OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

THE PROSTATE SPECIFIC MEMBRANE antigen (PSMA)-targeting therapy, lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 

Lu-PSMA617), was approved by the FDA for patients with metastatic castration-resistant prostate cancer (mCRPC) in March.

Investigators explored the efficacy of radioligand therapy lutetium Lu 177 vipivotide tetraxetan in combination with standard care options including treatments such as hormonal therapies radiation therapy, or glucocorticoid at any dose, in the phase 3 VISION trial (NCT03511664). Overall survival (OS) data supported the approval. The median OS among the 551 patients who received the combination was 15.3 months (95% CI, 14.2-16.9) vs 11.3 (95% CI, 9.8-13.5) among the 280 patients who received standard care alone (HR, 0.62; 95% CI, 0.52-0.74; P < .001).

“[PSMA-targeting] drugs are starting to become increasingly applied in patients who have not had good responses to the more standard therapies,” Richard L. Wahl, MD, said in an interview with 

. “I think [lutetium Lu 177 vipivotide tetraxetan] will become a relatively standard part of the care of patients with advanced prostate cancer. [This drug] targets the PSMA protein on the surface of prostate cancer [tumors]. Most metastatic prostate cancers have an abundance of PSMA on their surface and when the lutetium 177 label molecule is injected, it will home in to those tumors and deliver radiation selectively to the tumor [rather than the] normal tissue.” Wahl is the Elizabeth E. Mallinckrodt Professor of Radiology, chair of the Department of Radiology, and director of the Mallinckrodt Institute of Radiology at the Washington University School of Medicine in St Louis, Missouri.

Response was evaluated among those who had measurable disease at baseline. The overall response rate was 30% (95% CI, 25%-35%) vs 2% (95% CI, 0%-2%) among patients who received the combination (n = 319) vs those who received standard care (n = 120), respectively.

 The complete response rate and partial response rate with lutetium Lu 177 vipivotide tetraxetan and standard care were 6% and 24%, respectively. These rates were 0% and 2%, respectively, with standard care alone.

The OS analysis was performed in the intention-to-treat population, which included all patients who had undergone randomization. The coprimary end point, imaging-based progression-free survival (PFS), was assessed in the population enrolled following a protocol amendment that required enhanced education measures at trial locations to address high withdrawal rates.

Among the 385 patients who received the combination the median imagebased PFS was 8.7 months vs 3.4 months with standard care alone (n = 196; HR, 0.40; 99.2% CI, 0.29-0.57; P < .001).

 A key secondary end point analyzed in this patient population was time to first symptomatic skeletal event. The median time to event onset was 11.5 months in the investigative arm vs 6.8 months in the control arm (HR, 0.50; 95% CI, 0.40-0.62; P < .001).

Adverse effects (AEs) were more prevalent in the lutetium Lu 177 vipivotide tetraxetan arm than the control arm; however, Wahl noted that the treatment was well tolerated. “[One] exciting thing about the therapy was how well tolerated it was,” Wahl said. “The adverse effect profile was quite manageable. [There was a] modest reduction in appetite that was not uncommon and some drops in red blood cell count and white cell count occurred.”

The most common all-grade AEs with the radiotherapy were fatigue (43.1%), dry mouth (38.8%), nausea (35.3%), and anemia (31.8%). Among patients in the control arm the most common all-grade AEs were fatigue (22.9%), nausea (16.6%), back pain (14.6%), and decreased appetite (14.6%).

“One thing [to note with lutetium Lu 177 vipivotide tetraxetan] is that it accumulates in the salivary glands, so some patients could [experience] dry mouth,” Wahl said. He also noted that there were few contraindications for this therapy among this patient population.

Integrating PSMA Radiotherapy into Practice

In addition to approving lutetium Lu 177 vipivotide tetraxetan, the FDA also approved gallium Ga 68 gozetotide (Locametz), a diagnostic agent administered during a PET scan.

 “The PSMA-PET scan, a nuclear medicine procedure, is [used] to see if a small, safe tracer dose of the PSMA targeting agent will accumulate in tumors,” Wahl said. “If the tumors accumulate PSMA to a sufficient extent, then patients will be candidates for [lutetium Lu 177 vipivotide tetraxetan].”

Payment barriers regarding testing to identify eligible patients, and regarding the agent itself, represent one hurdle to integrating this agent into practice. “The scans that are done for this [patient population] are important and necessary to identify individuals who have the PSMA target,” Wahl said. “But one of the challenges we’re facing in nuclear medicine is the availability of funding from Medicare to pay for these scans. When these scans are introduced, there’s a passthrough period of 2 to 3 years when Medicare will pay the cost.” Wahl noted that after 3 years, if therapy is administered in the outpatient setting, reimbursement only covers a generic, nontargeted diagnostic agent. “One of the concerns is that the availability of the diagnostic agents may become limited if they weren’t paid for appropriately and that might limit access for patients to these innovative therapies. That’s something we want to avoid.” In terms of the longevity of nuclear therapy, Wahl said agents such as lutetium Lu 177 vipivotide tetraxetan “will make a real difference and change the way that prostate cancer is treated.”

He added that one area that could be explored is moving the therapy into earlier settings. Ongoing trials of the agent include the phase 3 PSMAfore (NCT04689828), a trial evaluating lutetium Lu 177 vipivotide tetraxetan plus best supportive care vs androgen receptor–directed therapy (ARDT) in patients with mCRPC who previously received an alternate ARDT and who are naïve to taxane-based therapy. The investigational agent is also being compared with standard therapy among patients with metastatic hormone-sensitive prostate cancer in the phase 3 PSMAddition trial (NCT04720157). 

