The approval of lisocabtagene autoleucel (Breyanzi; liso-cel) for the second-line treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL) represents an exciting shift in care allowing for earlier delivery of personalized medicine, according to Sherry Adkins, MSN, ANP-C.

 based on findings from the phase 3 TRANSFORM study (NCT03575351), which showed that patients who received the CAR T-cell therapy had significant clinical improvement compared with the standard of care of the past 20 years—salvage therapy followed by high-dose chemotherapy plus autologous stem cell transplant (ASCT).

, Adkins, a nurse practitioner in the Department of Myeloma and Lymphoma at University of Texas MD Anderson Cancer Center, discussed the significance of the approval. Adkins is the supervisor for the advanced practice providers who work with patients receiving CAR T-cell therapy at MD Anderson and has firsthand experiencing working on several CAR T-cell therapy clinical trials, including ZUMA-1 (NCT02348216), which led to the release of axicabtagene ciloleucel, the first commercial CAR T-cell therapy for the treatment of lymphoma.

®: What is the significance of the FDA approval of liso-cel in the second-line setting for patients with relapsed/refractory LBCL

 I am really excited that we now have a second-line CAR T-cell therapy for this patient population. Relapsed/refractory disease is known to not respond well to traditional therapies. The sooner we can give this therapy, the better the outcome.

We know from previous studies that patients who receive a lot of prior therapies do not have as robust T cells. With T cells [that] have been exposed to a lot of treatment, the outcome [may] not be as good as if we had healthy T cells.

Moreover, for patients with relapsed/refractory [disease], the chances of responding to traditional therapies is not very good. The sooner we can get to a targeted therapy the better, because then we have a decreased risk for the development of secondary malignancies—­­such as myelodysplastic syndrome and leukemia.

[Regarding] the cost of care, we know that this high-risk population is [probably] not going to respond to chemotherapies, [so if] we keep giving other chemotherapies until we get to the third line, then that is going to cost more for the health care system. There are a lot of positives about moving these therapies closer to the frontline.

Please comment on findings from TRANSFORM trial regarding liso-cel vs high-dose salvage chemotherapy and ASCT. What about the findings stood out to you?

The primary end point of the TRANSFORM study was event-free survival [EFS]. The median EFS for liso-cel was 10.1 months vs [2.3 months] with standard-of-care high-dose chemotherapy with ASCT [HR, 0.34; 95% CI, 0.22-0.52

 < .0001]. [The median] progression-free survival [PFS] for liso-cel was more than twice the standard-of-care arm; 14.8 months vs 5.7 months, [respectively; HR, 0.41; 95% CI, 0.25-0.66;

This is very exciting. We can see there is a big difference between these 2 therapies and it's great for the patient. It’s also important to note the objective response rate (ORR) for liso-cel was 86% vs standard of care which was 48%. And the complete response for liso-cel was 66% vs standard of care at 39%. The outcomes [were] definitely better for the liso-cel group.

We also saw acceptable toxicities. We do not want to have any toxicities, but for second-line therapy, the toxicity rate was even better than for patients in the TRANSCEND-NHL-001 study [NCT02631044]. The number of patients who had all-grade [cytokine release syndrome] CRS was approximately 45% [and] only 1.3% of patients had grade 3 or greater CRS. The findings were also great for neurotoxicity. The rate of all-grade neurotoxicity was 27%. For grade 3 or greater, the rate was only 7%. This is really great for the patients: good efficacy and less toxicity.

Now that CAR T-cell therapy is becoming more prominent, real-world datasets are showing that patients outside of the strict clinical trial criteria also benefit from this therapy. Which factors would providers need to weigh when deciding when to administer liso-cel?

The real-world data is very similar to the survival [data] in the clinical trials. There are a few things that are a little bit different, but in general, that is the case.

There are 2 factors that have been found affect both PFS and overall survival: the ECOG status and [lactate dehydrogenase] LDH levels are the key factors to look at in terms of patients having a positive outcome.

At MD Anderson, we review all patients who are going to [receive] commercial CAR T cells and we look at multiple factors. If they’re above the age of 65 years or their ECOG [performance status] is not good, we send them to a program called prehab to try to “tune them up” and get them ready for CAR T-cell therapy. We also look at their [glomerular filtration rate] GFR. If it is less than 50, that would be considered high risk. That helps us determine if there is a better product to use in that population.

Other [potential risk factors] include absolute monocyte counts less than 1000, platelet counts less than 50, a pulmonary function test detail less than 40, or ejection fraction less than 45%. If they have arrhythmias that are uncontrolled and a low ejection fraction, we also consult our cardiology group to try to see if there’s anything that we can do to “tune them up” quickly so that they can move on to CAR T-cell therapy.

We give CAR T-cell therapy to patients who have secondary CNS involvement, but not to those who have primary CNS. We also look for evidence of secondary malignancies that have been treated or are currently being treated.

Please comment on later care following treatment such as transitions to a community care setting or potentially persistent transfusion dependency.

The majority of patients are receiving CAR T-cell therapy at specialized centers, which are typically not in their hometown. Once the required 30-day stay after receiving the therapy…they travel back home.

It is very important that we communicate information to the local oncologist or [primary care provider]. Some [patients] don’t have an oncologist—we hope that they can find one, but some come from small areas with no oncologist. It is important [that] we communicate information to caregivers and physicians who are there providing follow-up care for these patients.

They need to know that it is not unusual for the patients to have low blood counts for quite [some time] after this therapy [and] they may recover their cell count and then drop again later related to an immune-mediated effect. It’s important to know if they can give growth factors, and when we would recommend transfusing patients for anemia and thrombocytopenia.

