombocytopenia, anemia, splenomegaly, constitutional symptoms or other? For anybody who said anemia or thrombocytopenia, do you want to comment on why those are challenging?

I chose anemia. Usually, patients have more symptoms related to anemia than thrombocytopenia, so they probably come to our attention more than thrombocytopenia. Obviously, thrombocytopenia can be a challenge during the treatment…but it is the anemia that I find challenging, because usually once the patient hits low hemoglobin, they become symptomatic, and we try to avoid a transfusion if possible. I find that anemia is more challenging than thrombocytopenia at the beginning.

That's a great point. Anemia is something that's more likely to immediately impact quality of life from the symptoms that it causes, as well as the time spent in clinic.

For myself, especially in the patients that I have, thrombocytopenia tends to be the most challenging for us, because some of our patients’ [platelet counts] are [less than 20,000/μL] or sometimes even less than 10,000/μL and we struggle because transfusions don't work a lot, and a lot of them have other medical comorbidities…especially older patients. These are the challenges that we deal with, and thrombocytopenia is further complicating the picture. Anemia is potentially challenging, but thrombocytopenia is something that makes it difficult.

I've seen a few patients, but the last 2 patients have had issues with constitutional symptoms. Even though their numbers don't translate into that much anemia, and even though the numbers improved, [whether due to] the medicine [or] the disease itself, one of them keeps on asking for prolonging his disability or his time off from work.

So sometimes there's a disconnect between what the blood counts are showing with how the patients are feeling. I think that's pretty common. So that's a great point.

I picked constitution symptoms because fatigue [and others] are so subjective, and I feel those are difficult. Even for patients with profound thrombocytopenia and anemia, we have now drugs available to target those with pacritinib [Vonjo] and momelotinib [Ojjaara], but I feel constitutional [symptoms are challenging] for me. Some of them are younger patients [who] want to keep on a working schedule. Because that's so subjective, I feel that would be the hardest for me.

That's a wonderful point. Sometimes the JAK inhibitors really help with the constitutional symptoms, but they don't always work all the way and like [Dr Samdani] mentioned, sometimes the numbers don't tell the full story, and especially for our younger working patients, fatigue can be a really debilitating symptom that keeps people from working, especially those young patients that are still working.

What patient symptoms prompt you to initiate therapy for myelofibrosis? ​

What symptoms are the most important to control? ​

When do you start JAK inhibitor therapy?​

Do you choose your initial JAK inhibitor based on patient symptoms? ​

What are the symptoms that will prompt you to initiate therapy with myelofibrosis? How do you decide who needs to get started on therapy?

Symptoms will [make me] decide; if the patient has a lot of constituent symptoms, then I will initiate, plus the blood counts. The symptoms and the blood count issues, and sometimes they're related—if somebody has significant anemia, they might have hemoglobin of 9 to 10 g/dL, but they have a lot of constitutional symptoms, like night sweats, fever, and splenomegaly.

The first drug is determined by the blood count. Usually, if their platelet count above 50,000/μL, you can go with ruxolitinib [Jakafi]. If the hemoglobin is down, you can now use momelotinib for patient with significant anemia.

Does anybody have a different approach to initial therapy [besides looking at] blood counts and symptoms, and choosing a JAK inhibitor based on the blood counts?

I have a similar situation as well. I have 1 or 2 patients who have such an indolent disease, even though they do have cytopenias, but because of lack of symptoms, I didn't start them on treatment. I've been following them, but it's predominantly because of cytopenias.

This patient has the platelet count running in the low 20,000s [per μL], but they don't have symptoms for the last at least 5 years I've been following him. For someone like that, [I consider] their goals of care as well, if someone is extremely anxious, worried, and concerned, vs someone who might be weighing in the adverse events of the treatment, or weighing in the risk and benefit and decide that they're comfortable closely being followed. I think that’s part of the discussion that comes into play. When I do start treatment…platelet count is something that I do consider. Usually, my go-to is ruxolitinib, but I had someone recently with post essential thrombocythemia myelofibrosis where I considered fedratinib [Inrebic].

 I just started. I want to see how it goes.

Sounds great. It is approved in first line, so it's not a wrong choice for sure, and it's OK to try it there, even though we're all probably more familiar with ruxolitinib.

His choice was because of the dosing. It's once a day dosing with fedratinib, compared with twice a day [ruxolitinib], and he's someone who works in construction for long hours, so he preferred it once a day.

1. Inrebic. Prescribing information. Bristol-Myers Squibb; 2023. Accessed August 14, 2024. 

2. Jakafi. Prescribing information. Incyte Corporation; 2023. Accessed August 14, 2024. 

During a Case-Based Roundtable® event, Gabriela S. Hobbs, MD, surveyed physicians on the disease features that are most challenging in primary myelofibrosis in the first article of a 2-part series.

Cytopenias and Symptoms Prompt Initiation of JAK Inhibitors in MF 

The FDA has approved the combination of sotorasib (Lumakras) and panitumumab (Vectibix) for the treatment of patients with previously treated 

 G12C-mutated metastatic colorectal cancer (CRC).

The approval is supported by data from the CodeBreaK 300 (NCT05198934) study.

The combination led to improvements in progression-free survival (PFS) and overall response rate (ORR) vs investigator’s choice of standard of care.

Sotorasib plus panitumumab has been approved by the FDA for the treatment of patients with previously treated CRC harboring a 

Data from the phase 3 CodeBreaK 300 study presented at the 

 support this approval. At a median follow-up of 7.8 months, the median PFS in patients treated with sotorasib 960 mg plus panitumumab was 5.6 months (HR, 0.49; 95% CI; 0.30-0.80), and the median PFS in patients treated with sotorasib 240 mg plus panitumumab was 3.9 months (HR, 0.58; 95% CI, 0.36-0.93). Comparatively, the median PFS in patients treated with investigator’s choice of trifluridine and tipiracil or regorafenib (Stivarga) was 2.2 months (95% CI, 1.9-3.9).

The most common grade 3 or higher treatment-related adverse effects in the combination arm were dermatitis acneiform (960 mg, 11%; 240 mg, 4%), hypomagnesemia (6%; 8%), rash (6%; 2%), and diarrhea (4%; 6%).

In September 2006, the FDA granted approval to panitumumab for the treatment of patients with EGFR-expressing, metastatic CRC with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

In May 2021, the granted accelerated approval to sotorasib for the treatment of locally advanced or metastatic 

 G12C-mutated non–small cell lung cancer that had received at least 1 prior line of therapy, supported by data from the phase 2 CodeBreaK 100 study (NCT03600883).

In October 2023, the FDA’s Oncologic Drug Advisory Committee voted 10 to 2 that the PFS data from CodeBreaK 200 (NCT04303780) could not be reliably interpreted, as the PFS difference between the sotorasib and docetaxel control arms was small, and there was no difference in overall survival.

complete response letter to the supplemental new drug application of sotorasib

 failing to convert the accelerated approval to traditional approval.

1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. FDA. January 16, 2025. Accessed January 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer

2. Amgen presents new Lumakras® (sotorasib) plus Vectibix® (panitumumab) data in patients with KRAS G12C-mutated metastatic colorectal cancer. News release. Amgen. October 22, 2023. Accessed October 14, 2024. 

3. Giusti RM, KaushikkumarSA, Cohen MH, et al. FDA drug approval summary: panitumumab (Vectibix). 

The approval of this combination is supported by data from the phase 3 CodeBreaK 300 study. 

Melina E. Marmarelis, MD

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