Of note, Novartis, the developer of lutetium Lu 177 vipivotide tetraxetan, temporarily suspended production of the agent in May and halted enrollment to ongoing clinical trials to address “potential quality issues in the production process.” 

In the news release, Novartis stated that they have set a target goal of 6 weeks to the return to manufacturing of their radiopharmaceuticals, which also includes the approved agent lutetium Lu 177 dotatate (Lutathera).

FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed May 20, 2022. bit.ly/3Mxr3yX 

Pluvicto. Prescribing information. Advanced Accelerator Applications USA, Inc; 2022. Accessed May 20, 2022. bit.ly/3wCjPCV 

Sartor O, de bono J, Chi KN, et al; VISION Investigators. Lutetium-177–PSMA-617 for metastatic castration- resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322 

Novartis provides update on production of radioligand therapy medicines. News release. Novartis. May 5, 2022. Accessed May 20, 2022. bit.ly/3luNTuZ

Articles

Oncology Live®

The prostate specific membrane antigen-targeting therapy, lutetium Lu 177 vipivotide tetraxetan, was approved by the FDA for patients with metastatic castration-resistant prostate cancer in March.

Radioligand Therapy Boosts Survival in mCRPC

The fruits of decades of investigative efforts in thoracic oncology are ripe for picking, according to Solange Peters, MD, PhD. Targetable alterations including 

 rearrangements have taken up recent focus for investigators as data are pushing novel agents through the regulatory processes. However, there are several hurdles preventing the translation of these agents into practice including the integration of standardized molecular testing.

In addition to novel therapies illuminating new treatment paths for patients, the success of immunotherapeutic regimens in the metastatic disease has driven investigators to evaluate the applications of the regimens in early-stage resectable disease.

“As the trends move more toward targeted therapies [and we have] agents that are being integrated preresection and postresection, some of the barriers [we need to address are the] issues regarding molecular testing and really integrating that into practice, especially for these patients with early-stage disease,” Peters said in an interview with 

. “Immunotherapy also has a large role to play early disease with surgery or any kind of radical treatment. That’s really a revolution.”

As a young investigator, Peters got her start in infectious disease research focusing the topic of her PhD at the Microbiology Institute at the University of Lausanne in Switzerland on the mechanisms of resistance for HIV infection. “If you think about HIV infection and the first treatment, we were [investigating] the clonal divergence of HIV viruses creating resistance. And if you think about my wording it reminds you of cancer, right? How [do we] address something which might kill [an individual] taking into consideration genetic changes over time.” As advances in HIV research plateaued, Peters looked for a way to translate her interest in genetic research to a new field.

“I was working in HIV as a biologist and an MD and, at the time, HIV [infection] was almost under control, I was looking for a field where in the sensitivity of first disease, a second grows, where there is an unmet need in bridging medicine and biology, but also bridging genetics and genetic modifications with treatments. There is no better discipline than oncology,” Peters said. “I immediately found there what I loved in HIV. It’s amazing how [rapidly] the discoveries are now coming, [in particular] looking at genetics.”

Peters has earned a place of prominence among lung cancer investigators and in the oncology area as a whole. She is serving her second year as president of the European Society for Medical Oncology (ESMO). Additionally, Peters is chief of the Medical Oncology Service, an associate professor and chair of Thoracic Oncology, and the chief resident of thoracic malignancies in the Oncology Department at the University Hospital of Lausanne (CHUV) in Switzerland.

Peters is also an active participant in many scientific meetings, including the upcoming 

 taking place July 28-30, 2022, in Huntington Beach, California. The program, hosted by Physician’s Education Resource

), LLC, will cover a wide range of topics in thoracic oncology including updates on biomarkers, surgical treatment modalities for resectable disease, and more (

“I want to know what my colleagues think about the [available] data,” Peters said. “I learn something about the nuance of the data, or the limitations, or maybe something I haven’t thought about. The Congress’ [agenda] is broad, so you do the same exercise [as in other meetings], but in a very comprehensive fashion and this is of tremendous importance.”

Lung cancer had beginnings in a category of diseases associated with very poor outcomes, Peters noted. “Using the traditional surgery, chemotherapy, and radiation, the outcomes for [patients with] lung cancer have been very, very disappointing for years.” However, as data began to read out from several landmark trials, Peters said that a new story began to unfold in the field in 2 important chapters for thoracic malignancies.

“The first chapter is molecular biology,” Peters said. “We’re trying to understand and discover what are the oncogenes leading to the malignant phenotype. [This research] has led to a wonderful portfolio of targeted therapies.”

This course of molecular discovery kicked off when investigators identified the role of 

 mutations in non–small cell lung cancer (NSCLC) leading to the introduction of personalized medicine in the field, specifically with the EGFR inhibitor gefitinib (Iressa).

In the following decade, progress to uncover aggressive mutations accelerated with the identification of 15 mutations that afford patients opportunities for therapy beyond chemotherapy and radiation.

For example, in the past 2 years, treatment options for metastatic NSCLC have risen exponentially with agents including mobocertinib (Exkivity) and amivantamab-vmjw (Rybrevant) for patients with 

 exon 20 insertions, tepotinib (Tepmetko) and capmatinib (Tabrecta) for patients with 

 exon 14 skipping mutations, sotorasib (Lumakras) for patients with 

 G12C mutations, and lorlatinib (Lorbrena) for patients with 

“From time to time we will discover new compounds or new targets,” Peters said. “I think the low hanging fruits might have been caught by in terms of oncogenes.” Although progress has not stalled in discovery, Peters noted that the focus is now shifting toward improvements in the pharmacology of the agents being developed. “We have been handling more potent drugs, broader drugs in terms of preventing resistance, and very often drugs [developed for metastatic disease], which with lung cancer [can] spread over everywhere in the body, including the brain.”