Also, it is important that they know what prophylactic antimicrobials the patient should be [receiving]. At MD Anderson, our guidelines are that we treat patients with antiviral and anti-pneumocystis pneumonia prophylactically for 1 year post CAR T-cell therapy and at that point we measure the CD4 count. If it is less than 200, we continue with that prophylaxis, because we did see early-on that a large percentage of patients were developing shingles post CAR-T cell therapy [after being] taken off their antiviral prophylaxis. Those are all important things for the local caregivers to know.

It is important for the patient to know [this information as well.] I encourage my patients to take a copy of the letter that we send to the physicians and to keep it on their person. If they ever need to go to the emergency department, they can present that to the emergency department to help [the care team] understand some things about [their] CAR T-cell therapy.

US FDA approves Bristol Myers Squibb’s CAR T cell therapy Breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy. News release. Bristol Myers Squibb. June 24, 2022. Accessed August 2, 2022. 

Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (Pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL): results from the randomized phase 3 Transform study. 

. 2021;138(suppl 1):91. doi:10.1182/blood-2021-147913

Articles

Sherry Adkins, MSN, ANP-C, discusses the significance of incorporating CAR T-cell therapy regimens, such as lisocabtagene autoleucel, into earlier lines of treatment for patients with relapsed/refractory large B-cell lymphoma.

Adkins Discusses Benefit of Second-line CAR T-Cell Therapy in Large B-Cell Lymphoma

Although the use of immunotherapy in gastrointestinal (GI) cancers is still limited, new research is bringing this treatment approach to the forefront, according to Kelley A. Rone, DNP, RN, AGNP-c, a nurse practitioner at Mayo Clinic in Arizona.

“The addition of immunotherapy will [hopefully] give a boost to some of these difficult-to-treat cancers,” said Rone, who recently gave a presentation on advances in GI cancers as part of the 

 School of Nursing Oncology®. In an interview with 

®, she discusses how immunotherapy represents a promising avenue for many patients in this population.

According to Rone, 3 recently published studies are changing the landscape of GI oncology. These include the CheckMate 648 trial (NCT03143153),

 which assessed nivolumab (Opdivo) plus ipilimumab (Yervoy), and nivolumab plus chemotherapy, against chemotherapy alone in patients with esophageal squamous cell carcinoma (ESCC); the MOUNTAINEER trial (NCT03043313),

 in which tucatinib (Tukysa) combined with trastuzumab (Herceptin) was evaluated in patients with HER2-positive metastatic colorectal cancer; and TOPAZ-1 (NCT03875235), a head-to-head trial of durvalumab (Imfinzi) in combination with gemcitabine plus cisplatin vs chemotherapy alone in patients with advanced biliary tract cancer.

Findings from CheckMate 648 showed that the addition of immunotherapy in the frontline treatment of ESCC improved overall survival (OS) in the intention-to-treat population. The median OS with nivolumab plus ipilimumab was 12.8 months (95% CI, 11.3-15.5) and 13.2 months (95% CI, 11.1-15.7) with the chemoimmunotherapy regimen. These were compared with patients treated in the chemotherapy alone arm who had a median OS of 10.7 months (95% CI, 9.4-11.9). The reduction in risk of death was 22% (HR, 0.78; 95% CI, 0.65-0.95; 

 = .0110) and 26% (HR, 0.74; 95% CI, 0.61-0.90; 

 = .0021), respectively. The OS benefit was consistent across subgroups, irrespective of PD-L1 status.

“We used to not have a lot of immunotherapy options for our [patients with] GI cancer,” Rone said. “We still only use immunotherapy in colon cancer or pancreas cancer if [it is] microsatellite instability–high, but we are seeing more immunotherapy used in ESCC.” She added that although patients with ESCC used to require PD-L1 tumor positivity to receive immunotherapy, new findings have shown that this is no longer necessary, and more patients are able to receive immunotherapy along with chemotherapy.

Data from the phase 2 MOUNTAINEER trial, presented at the 2022 ESMO World Congress on Gastrointestinal Cancer (World GI) showed that patients with previously treated metastatic HER2-positive colorectal cancer had a sustained response to treatment with dual-HER2 inhibitors tucatinib plus trastuzumab.2 Specifically, among 84 treated patients the confirmed objective response rate by blinded independent central review was 38.1% (95% CI, 27.7%-49.3%). Further, at a median follow-up of 20.7 months, the median progression-free survival was 8.2 months (95% CI, 4.2-10.3) with a median OS of 24.1 months (95% CI, 20.3-36.7).

Data from phase 3 TOPAZ-1 trial presented at the 2022 ASCO Annual Meeting showed a 20% reduction in the risk of death with durvalumab plus chemotherapy vs placebo plus chemotherapy for patients with biliary tract cancer (HR, 0.80; 95% CI, 0.66-0.97; 

“The use of immunotherapy to treat something like cholangiocarcinoma is very intriguing to me,” Rone remarked. “I just saw our first patient this week who had durvalumab added to her gemcitabine and cisplatin. That opens up a lot of doors for patients, because chemotherapy plus immunotherapy seems to have better longevity for [patients with] cholangiocarcinoma.

“Sometimes if we can treat with the combination of chemotherapy and immunotherapy initially, then, at some point, we can drop the chemotherapy and use immunotherapy alone to keep the cancer stable,” she explained. “Immunotherapy, in general, is much more tolerable [for] patients. It does not cause all the toxicities that chemotherapy does.”

Rone cautioned that, when administering immunotherapy to patients, there are some key factors to keep in mind. In addition to other immune-related adverse events, patients will likely experience diarrhea with this treatment modality, and joint pain is also quite prevalent. According to Rone, nurses need to stay abreast of these possibilities and to patients directed questions to determine if they are being affected by these toxicities.