Peters noted that faced with all progress in molecularly defined disease, testing rates across countries creates limitations in identifying appropriate patients for select therapies. “In Switzerland, [for example], we are very well served, I would say that today every patient with lung cancer can be tapped for the genetic alterations,” Peters said of her home country. “This is not the case elsewhere. Unfortunately, if you look at the picture of molecular testing in Europe, less than half of patients can get access to a decent testing. That’s probably where most advances are needed because it creates unacceptable inequities in the cancer journey.”

For lung cancer specialists, the plethora of actionable mutations has exploded over the past decade. Most recently, advances in the breast cancer space has opened new options for patients with lung cancer with 

“This new journey lung cancer specialists are on is because of [discoveries in] breast cancer,” Peters said. In lung cancer, the development of HER2-targeted therapies required looking at the disease in a different light. “We discovered that [in lung cancer] we don’t speak about the same HER2 alteration,” Peters said. “We call amplification, which translates into an overexpression, the quantity. It’s really a modification of the protein.”

Early efforts to identify therapies for patients with 

-mutant disease—which accounts for approximately 2% of all NSCLC cases—found that translation of select agents deemed successful in breast cancer did not afford the same risk/benefit ratio for patients with lung cancer.

 For example, 18 patients treated ado-trastuzumab emtansine (T-DM1; Kadcyla) in a phase 2 basket trial (NCT02675829) showed that among the overall response rate (ORR) was 44% (95% CI, 22%-69%) with a median progression-free survival (PFS) of 5 months (95% CI, 3.0-9.0).

“We tried all of these drugs [that were successful in breast cancer], as well as afatinib [Gilotrif], which is a pan-HER inhibitor, in lung cancer, [for patients with] exon 20 insertions,” Peters said. “These compounds have given rise to small activity, [but] if you try to [determine the] risk/ benefit assessment, none of them have really reached the bar which you would consider standard of care.”

However, data from a trial investigating the use of fam-trastuzumab deruxtecan-nxki (Enhertu) has resulted in a breakthrough for patients with 

-mutant disease, regardless of mutation site.

 Data from the DESTINY-Lung01 trial (NCT03505710), which evaluated a total of 91 patients with 

-mutant NSCLC, demonstrated that the antibody-drug conjugate elicited an objective response rate of 55% (95% CI, 44%-65%), the median duration of which was 9.3 months (95% CI, 5.7-14.7) (

). Further, the median PFS was 8.2 months (95% CI, 6.0-11.9), and the median overall survival was 17.8 months (95% CI, 13.8-22.1).

“I wouldn’t say there were no options but there was no standard option in 

-mutant NSCLC,” Peters said. “Suddenly this new generation antibody-drug conjugates have given rise to wonderful results in breast cancer [and now in] lung cancer, where suddenly you reach a threshold where probably with close to 60% response rate. We have gone through these limitations, and we [now] have an option.”

The FDA has accepted for priority review a supplemental biologics license application for trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have a 

 mutation and who have received a prior systemic therapy.

The application is supported by findings from the phase 2 DESTINY-Lung01 as well as data from the phase 1 DS8201-A-J101 trial (NCT02564900). In the phase 1 study, trastuzumab deruxtecan led to an overall response rate (ORR) of 72.7% (n = 8) among 11 patients with HER2-mutant NSCLC.

 The median PFS in these patients was 11.3 months (95% CI, 8.1-14.3).

Regarding the agent’s safety profile, the adverse effects (AEs) observed with trastuzumab deruxtecan in DESTINY-Lung01 were comparable with those reported in prior clinical trials.

The most common grade 3 or higher drug- related, treatment-emergent AEs included neutropenia (18.7%), anemia (9.9%), nausea (8.8%), fatigue (6.6%), leukopenia (4.4%), diarrhea (3.3%), and vomiting (3.3%).

Twenty-three patients (25%) discontinued treatment because of drug-related, treatment-emergent AEs. Of note, 26% of patients had interstitial lung disease (ILD) or pneumonitis related to treatment per assessment by an independent committee. The majority of ILD events (75%) were low grade (grade 1, 12.5%; grade 2, 62.5%). Additionally, 4 grade 3 (4.4%) and 2 grade 5 (2.2%) ILD or pneumonitis events were reported.

Immunotherapy Carves Out a Role in Early-Stage Disease 

The second chapter of the lung cancer revolution is one that Peters refers to as “exciting”: immunotherapy. “Immunotherapy has led to long term survival for some patients in lung cancer despite [having] metastatic disease,” Peters said. “When I started oncology, one could not conceive that the patient with metastatic [disease] would survive years. We now have very strong data showing that immunotherapy should be used alone or in combination in nearly all metastatic patients.”

Peters noted that the refinement of strategies with immunotherapy is an area that will take investigators into the next wave of clinical advances. “Immunotherapies are now moving into early disease. When I say early these are [patients with] small nodules that are resected. These approaches are about combining [immunotherapy] with surgery and curative intent treatments. How can you make surgery more efficient in creating cure?”

Data for patients with early-stage disease have generated excitement including data from the phase 3 CheckMate 816 trial (NCT02998528). Investigators compared nivolumab (Opdivo) plus chemotherapy with chemotherapy alone for treatment of patients with resectable NSCLC.

 The median eventfree survival (EFS) was 31.6 months in the nivolumab plus chemotherapy arm vs 20.8 months in the control arm (HR, 0.63; 97.38%, 0.43-0.91). The 1-year EFS rate was 76% in the experimental arm and 63% in the control; the 2-year EFS was 64% vs 45%, respectively.

These data supported the approval of the combination, making it the first approval for patients in the neoadjuvant setting for patients with NSCLC in March 2022.

In terms of adjuvant therapy for earlystage disease, data from the IMpower010 study, supported the approval of atezolizumab (Tecentriq) for patients with stage II-IIIA NSCLC whose tumors have PD-L1 expression of at least 1%.

The primary end point was disease-free survival (DFS). Among patients who received atezolizumab the median DFS was not reached (95% CI, 36.1-not estimable [NE]) vs 35.3 months (95% CI, 29.0-NE) with best supportive care (HR, 0.66; 95% CI, 0.50-0.88; P = .004).

Investigators also assessed patients with PD-L1 expression of at least 50%, among whom the DFS benefit was more pronounced with atezolizumab compared with best supportive care (HR, 0.43; 95% CI, 0.27-0.68). However, an exploratory subgroup analysis of patients with PD-L1 expression 1%-49% the DFS benefit was less pronounced (HR 0.87; 95% CI, 0.60-1.26).

“We are seeing the first data from these trials already,” Peters said, noting that the road for determining optimal treatment strategies for patients is a long one. “In the [next several] years there will be way more trials in early disease,” Peters said.

Peters remains hopeful about the future of the space, as it moves toward integration of molecular testing strategies and opening up new and potentially curable avenues for patients with thoracic cancers. Within that pipeline she noted that prevention strategies that may shift the curve in terms of disease incidence.

“We need to do more screening for lung cancer and we need to start to implement programs for heavy smokers, [which incorporate] regular CT scans,” Peters said adding that with these efforts to improve the identification of early-stage disease coupled with improvements in the landscape would be a step toward curable disease.

“I think what is really for us, something which really makes us feel differently as being lung cancer clinic and, is this new [direction of the] field—trying to cure more patients,” Peters said. “That’s maybe what differentiates us a lot from breast cancer specialists. When breast cancer specialists treat with chemotherapy and hormonal therapy, as well as surgery, they get to cure individuals, the [survival] curves in breast cancer can be very, very high between 80% and 100%. In lung cancer, when you perform surgery, and maybe [administer] chemotherapy for patients, only half of the patients will be cured, or even less, maybe 40%. Even with all the lung specialists, we still [making efforts to] cure the disease.”

On a more personal note, Peters said that although being on the ground floor of breakthrough research are moments in a career that standout, her attention is now on the future successes of her fellows and mentees. “My proudest moments now are to have one of my young fellows or mentees being recognized for something he or she has done,” Peters said.

She noted that in preparing the next generation of investigators mentorship is of the utmost importance. “I was carried by wonderful mentors,” Peters said. “A mentor is someone who will put you on the scene, give your name to give a talk.”

In addition to promoting early and lasting relationships among physician scientists, Peters said that promoting the interprofessional dimension of cancer care is one of the items that she placed a focus on as the president of ESMO. “The medical oncologist cannot work alone, everything has become multiprofessional—molecular pathologists, the surgeons the radiologists, and so on—we need to understand that these data have to go through all these layers [to convey information.”

Broadening the scope of conveying information, Peters spearheaded the creation of the International Cancer Foundation (ICF) at ESMO.

 The ICF aims to provide educational activities to clinicians in areas that are underserved, opening the expansion of knowledge of advances in cancer to the world.

“We’re doing the same thing we do in ESMO, but translating into a visibility concept, which can be also used in Africa, in South and Central America, and in all countries of India, for example,” Peters said. “We realized that ESMO is in a position to reach out to them and address their specific needs and concerns. The ICF aims to support, financially and practically, activities that enhance cancer prevention, diagnosis, treatment and follow-up where they are most needed. If we can give a little bit of our energy to help the [clinicians who may be] a little bit delayed in receiving these data], it would be a good move.”

Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. 

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Russo A, Franchina T, Ricciardi GRR, et al. A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): old successes and future perspectives. 

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Chaft JE, Shyr Y, Sepesi B, Forde PM. Preoperative and postoperative systemic therapy for operable non-small-cell lung cancer. 

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Oncology (cancer) / hematologic malignancies approval notifications. FDA. Updated May 31, 2022. Accessed June 5, 2022. bit.ly/3qpecqn

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Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. 

. 2018;36(24):2532-2537. doi:10.1200/JCO.2018.77.9777

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. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431

Enhertu granted priority review in the U.S. for patients with previously treated HER2 mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo. April 19, 2022. Accessed June 4, 2022. bit.ly/3rAE1mS

Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. 

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Targetable alterations including BRAF V600E, EGFR exon 20 insertions, KRAS G12C mutations, MET exon 14 alterations, NTRK and RET rearrangements have taken up recent focus for investigators as data are pushing novel agents through the regulatory processes. 

A Molecular Revolution Is Underway in Thoracic Oncology

, editor-in-chief Maurie Markman, MD, offers expert insights on the hurdles facing community oncologists, the uptake of biomarkers in the clinic, and an overview of what to look forward to in his area of expertise: gynecologic oncology.

What are some of the hurdles in the translation of molecular testing strategies into community settings?