“You have to be aware of kind of the subtle immune-mediated toxicities that can occur and you [need] to ask more directed questions,” she concluded.

1. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): first results of the CheckMate 648 study. 

 2021;39(suppl 15):LBA4001. doi:10.1200/JCO.2021.39.15_suppl.LBA4001

2. Seagen announces results from pivotal MOUNTAINEER trial demonstrating clinically meaningful antitumor activity of Tukysa (tucatinib) in combination with trastuzumab in previously treated HER2-positive metastatic colorectal cancer. News release. Seagen Inc. July 2, 2022. Accessed August 1, 2022. https://bwnews.pr/3yC4xQH

3. Oh DY, He AW, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. 

. 2022;40(suppl 4):378. doi:10.1200/JCO.2022.40.4_suppl.378

Kelley A. Rone, DNP, RN, ADNP-c, highlights the pivotal trials assessing the role of immunotherapy in gastrointestinal cancer and what the findings may mean for oncology nurses.

Rone Discusses Exciting Immunotherapy Research in Gastrointestinal Cancer 

Biomarker testing in lung cancer has never been more important, according to Beth Sandy, MSN, CRNP. Targeted treatments are associated with better outcomes and fewer toxicities for patients with select mutations, and although there are multiple barriers to testing, she urges all oncology nurse practitioners to order molecular tests for all newly diagnosed patients with lung cancer.

“It is really important that we are doing the testing,” Sandy, who is a nurse practitioner at Abramson Cancer Center at the University of Pennsylvania, said in an interview with 

®. “Recent studies have shown that we’re not testing at great rates—less than 50% of [individuals] are getting the full next-generation sequencing [NGS] panel, which is testing for all these things. We need to make sure we’re doing a good job.”

Current National Comprehensive Cancer Network recommendations for biomarker testing say that, whenever feasible, providers should recommend a broad panel-based, molecular test. NGS is the most common way to complete this. These can be performed either in-house or through a commercial company. If no biomarkers are uncovered, providers should consider an RNA sequencing panel to detect RNA fusions.

In addition, all patients with metastatic NSCLC with nonsquamous histologic subtypes and NSCLC not otherwise specified should be tested for biomarkers. Testing should be considered in any patients with squamous disease. Further, as of 2022, patients with IB-IIIA NSCLC should be tested for 

 mutations when they are being considered for adjuvant therapy, and patients with II-III NSCLC being considered for adjuvant therapy should be tested for PD-L1.

In addition, patients with stage II-III NSCLC being considered for neoadjuvant therapy should be tested for 

 mutations prior to receiving immunotherapy/chemotherapy, because the presence of the biomarker renders the treatment less effective, Sandy noted.

Sandy recently presented on the value and practicalities of 

® ahead of the conference, Sandy discusses some of the challenges for nurses to consider when ordering the tests.

“There are barriers,” she said. “First of all, you have to make sure that [the test] has been ordered and that the patient has quality tissue for it. For example, sometimes you will order an NGS panel, and it comes back as an “S,” which means quality or quantity is not sufficient to run the test. What do you do then? Do you retest [the patient]? There are a lot of [questions] there.”

“[Further], a lot of these reports are going to an outside company,” Sandy added. “So [you need to check] for a result. Did it go to a portal online that you have to look it up? Did it come across a fax machine, and it’s sitting on a fax machine, and no one’s looked it up? At the University of Pennsylvania, we do in-house testing and even I sometimes can’t find [the results] in our electronic medical records. If it’s embedded in the pathology report, it [may be] hard for me to find—I may overlook it—I [may] have an unconscious bias [and think] a patient isn’t going to have a mutation.”

It is key to ensure that all patients receive molecular testing and that the results find their way into the electronic medical report. Once this has been completed, the next barrier is understanding the results, Sandy said, adding that collaboration with the molecular pathologists is crucial.

“There’s a whole line of numbers and letters that don’t make any sense to me,” she admitted. “I recommend calling the molecular pathologist, whether it’s in your institution or an outside institution, they love to talk about this stuff. I call them and say: What does this mean? Is this targetable? Is there something approved? Is there something in clinical trials? Does it mean that that’s actually actionable?”

Moreover, Sandy noted that the oncology nurse plays a vital role in ensuring that these processes are completed and the test was done. Once it’s been ordered, the oncology nurse ensures the report has been received, deciphered, and explained to the patient. Then, once the report has been conducted, the team can see whether there are any approved targeted therapies that correlate with the mutations.

When it comes to ordering liquid vs tissue biopsies, Sandy noted that there are advantages and disadvantages associated with each.

“Everyone has lung tissue,” she said. “But sometimes tissue come back as QMS: quality not sufficient.”

Blood biopsies are less invasive, and results come back quicker; however, if the tumor did not shed DNA on the day the blood was drawn, the mutations might not show on the report. In addition, these tests cannot detect histology, and cannot therefore determine a “small cell transformation” from 

“[Individuals] who don’t have a big disease burden might not have [tumor] shedding that day. But if you [don’t] actually find a mutation [via liquid biopsy], that doesn’t mean they don’t have a mutation,” she said.

To address these concerns, Sandy recommended ordering both tests. “I would make an argument to do both from the beginning,” she said. “At my institution, the day the patient comes to see me, we do both [tests].”

Because the tissue biopsy takes longer but may be more accurate, by ordering both at the same time, you are providing you patient with the best chance to start treatment sooner, she explained.

“The blood [tests] comes back in less than 5 days. It’s really quick. In comparison, the tissue 2 to 3 weeks,” she said. Further, if something actionable is detected in the liquid biopsy, the patient can be treated right away. If nothing appears in the blood, by already having ordered the solid biopsy, the patient is still waiting for a shorter amount of time to received treatment.

‘By doing both together [liquid] and tissue, you’re going to find more results, and cover all the bases you can to try to find one of these actionable mutations” she concluded.

Sandy B. Molecular testing and targeted therapies in lung cancer. Presented at: 

 School of Nursing Oncology®; July 29-30, 2022; San Diego, CA.

Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer, version 3.2022, NCCN Clinical Practice Guidelines in Oncology. 

. 2022;20(5):497-530. doi:10.6004/jnccn.2022.0025

Beth Sandy, MSN, CRNP, discusses some of the challenges that may be associated with molecular testing, and how oncology nurses can help play a role in ensuring that the reports are received. 

Sandy on the Practicalities of Molecular Testing in Newly Diagnosed Lung Cancer

The role for immunotherapy has evolved over the past decade for patients with gastrointestinal (GI) cancers, according to Kelley A. Rone, DNP, RN, AGNP-c.

Rone, a nurse practitioner in the GI department at Mayo Clinic in Arizona, will discuss advances in GI Cancer as part of the Physician’s Education Resources’ 

® to unpack the latest changes in the field.

Treatment options with immunotherapy are still limited for patients with GI cancers compared with other tumor types, says Rone, adding that patients with colon or pancreatic cancer still need to have microsatellite instability–high disease in order to qualify for immunotherapy. However, the recent FDA approval of 2 nivolumab (Opdivo)-based regimens for the frontline treatment of patients with esophageal squamous cell carcinoma, found that the immunotherapy in combination with chemotherapy or ipilimumab (Yervoy), resulted in durable responses in this population, according to findings from the 

Moreover, Rone is optimistic about the addition of durvalumab (Imfinzi) to gemcitabine and cisplatin for patients with cholangiocarcinoma, and its potential for 

 compared with chemotherapy alone, especially because, for many patients, immunotherapy is more tolerable, she says.

“Chemotherapy is difficult,” Rone says. “Immunotherapy, in general, is much more tolerable [for] patients. It does not cause all of the toxicities that chemotherapy does.”

Rone notes that immunotherapy does come with a host of adverse effects unique to its class. Therefore, nurses who care for patients receiving immunotherapy must ask more directed questions in order to be aware of subtle immune-mediated toxicities that may occur.

Videos

Kelley A. Rone, DNP, RN, AGNP-c, discusses the advantages associated with immunotherapy in the treatment of patients with gastrointestinal cancers. 

Kelley Rone on the Evolving Role of Immunotherapy in GI Cancers

Recommendations for the use of liquid biopsies to detect circulating tumor DNA (ctDNA) were recently released by the European Society for Medical Oncology (ESMO). Investigators reviewed available evidence to provide tumor-specific and general consensus on the use of ctDNA and clarify quality standards required for decision-making.

The assay, which is minimally invasive and can provide more convenient and rapid results compared with tissue samples, has become increasingly used in clinical practice to molecularly profile tumors. The release of ctDNA is believed to be proportional to tumor growth with more ctDNA being shed as a tumor grows.

In early-stage cancers, ctDNA has a role in screening, neoadjuvant monitoring, identification of molecular residual disease (MRD), molecular relapse monitoring, and early assessment of treatment response. Of note, the guideline authors state there is a lack of clinical evidence to support the recommendation of ctDNA assays in these areas.

“New technologies currently in development, such as methylation pattern-based sequencing, fragmentation pattern-based sequencing or novel ultra-sensitive mutation detection methods, have the potential to optimize utility in these new settings,” the study authors wrote. “Multiple clinical trials are underway that may provide the evidence base to adopt ctDNA assays for decision making in multiple clinical scenarios.”

However, ctDNA assays have a larger role for patients with advanced disease as it can be used to guide adoptive adjuvant strategies upon clinical relapse, identify biomarkers to guide therapy and monitor response to therapy, and, upon disease progression, ctDNA assays can be used to identify acquired resistance mechanisms and the emergence of driver and resistance clones.

The evaluation of ctDNA varies and a single ctDNA assessment is fit for all purposes. Investigators noted that the ctDNA fraction changes based on tumor features such as extent of necrosis, disease burden, tumor location, inflammation, rates of proliferation and apoptosis, tumor microenvironment and host-related phenomena. Treatments such as chemotherapy, targeted therapy, radiation, and immunotherapy can also affect levels of ctDNA and ctDNA fraction.

Liquid genotyping consists of polymerase chain reaction (PCR)-based technologies and many studies have shown positive predictive values between ctDNA liquid biopsy and tissue-based PCR and next-generation sequencing testing in advanced malignancies (95%-99%). High accuracy of liquid biopsy in breast, gastrointestinal and lung cancer for single-nucleotide variants have been reported in large prospective studies of liquid biopsy.

The ESMO guidelines include tumor-specific recommendations for tier 1 and tier 2 variants across tumor types including the following:

 ctDNA genotyping recommended in treatment-naïve patients with cancer with resistance to prior TKIs. ctDNA testing may not have adequate sensitivity to detect 

 true high copy number gain as resistance mechanism to osimertinib (Tagrisso) or lorlatinib (Lorbrena). Further, amplification and fusion detection is suboptimal with ctDNA assays, and should be repeated in tissue where possible.

mutations should preferentially be tested in ctDNA. 

fusions only when advanced tissue biopsy not available.

 ctDNA testing if tissue not available or when fast turnaround time is needed for urgent therapeutic decision-making.