The question of the use of genomic testing for targeted therapeutics is a critically important one in oncology. There is no question that there are major advances occurring weekly and monthly in the cancer sphere in many diseases, [but] that is a problem. The community oncologist who is taking care of patients with many different types of tumors is simply overwhelmed. Every oncologist wants the best for his or her patients, but with the number of new genetic tests for unique markers that they [must] understand across dozens of different diseases, it makes this [almost] impossible. And there is no universal decision support mechanism available to them to help them and, as a result, they fall behind.

For example, in the gynecologic cancer space, [the oncologist] looks at probably the best, most important single marker, which is 

, because we know the value of this testing. A recent study showed that 40% or fewer of patients, looking at electronic health records, have had the test. The recommendations from ASCO [the American Society of Clinical Oncology], the Society of Gynecologic Oncology, and the National Cancer Institute are very clear, but it is not being done—not because the doctors do not want to do the best for their patients, but because they are simply overwhelmed. And we need to figure out how to do something about this.

Lung cancer is another good example. We have progressed so far, yet we still have doctors who are trying to appropriately figure out the best tests to order for their patients. And we now have multiple molecular tests, multiple different drugs with recommendations for frontline and second line, and multiple immune-therapeutic agents in 1 disease.

How can clinicians who take care of multiple different tumor types, including lung cancer, stay up to date on all the things that are going on in lung cancer? It is a very simple issue. We have got to figure out how to develop decision support mechanisms for doctors in the community.

What strategies should be further explored in ovarian cancer and beyond?

One is we have got to come up with decision support in the oncology community to figure out how to use these incredibly important biomarkers and targeted therapy. This is true across the board. The fact that data have come out from several sources, looking at electronic medical record use, that less than 40% of patients with ovarian cancer will absolutely need 

 testing is a huge problem. We need to figure that out.

The second thing we need is we [must] figure out how to do these comparative effectiveness trials. We have [several] drugs that have been approved and a number of strategies approved, and we are seeing more of them. [These are agents] that are approved by the FDA in the first line, second line, third line. The treating oncologist and their patients are going to ask, “What’s best?” and there will not be an answer because we have not done those kind of [comparative] trials. We have got to come up with a strategy.

If the patient asks what will work best for me and the oncologist says, “I don’t know,” where are we? And I would argue we’re still in the dark. But we can answer those questions. We don’t need 1000 patient studies [to] get a handle on [how these agents compare]. If they’re relatively the same, that’s great. You can pick based on toxicity. You can pick on the basis of efficacy. You can pick on the basis of convenience. But we won’t know any of that because we will not have done those comparative trials.

The problem in the absence of comparative trials is that 1 trial may be an entirely different patient population that were compared with another. Beyond that is figuring out decision support for oncologists and figuring out how we’re going to do these comparative effectiveness trials.

Since the introduction of immune checkpoint inhibitors into clinical practice a decade ago, we have been hearing about the need for predictive biomarkers in response to treatment. We do not seem to have moved past PD-L1 as a biomarker, which often has been described as “imperfect.” Is there any progress on this front in terms of getting closer to more specifically defining the patient populations who would benefit?

It is clear we need biomarkers. For a number of diseases and drugs, immunotherapy is a classic example of that. And obviously we hoped we would be able to find them relatively easily, but this has not been the case. We had PD-L1 [expression as a marker] in some tumor types and it is actually predictive, not as a yes or no, but more as an expression of seeing the higher the probability of response. This is not perfect, because then you [must] ask, “Where is the cutoff?” as opposed to “yes or no?”

We also have the [tumor] mutational burden in tumors that has been used and FDA approved for several agents. Obviously, again, individuals who say that’s not perfect—nothing is perfect. One of the issues here is that we are looking for a universal marker in all tumor types. It is likely going to be the case that we will find some markers and tumor types that are more predictive than others.

There may be universal relevance for immunotherapy across the tumors. [Microsatellite instability–high] MSI-H is a wonderful example of a tumor marker that was discovered serendipitously in retrospect. It should have worked because now you have all these neoantigens that were unknown until the people who examined the question found it to be relevant.

Hopefully, we will find those biomarkers as we move forward. It may take a different understanding of pathways. You are often looking now for single abnormalities. It may be a pathway that we were looking at as opposed to a particular biomarker, which only makes things more complicated.

What are some of the areas of focus for the future of ovarian cancer?

With ovarian cancer, clearly bevacizumab [Avastin] remains, although it is a biosimilar, an incredible standard care option. And, of course, we have PARP [inhibitors]. What has been disappointing is the use of checkpoint inhibitors in ovarian cancer. There are specific indications including a small percentage of patients who have MSI-high [disease] who would be eligible for a checkpoint inhibitor or patients with high tumor mutational burdens. Again, it is a small percentage of patients with ovarian cancer, where an immunotherapeutic agent would be relevant, but in terms of using this in the standard of care with chemotherapy or to subsidy chemotherapy, [several] trials have shown no benef it for the addition of a checkpoint inhibitor.

I would have to say that though I am always optimistic. As one of my former mentors said, “You’re an oncologist; you have to be optimistic.” I am always optimistic. The data [we have] so far, whichever inhibitors of ovarian cancer, have not been positive. They are not positive to call this standard of care or to get FDA approval, except in the settings I noted.

It may very well be we simply that we do not have the right biomarkers. It also may be that we don’t have the right drugs. And there are other drugs that might work in this setting that need to be tested to be examined or it could be combination of checkpoint inhibitors. I am optimistic that there is a major role for immunotherapy in ovarian cancer. We just have not figured out what that is yet and I look forward to 2023, and 2024 being able to sort this out.