 V600E/microsattelite instability for chemotherapy-naïve metastatic colorectal cancer is recommended when tissue testing is not feasible or urgent therapeutic decision-making. 

 pathogenic or likely pathogenic somatic variants may be carried out if tissue not available.

 for potential PARP inhibitor therapy. Caution is needed when interpreting results of ctDNA assays due to false-positive CHIP mutations in DNA repair genes.

Pancreatic, hepatocellular, endometrial, urothelial, thyroid, and soft tissue sarcoma

In terms of general tumor site recommendations, the ESMO guideline committee noted the occasions where tissue testing may provide confirmatory or more accurate guidance for treatment decision-making. These include interpretation of pathogenic variants such as 

; retesing results that are deemed “not detected” by ctDNA; and for the detection of fusions and copy number events. Further, liquid biopsy should not be taken when a tumor is responding to treatment.

Liquid biopsy may have limitations for the detection of specific deviations, and they risk false negative results and the authors recommend that clinicians take these into consideration when evaluating the results. A false negative result may occur when a patient’s plasma sample does not have sufficient levels of ctDNA or ‘non-shedding’ happens, preventing the detection of a variant. False positive results may occur when clonal expansion takes place in apoptotic hematopoietic cells, where plasma DNA mainly originates; the frequency of clonal hematopoiesis of indeterminate potential (CHIP) increases with age, previous systemic cancer treatment and smoking. False positives can be minimized with either the sequencing of white blood cell DNA or the pairing sequencing of a tumor tissue sample. Additional limitations of ctDNA testing include a low tumor fraction presence in the sample, which prevents reliable assessment of variant allele fraction and limits copy number alteration analysis.

The guidelines recommend that clinicians consult a molecular tumor board for to assess results.

Pascual J, Attard G, Bidard FC, et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. 

. Published online July 6, 2022. doi:10.1016/j.annonc.2022.05.520

In early-stage cancers, ctDNA has a role in screening, neoadjuvant monitoring, identification of molecular residual disease (MRD), molecular relapse monitoring, and early assessment of treatment response.



ESMO Guideline on Liquid Biopsy Address Quality Standards for Clinical Implementation

Adding a single priming dose oftremelimumab to regular interval durvalumab (Imfinzi; the STRIDE regimen) was associated with superior overall survival (OS) compared withsorafenib (Nexavar) for patients receiving frontline treatments for unresectable hepatocellular carcinoma (HCC), according to updated data from the phase 3 HIMALAYA trial (NCT03298451). The findings, resented at the 2022 ESMO World Congress on Gastrointestinal Cancer, also found the OS benefit to be consistent, regardless of a patient’s baseline albumin-bilirubin (ALBI) grade.

In patients with ALBI grade 1, the STRIDE regimen elicited a median OS of 23.43 months (95% CI, 19.19-28.75), compared with 19.02 months (95% CI, 15.67-23.16) for sorafenib (HR, 0.79; 95% CI, 0.62-1.01). In patients with ALBI grade 2/3, the STRIDE regimen produced a median OS of 11.30 months (95% CI, 9.33-14.19), vs 9.72 months (95% CI, 7.23-11.76) for sorafenib (HR, 0.83; 95% CI, 0.65-1.05).

Additionally, single-agent durvalumab produced favorable OS outcomes vs sorafenib, irrespective of ALBI grade. In patients with ALBI grade 1, the median OS for durvalumab was 21.16 months (95% CI, 17.38-25.86), compared with 19.02 (95% CI, 15.67-23.16) for soreafenib (HR, 0.91; 95% CI, 0.71-1.15). In patients with ALBI grade 2/3, the median OS for durvalumab was 12.29 months (95% CI, 9.30-16.03), vs 9.72 (95% CI, 7.23-11.76) for sorafenib (HR, 0.87; 95% CI, 0.69-1.09).

“We need to acknowledge that this was a post-hoc analysis, and all analyses that we have performed so far have been in respect to liver function, and they have never been prospectively evaluated,” said Arndt Vogel, MD, PhD. “We have a very clear picture that liver function has a strong prognostic impact, which is important when we talk to our patients.”

®, Vogel, a managing senior consultant and professor in the Department of Gastroenterology, Hepatology and Endocrinology, and the head of the GI-Cancer Center at the Hannover Medical School, discussed the post-hoc analysis from the randomized, open-label, multicenter, global HIMALAYA trial presented at the 2022 ESMO World Congress on Gastrointestinal Cancer.

®: Can you expand on the rationale of combining tremelimumab and durvalumab in the phase 3 HIMALAYA trial?

: We have seen in the past that immunotherapy has activity in HCC, but monotherapy with just a PD-1 or PD-L1 inhibitor has not been sufficient enough to achieve a positive phase 3 study. We have seen this in trials with pembrolizumab [Keytruda] and nivolumab [Opdivo].

We have seen in the past that CTLA-4 has activity in a subgroup of patients with HCC. This led to a clear rationale to combine CTLA-4- and PD-1­–targeted agents, as we have seen in other tumor types.

There were early data from the phase 3 CheckMate040 trial [NCT01658878] with nivolumab and ipilimumab [Yervoy] that suggested synergistic activity. There was a clear rationale to proceed with [HIMALAYA] in this setting.

What were the unmet needs that the trial aimed to address?

The majority of our patients are diagnosed in an advanced setting. In early HCC, we can perform resection or liver transplantation, but when the tumor gets bigger, a patient [can present] with vascular infiltration or extra hepatic metastases. We are in a palliative setting, and for many years, we had few options. The major breakthrough came with immunotherapy-based combinations, and this combination of PD-1 and CTLA-4 antibodies is now another important step for the armamentarium for advanced HCC.

What were the primary objectives of the HIMALAYA trial?