Maurie Markman, MD, offers expert insights on the hurdles facing community oncologists, the uptake of biomarkers in the clinic, and an overview of what to look forward to in his area of expertise: gynecologic oncology.

Markman Highlights Key Areas of Investigation in Oncology

Despite an abundance of novel and established treatment modalities for patients in the first-line setting, surgical approaches remain the only curative option for patients with advanced clear cell renal cell carcinoma (RCC). However, for patients with intermediate/high or high-risk of recurrence prior to surgery, the 5-year recurrence rate is approximately 60%, which represents an unmet need for this patient population.

Investigators have explored several avenues to convert patients with unresectable disease to candidates for nephrectomy with neoadjuvant regimens and to identify adjuvant treatment strategies to maintain disease control.

“It’s worth taking a step back and acknowledging that we’ve had tremendous improvement in change in the management of advanced kidney cancer over the past 10 years,” David A. Braun, MD, PhD, said in a recent 

“We’re at the point where more patients are [experiencing] long-term durable survival.” Braun added that despite improvements in treatment-free survival there is work to be done to address the number of patients who develop refractory disease. “That’s going to require careful clinical studies but also translational studies and scientific investigation, to understand mechanisms of response and resistance and combine things in a rational way,” he said.

A panel of kidney cancer experts joined Braun to discuss how therapeutic strategies in the neoadjuvant and adjuvant settings are affecting outcomes and how treatment selection in the first line has shifted approaches in the second and later lines of therapy.

Adjuvant treatment options historically included treatment with sunitinib (Sutent) for patients without evidence of disease. However, the toxicity profile of the agent makes it an unfavorable option for patients with intermediate-risk or high-risk RCC who undergo nephrectomy without receiving prior systemic treatment.

Adjuvant immunotherapy, specifically with pembrolizumab (Keytruda), affords patients a tolerable and efficacious option according to data from the phase 3 KEYNOTE-564 trial (NCT03142334).

 The data supported the approval of pembrolizumab for the treatment of patients with intermediate/high risk or high risk of disease recurrence after nephrectomy, or following nephrectomy and resection of metastatic lesions.

In 30-month follow-up data presented at the 2022 Genitourinary Cancers Symposium, the disease-free survival (DFS) benefit of pembrolizumab was sustained vs placebo in this patient population. The intention-to-treat population included 496 patients in the pembrolizumab arm and 498 patients in the placebo arm. At baseline approximately 86% of patients in both arms had had intermediate/high-risk disease and approximately 11% of patients had sarcomatoid features. Further, most tumors were stage T3.

The median DFS was not reached in either arm (HR, 0.63; 95% CI, 0.50-0.80; nominal 

 < .0001). At 2 years, 78.3% of patients in the pembrolizumab arm were progression free compared with 67.3% in the placebo arm. The benefit was observed across key subgroups, including those with PD-L1 combined positive score (CPS) of less than 1 (HR, 0.68; 95% CI, 0.37-1.24), CPS of at least 1 (HR, 0.63; 95% CI, 0.49-0.82), and tumor grade 4 (HR, 0.55; 95% CI, 0.37-0.83).

“There was an interesting benefit that we saw for the higher-risk populations,” moderator Tian Zhang, MD, MHS, said. “[Including] pathologic, T4 disease, or any T stage with node-positive disease, we saw this high-risk population with benefit of the 2-year disease-free survival rates.”

The high-risk group comprised 40 patients on the pembrolizumab arm and 36 on the placebo arm. The median DFS was 22.4 months with pembrolizumab with immunotherapy is more effective in the long term,” Zhang said. At the 30-month follow-up the 2-year OS rates were 96.1% with pembrolizumab vs 93.8% with placebo (HR, 0.52; 95% CI, 0.31-0.86; 

 = .0048), which did not cross the boundary for statistical significance.2 Progression beyond adjuvant therapy Tian Zhang, MD, MHS vs 11.4 months with placebo (HR, 0.60; 95% CI, 0.33-1.10). The 2-year DFS rates were 48.7% vs 35.4%, respectively.

“The highest DFS benefit I saw was for [patients with] M1 [no evidence of disease]. In this population, there might be micrometastatic disease or disease we don’t see. In that population, the 2-year DFS rate was 38% for patients treated with placebo and 78% for patients treated with pembrolizumab for 1 year. That hazard ratio was quite different. It was 0.28 favoring pembrolizumab,” Zhang said. In this population, which included 29 patients on both arms, the median DFS was not reached with pembrolizumab vs 11.6 months with placebo (HR, 0.28; 95% CI, 0.12-0.66).

The median DFS was not reached for either those with intermediate/high-risk disease who received pembrolizumab (n = 422) or those who received placebo (n = 433; HR, 0.68; 95% CI, 0.52-0.89). The 2-year DFS rates were 81.1% vs 72.0%, respectively.

Individuals with sarcomatoid features had a marked improvement in sustained DFS with pembrolizumab (n = 52) vs placebo (n = 59). The 2-year DFS rates were 71.8% vs 52.0%, respectively, with the median DFS not reached with pembrolizumab vs 40.5 months with placebo (HR, 0.54; 95% CI, 0.29-1.00).

Although DFS served as the primary end point of the study, Zhang noted that the long-term efficacy of adjuvant pembrolizumab requires longer follow-up. “We didn’t see enough overall survival [OS] as there weren’t enough deaths on the study to warrant further [investigation into] differences between the 2 populations. More follow-up will be necessary to decide whether we’ll see an OS benefit and whether truly this early treatment with immunotherapy is more effective in the long term,” Zhang said.

At the 30-month follow-up the 2-year OS rates were 96.1% with pembrolizumab vs 93.8% with placebo (HR, 0.52; 95% CI, 0.31-0.86; 

 = .0048), which did not cross the boundary for statistical significance.

Principles are in place for addressing disease progression following adjuvant therapy. However, Braun noted that after pembrolizumab there are no clear directions for subsequent therapy. “For an individual who’s progressed on adjuvant pembrolizumab, we don’t have the data to know the next best thing to do,” he said. “I’ve talked to a lot of colleagues, and some are invoking the platinum paradigm—platinum sensitivity, platinum resistance, or platinum refractory—depending on when the progression occurs. I’m not sure biologically it has the same linkage between immunotherapy and cytotoxic chemotherapy, but in the absence of a better paradigm that’s a very reasonable approach.”

Braun said to guide post–pembrolizumab treatment decisions he would consider several factors including timing of progression (during or after conclusion of treatment), type of progression (radiographic vs symptomatic), and whether the progression is rapid. “It’s a very different story for a patient who got adjuvant pembrolizumab and then has progression 5 years later [vs on treatment]. I would factor differently in my mind of how I think of them as sensitive or resistant to anti–PD-1 based therapy,” Braun said.

If the progression is symptomatic, Braun noted that initiating therapy that would maximize response to an impending visceral crisis may guide clinicians toward combination therapies over single-agent therapies. Additionally, patient-specific factors may play a role. “How did the patient tolerate immunotherapy? How did the patient tolerate pembrolizumab? Was it a relatively easy course of treatment? Are there a lot of immune-related adverse events [AEs]? Some of the [AEs] are substantial. That might help us think about how much we push more immunotherapy and in what setting,” Braun said.

He suggested treatment modalities for patients who progressed during the 1-year treatment period vs those who may experience disease progression after completion of adjuvant therapy. “If a patient had progression on pembrolizumab— it was in that 1-year period of treatment—I would be more inclined to switch to TKI [tyrosine kinase inhibitor]-based therapy,” Braun said. “For patients who are the opposite—they’ve had treatment with pembrolizumab and years later they’ve experienced disease recurrence—I’m more inclined to treat them similar to how I would treat a [treatment-]naïve patient. I’d be more inclined to use an up-front immunotherapy- based combination.”

As for the patients who fall somewhere in between, Braun said that is where patient-specific factors—the timing of progression, the rapidity of progression, and the tolerance of prior therapy— will have the largest role.

Several investigations in the adjuvant setting are exploring combination and single-agent regimens for patients with RCC, including IMmotion010 (NCT03024996), CheckMate 914 (NCT03138512), and RAMPART (NCT03288532). These studies are exploring the use of atezolizumab (Tecentriq), nivolumab (Opdivo) with or without ipilimumab (Yervoy), and durvalumab (Imfinzi) plus tremelimumab, respectively (TABLE

“Most of us want to see the data and want to look at the efficacy, not only progression-free survival but also OS, because at the end of the day, I think this is very important for this patient population,” Mehmet A. Bilen, MD, said of the ongoing trials. “We really want to cure patients in addition to delaying disease recurrence.”

He noted that toxicity will be another important factor to consider as data are reported in the adjuvant setting. “Toxicity is even more important for the adjuvant space because they are not having any AEs or symptoms from the disease itself, and whatever AE patients are going to experience is from the drug. We want to make sure that we don’t see any excessive toxicity that’s going to affect our patient. But overall, if you want to cure someone, I think this is the opportunity. I think for patients with very high risk [of recurrence] we may want to choose a doublet rather than a single agent.”

Aimed at tumor shrinkage and/or preemptively addressing residual tumor cells following nephrectomy, clinical trials assessing the role of neoadjuvant treatment strategies are ongoing.

For example, data from the phase 2 NeoAvAx trial (NCT03341845) presented at the 2022 Genitourinary Cancers Symposium showed that neoadjuvant treatment with axitinib (Inlyta) plus avelumab (Bavencio) elicited a partial response in the primary tumors of 30% of patients with advanced high-risk RCC (n = 40).

“What is interesting about this study, is that it is one of the first to [report] data with a combination regimen in this setting after a disappointment in general efficacy in the TKI monotherapy setting. It was very interesting to see what these data looked like,” Pedro C. Barata, MD, MSc, said.

Investigators evaluated participants taking 12 weeks of neoadjuvant axitinib at 5 to 10 mg once daily and avelumab at 10 mg/kg intravenously once every 2 weeks. Surgery was conducted at least 36 hours following the last dose of axitinib. A majority of patients had T3a tumors (60%). At baseline the mean tumor diameter was 10.3 cm (range, 5.6-18.8).

The median tumor downsizing was 20% (range +3.8% to –43.5%). Of the 12 patients who achieved a partial response, 10 were disease free at the time of data cutoff. Secondary end points of DFS and OS were not reached at a median follow-up of 23.5 months. Recurrence was reported in 13 patients, and 3 died of disease. 

Investigators noted that surgical AEs aligned with previously reported findings and no new safety signals were reported with the neoadjuvant immune checkpoint/VEGFR-TKI combination.

Investigators also are evaluating the use of nivolumab in the neoadjuvant and adjuvant setting vs surgery alone in the phase 3 PROSPER trial (NCT03055013). Patients enrolled in the experimental arm prior to a protocol amendment received nivolumab administered intravenously (IV) over 30 minutes on day 1 of a 14-day cycle for 2 cycles followed by partial or radical nephrectomy 7 to 28 days after treatment. After surgery patients will receive nivolumab on day 1 of a 14-day cycle for 6 cycles followed by nivolumab on day 1 of a 28-day cycle for 6 cycles in the absence of disease progression or unacceptable toxicity.