The HIMALAYA study was a 3-arm study looking at the combination of durvalumab and 1 single [dose] of tremelimumab, referred to as the STRIDE regimen. This was compared to sorafenib, with a primary end point of showing superiority [in efficacy]. Additionally, the third arm [evaluated] durvalumab monotherapy. Here, this was a key secondary end point to show noninferiority compared with sorafenib.

This was a global study for patients with unresectable HCC that were not suitable for local regional therapies.

What key findings have been found thus far, and what updates were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer?

The HIMALAYA study has been now published as a full paper, and it was a positive study. For the STRIDE regimen, there was superior activity shown in terms of OS compared with sorafenib. Additionally, [single-agent] durvalumab was noninferior to sorafenib.

In HCC, we usually have 2 diseases, including chronic liver disease in many cases, such as liver cirrhosis, and the tumor. Based on past post-hoc analyses from phase 3 studies, liver function is a very important prognostic marker. At the 2022 ESMO World Congress on Gastrointestinal Cancer, we analyzed the affect of liver function on OS for the 2 immunotherapy-based regimens. We grouped patients according to their liver function scores, which was part of the inclusion criteria.

To distinguish 2 groups of patients with different preserved liver function, we utilized the ALBI score, where half of the patients were ALBI grade1, with a good liver function, and the other half was ALBI grade 2/3.

We were able to show in the HIMALAYA study that liver function has a very important prognostic effect. The median OS was almost twice as long in patients with a more well-preserved liver function compared with those with ALBI grade 2.

In terms of efficacy, it was very evident that the STRIDE regimen specifically has clear activity in both groups of ALBI grade 1 and ALBI grade 2/3. There was almost no significant difference in terms of the hazard ratio. We can say the prognostic impact of liver function was confirmed. Importantly, the STRIDE regimen was effective independent from the underlying liver function.

What should be known regarding the safety profile and toxicities associated with the STRIDE regimen?

In the HIMALAYA study, we saw the expected adverse effect [AE] profile, though we have slightly more AEs with the STRIDE regimen compared with the durvalumab monotherapy. There were more immune-related AEs and more steroid use, but overall, there was no negative impact on the quality of life. In our analysis here, there was no impact of liver function on the safety prolie for the patients.

Based on the findings from this trial, what could this potentially mean for the treatment paradigm for patients with unresectable HCC?

We need to acknowledge that this was a post-hoc analysis, and all analyses that we have performed so far have been in respect to liver function, and they have never been prospectively evaluated. We have a very clear picture that liver function has a strong prognostic impact, which is important when we talk to our patients.

In terms of efficacy, the data are not crystal clear. But for the HIMALAYA study, we can clearly conclude that more impaired liver function of ALBI grade 2/3 has no negative impact on the efficacy of durvalumab and tremelimumab. These data need to be confirmed in a real-world setting. But it is reassuring that we do not need to select our patients based on liver function when we consider the use of durvalumab or durvalumab/tremelimumab.

Vogel A, Chan SL, Furuse J, et al. Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the Phase 3 HIMALAYA study. Presented at: 2022 ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022; Barcelona, Spain. Abstract O-5.

Arndt Vogel, MD, PhD, discusses a post-hoc analysis of the phase 3 HIMALAYA trial which found tremelimumab plus durvalumab to be superior to sorafenib in improving overall survival. 



Tremelimumab Plus Durvalumab Bests Sorafenib OS Rates In Frontline HCC Treatment

At a 7.5-year follow-up, nivolumab (Opdivo)-based treatment regimens continued to display superior overall survival (OS) rates, duration of response (DOR), and health-related quality of life (HRQOL) compared with ipilimumab (Yervoy) monotherapy, according to a long-term follow-up analysis of CheckMate 067 (NCT01844505) presented during the 2022 ASCO Annual Meeting.

In the trial, 314 patients received nivolumab/ipilimumab, 316 received nivolumab alone, and 315 received ipilimumab alone. The OS survival rate among those receiving dual immunotherapy was 48% compared with 42% with nivolumab alone and 22% ipilimumab alone. The median OS in these groups was 72.1 months (95% CI, 38.2-not reached [NR]), 26.9 months (95% CI, 28.2-58.7), and 19.9 months (95% CI, 16.8-24.6), respectively.

The progression-free survival (PFS) rate among the 3 cohorts was 37%, 36%, and 33%, respectively. Median PFS was 11.5 months (95% CI, 8.9-10.0), 6.9 months (95% CI, 5.1-10.2), and 2.9 months (95% CI, 2.8-3.1).

Moreover, the median melanoma-specific survival (MMS) rates among the 3 treatment groups were 55%, 47%, and 26%, respectively; however, the median MSS rate was NR in the dual group. Median MMS was not reached (95% CI, 71.9-NR), 49.4 months (95% CI, 35.1-NR), and 21.9 months (95% CI, 18.1-27.4).

The median DOR was not reached in the nivolumab/ipilimumab group (95% CI, 69.1-NR), vs 90.8 months in the nivolumab cohort (95% CI, 45.7-NR), and 19.2 months in the ipilimumab cohort (95% CI, 8.8-47.4).

Furthermore, compared with patients who received monotherapy, patients receiving nivolumab/ipilimumab experienced more time treatment free and were less likely to receive subsequent systematic therapy. The median time to subsequent systemic therapy was NR, 24.7 months, and 8.0 months, respectively. Among patients who were alive at the data cutoff, (138 patients in the combination cohort, 115 in the nivolumab cohort, and 60 in the ipilumumab cohort), 77%, 70%, and 45%, respectively were off study treatment and had not required any subsequent systemic therapy. The median treatment-free interval for these patients was 69.8, 45.4, and 30.3 months, respectively

“At a 7.5-year follow-up, OS and progression-free survival remained superior in the nivolumab containing treatment arms compared with ipilimumab alone,” F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, said in a presentation of the data.

The study authors noted that targeted therapies and immunotherapies have revolutionized the treatment and management for patients with metastatic melanoma. The CheckMate 067 and 069 trials (NCT01927419) were pivotal in establishing the superiority of nivolumab plus ipilimumab in the treatment landscape.

At a 6.5-year follow-up, investigators found that patients with previously untreated, stage III/IV unresectable or metastatic melanoma derived superior clinical benefit with nivolumab/ipilimumab vs with nivolumab or ipilimumab alone. The median OS was 72.1 months, and the OS rate was 49%. Further, the median MSS was not reached, and the MSS rate was 56%. Investigators therefore planned to conduct an additional follow-up after 12 months to evaluate to the long-term efficacy and HRQOL outcomes with the combination.

Overall, 945 patients with previously untreated, unresectable or metastatic melanoma were randomized 1:1:1 across the 3 treatment cohorts and were stratified by 

 status, AJCC M stages, and tumor PD-L1 expression.

mutant tumors, the OS rates were 57%, 42%, and 25%, across the combination, nivolumab, and ipilimumab groups, respectively. Further, in patients with 

 wild type status, the OS rates were 43%, 41%, and 21%. There was a total of 4 melanoma progression-related deaths across all 3 cohorts.

The overall response rate was unchanged from the 6.5-year analysis, and was 58%, 45%, and 19%, respectively.

The European Quality of Life 5-dimenisons 3-vevel utility index was used to evaluate HRQOL. Findings revealed that the mean changes in HRQOL from baseline were maintained for the durations of therapy in patients receiving treatment, with patients receiving nivolumab monotherapy reporting data for a longer follow-up period. No sustained deterioration in HRQOL following treatment discontinuation was detected. During the treatment-free intervals, HRQOL was maintained, and a few improvement time points were noted for nivolumab/ipilimumab.

Hodi FS, Chiarion-Sileni, Lewis KD, et al. Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067. 

2022;40(suppl 16): 9522. doi:10.1200/JCO.2022.40.16_suppl.9522

Nivolumab, whether in combination with ipilimumab or as a monotherapy, was associated with improved overall survival, progression-free survival, and melanoma-specific survival, compared with ipilimumab in advanced melanoma. 

7.5-Year Follow-Up Affirms Nivolumab’s Superiority Over Ipilimumab in Advanced Melanoma

In a subgroup analysis of the phase 3 TOPAZ-1 trial (NCT03875235), the addition of durvalumab (Imfinzi) to gemcitabine and cisplatin continued to improve overall survival (OS) in patients with advanced biliary tract cancer compared with patients who received chemotherapy alone. Moreover, the findings were consistent across primary tumor location, according to Aiwu Ruth He, MD, PhD, who presented the results during the 2022 ESMO World Congress on Gastrointestinal Cancer.

Findings previously presented from the primary analysis

 demonstrated a 20% reduction in the risk of death with durvalumab plus chemotherapy vs placebo plus chemotherapy in this patient population (HR, 0.80; 95% CI, 0.66-0.97; 

At a median follow-up of 13.7 months in the durvalumab/chemotherapy arm and 12.6 months in the placebo/chemotherapy arm, the median OS was 12.8 months (95% CI, 11.1-14) vs 11.5 months (95% CI, 10.1-12.5), respectively. The 18-month OS rates were 35.1% (95% CI, 29.1%-41.2%) and 25.6% (95% CI, 19.9%-31.7%), respectively. The 24-month OS rates were 24.9% (95% CI, 17.9%-32.5%) and 10.4% (95% CI, 4.7%-18.8%), respectively.

On May 4, 2022, the FDA accepted a supplemental biologics license application and granted priority review to the combination for the treatment of patients with locally advanced or metastatic biliary tract cancer based on findings from the trial.2

“Based on the subgroup analysis and the primary report, I feel comfortable recommending the combination of durvalumab plus gemcitabine and cisplatin as frontline systemic therapy for patients with biliary tract cancer, if those patients do not have any contraindications for immunotherapy,” said He.

®, He, the scientific lead in liver and biliary cancers at MedStar Georgetown University Hospital, discussed the benefit seen with the combination in patients with advanced biliary tract cancer and the importance of additional correlative research evaluating potential biomarkers of response.

: Findings from the interim analysis of TOPAZ-1 were presented during the 2022 Gastrointestinal Cancers Symposium. What was the significance of the results?

: The combination of cisplatin and gemcitabine had been the standard first-line therapy based on the phase 3 ABC-02 study [NCT00262769] for over a decade. [TOPAZ-1] is the first positive randomized, phase 3 study that has shown benefit of adding another drug to this standard chemotherapy combination.

The preplanned interim analysis of TOPAZ-1 showed the study met the primary end point. There was a statistically significant improvement in OS in patients treated with the combination of durvalumab plus gemcitabine and cisplatin vs gemcitabine and cisplatin plus placebo.

[At the 2022 ESMO World Congress on Gastrointestinal Cancer,] I presented a subgroup analysis of the efficacy and safety data from the trial based on primary tumor location. Biliary cancer is a very heterogeneous disease that includes intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. Each anatomic location can have different risk factors, etiology, and presentation or prognosis.

In this subgroup analysis of TOPAZ-1, the addition of durvalumab to gemcitabine and cisplatin was associated with improved OS in patients with advanced biliary tract cancer, irrespective of primary tumor location.

What are the next steps for research with this regimen?