The amendment regimen is nivolumab IV over 30 minutes on day 1 followed by followed by partial or radical nephrectomy 7 to 28 days after treatment. Nivolumab is then administered nivolumab IV over 30 minutes on day 1 of a 4-week cycle for up to 9 cycles in the absence of disease progression or unacceptable toxicity.

“Initially it was planned for a longer time of neoadjuvant nivolumab, but the study had to be amended to be more feasible,” Barata said. “The end point here is event-free survival. This study completed accrual, and now we are waiting for events so that we can see what happens. But I think these studies will add significant information to what we saw with adjuvant pembrolizumab, in my opinion, and what we’re going to see with other checkpoint inhibitors in this setting. I think it’s a very important study to keep an eye on.”

Despite only one of the treatment approaches discussed in this segment of the Peer Exchange being FDA-approved, the investigational studies offer promise of a new treatment landscape for patients with RCC.

“Most of the investigations in the neoadjuvant setting are still just that— they’re investigational. A lot of us in our clinics have been using [these approaches] for years,” said Moshe C. Ornstein, MD, MA. “We’re hoping to spare some nephrons and avoid having that patient be dialysis dependent after a nephrectomy.”

Ornstein added that the data are helpful in terms of providing safety and tolerability data as well as efficacy data. “These data tell us that this approach is at least safe and that the patients are getting to surgery and getting through surgery OK. I wouldn’t say necessarily that this is a practice-changing trial. It must be a case-by-case decision. But it comforts those of us who do this in practice in an effort to spare some nephrons at the time of nephrectomy in the right patient in close collaboration with the urologist. There’s also some efficacy in terms of tumor burden shrinkage.”

Ornstein noted that sequencing upon disease progression will also depend on patient-specific factors. “The overwhelming majority of patients don’t have disease progression within 3 months of surgery. That’s a real minority. What’s going to happen—this gets back to what Dr Braun highlighted, in terms of taking a play out of the cisplatin-refractory lung cancer/bladder cancer space—is that most of these patients will have the therapy washed out of their system by the time the cancer progresses.” Finally, he noted that adjuvant pembrolizumab will likely have a prominent role as a frontline therapy in the metastatic setting, but that neoadjuvant therapy is less likely to have a similar affect.

Long-term outcomes of follow-up for initially localised clear cell renal cell carcinoma: RECUR database analysis. 

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Choueiri TK, Tomczak P, Park SH, et al; KEYNOTE-526 Investigators. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: results from 30-month follow-up of KEYNOTE-526. 

. 2022;40(suppl 6):290. doi:10.1200/ JCO.2022.40.6_suppl.290

FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed June 1, 2022. bit.ly/3NFDEQJ

A study of atezolizumab as adjuvant therapy in participants with renal cell carcinoma (RCC) at high risk of developing metastasis following nephrectomy (IMmotion010). ClinicalTrials.gov. Updated January 14, 2022. Accessed June 1, 2022. 

https://clinicaltrials.gov/ct2/show/ NCT03024996

A study comparing nivolumab, nivolumab in combination with ipilimumab and placebo in participants with localized kidney cancer who underwent surgery to remove part of a kidney (CheckMate 914). ClinicalTrials.gov. Updated May 25, 2022. Accessed June 1, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03138512

Renal adjuvant multiple arm randomised trial (RAMPART). ClinicalTrials.gov. Updated September 7, 2020. Accessed June 1, 2022. 

https:// clinicaltrials.gov/ct2/show/NCT03288532

Bex A, Abu-Ghanem Y, van Thienen H, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). 

. 2022;40(suppl 6):289. doi:10.1200/JCO.2022.40.6_suppl.289

Nivolumab in treating patients with localized kidney cancer undergoing nephrectomy. ClinicalTrials.gov. Updated May 18, 2022. Accessed June 6, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03055013

A panel of kidney cancer experts discuss how therapeutic strategies in the neoadjuvant and adjuvant settings are affecting outcomes and how treatment selection in the first line has shifted approaches in the second and later lines of therapy.

Adjuvant and Neoadjuvant Treatments Chart New Course  in Advanced RCC

Despite a steady decline in incidence and mortality rates of many cancers among older individuals in the United States and other high-income countries, an alarming rise in young-onset gastrointestinal (GI) cancers has simultaneously occurred.

 The incidence of young-onset colorectal cancer has risen by 51% since 1994.

 As a result, approximately 11% of all new diagnoses of colorectal cancer occur in individuals younger than 50 years.

Increasing incidence rates of young-onset pancreatic cancer and gastric cancer also have been reported.

Despite a steady decline in incidence and mortality rates of many cancers among older individuals in the United States and other high-income countries, an alarming rise in young-onset gastrointestinal cancers has simultaneously occurred.

Vol. 23/No. 12 | Oncology Live®

Radioligand Therapy Boosts Survival in mCRPC

A Molecular Revolution Is Underway in Thoracic Oncology

Markman Highlights Key Areas of Investigation in Oncology

Adjuvant and Neoadjuvant Treatments Chart New Course in Advanced RCC

Efforts Are Needed to Address the Enigmatic Rise of Young-Onset Gastrointestinal Cancers

Precision Medicine in Oncology®: TROP-2, Nectin-4 Are Highly Expressed in Urothelial, Variant Histology Bladder Cancer