I am very excited about additional biomarker analysis. Blood samples have been collected from patients enrolled in this study. In this cancer, there are a lot of potentially targetable mutations [because it’s] genetically very heterogeneous. There will be a lot of information we can learn [from these analyses]. Are we able to find patients with a certain genetic background or molecular profile that would benefit most from the combination therapy? That information also may teach us how to overcome resistance.

Within the scope of biliary tract cancer, what research are you excited to see develop?

I always talk about targeted therapy, because 40%-50% of patients with biliary tract cancer may have targetable mutations. We keep identifying targetable mutations and [ways] to use targeted therapy to treat those patients with certain genetic alterations. We have FDA-approved agents for 

 mutations. Now there are data coming out in 

amplified biliary cancer. Those are always very exciting areas for us who treat patients with cholangiocarcinoma. We expect better targeted therapies to come out, and better selective biomarkers will define the patient population that responds to this therapy.

Second, durvalumab has shown, for the first time in the phase 3 TOPAZ-1 study, improved outcomes in combination with chemotherapy. I expect more work will be done with immune checkpoint inhibitors in cholangiocarcinoma evaluating dual immunotherapy and immunotherapy plus another targeted therapy in combination with chemotherapy. Also, the combination of durvalumab plus gemcitabine and cisplatin was quite well tolerated. Durvalumab did not increase toxicity much [in the trial]. This could be a good regimen to build on with additional immunotherapy in combination with the goal of improving patient outcome.

The other thing that’s always exciting is circulating [tumor DNA (ctDNA)] biomarkers, because in cholangiocarcinoma it’s very difficult to get a lot of tissue to do profiling. Circulating biomarkers will help us identify mutations and track patients’ response to therapy and development of early resistance. There’s a lot of ongoing research [aiming] to make ctDNA markers work better for cholangiocarcinoma. Those are the 3 areas we’ll have a lot more information on in the next couple of years.

Oh DY, He AW, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. 

Imfinzi plus chemotherapy granted priority review in the US for patients with locally advanced or metastatic biliary tract cancer based on TOPAZ-1 phase III trial. News release. AstraZeneca. May 4, 2022. Accessed June 29, 2022. 

A subgroup analysis found that the addition of durvalumab to chemotherapy resulted in maintained overall survival benefit in patients with advanced biliary tract cancer, regardless of primary tumor location. 

Adding Durvalumab to Chemotherapy Continues to Improve Overall Survival in Advanced Biliary Tract Cancer

An expanded safety analysis of CheckMate 648 (NCT03143153) illustrated a manageable safety profile with nivolumab (Opdivo) plus chemotherapy, and nivolumab plus ipilimumab (Yervoy), as frontline treatment for esophageal squamous cell carcinoma (ESCC).The analysis, which was presented during the 

, also highlighted key differences in median onset and resolution times between the dual immunotherapy and chemotherapy combinations, as well as the number of patients receiving immune modulating medications (IMM) at a 1-year follow-up.

 nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy or ipilimumab for unresectable advanced or metastatic ESCC based on 

. Overall, the study demonstrated that these frontline combinations may be a viable method of extending overall survival in all-randomized patients with ESCC as well as those with a tumor cell PD-L1 score of at least 1%, compared with chemotherapy alone.

In addition, the nivolumab plus ipilimumab and nivolumab plus chemotherapy regimens, yielded superior time to second disease progression (PFS2) and demonstrated greater efficacy in prolonging duration of response compared with chemotherapy, regardless of tumor cell PD-L1 score. Deep responses were reported across all 3 treatment regimens.

The updated data confirmed the adverse event (AE) profiles were consistent with previously reported safety outcomes of the individual components at similar doses. Further, 2% or less of patients treated with nivolumab plus chemotherapy and 6% of less of patients treated with nivolumab pus ipilimumab developed grade 3/4 TRAEs with potential immunologic etiology.

Across the 3 treatment arms, the percentage of patients who experienced a TRAE of any-grade in the nivolumab/chemotherapy (n = 310), nivolumab/ipilimumab (n = 332), and chemotherapy alone arms (n = 304) were 96%, 80%, and 90%, respectively. Among these, the percentage of grade 3/4 TRAEs was 47%, 32%, and 36%.

The percentage of TRAEs leading to treatment discontinuation across the 3 arms was 34%, 18%, and 19%, respectively, and the number of treatment-related deaths was 5 (2%), 8 (2%), and 6 patients (2%), respectively.

Data on TRAEs with potential immunologic etiology showed that any-grade endocrine-related toxicities occurred in 12%, 27%, and fewer than 1% of patients receiving nivolumab/chemotherapy, nivolumab/ipilimumab, and chemotherapy alone, respectively. The rates of any-grade gastrointestinal-related toxicities were 21%, 12%, and 15%; hepatic toxicities were 10%, 13%, and 4%; pulmonary toxicities were 6%, 8%, and fewer than 1%; and renal toxicities were 24%, 2%, and 19%, respectively. Skin-related toxicities were the most common, the rate of these toxicities in the nivolumab/ipilimumab arm (34%) and occurred at rates of 17% and 4% in the nivolumab/chemotherapy and chemotherapy alone arms, respectively.

Among patients who received nivolumab plus chemotherapy and experienced a non-endocrine TRAE with potential immunological etiology, most were resolved (57%-91% across organ categories). The median time to resolution had a range of 1.5 to 17.1 weeks.

Data from the CheckMate 648 trial informed the FDA’s recent approval of 2 nivolumab combinations for esophageal squamous cell carcinoma. A 1-year follow-up analysis highlighted key safety and time-to-event data surrounding immune-related toxicities. 

Immuno-Oncology