Jax DiEugenio joined MJH Life Sciences in 2024, first as an editorial intern before transitioning into a full-time assistant editor for 

. A recent College of New Jersey graduate, Jax majored in Journalism/ Professional Writing with minors in Public Health and Anthropology. He is also pursuing a Master's Degree in Public Health, concentrating on health communications.

Despite advances in treatment, prevailing health care disparities remain alarmingly high within the management of prostate cancer, according to Mary-Ellen Taplin, MD, who applauded Mass General Brigham’s United Against Racism initiative which seeks to provide equitable access to health care services in the community.

The Prostate Cancer Outreach Clinic, which falls under the initiative, was cofounded by Quoc-Dien Trinh, MD, MBA, of Mass General Brigham, and Adam Feldman, MD, MPH, of Massachusetts General Hospital. Central to the clinic’s operational framework is its reliance on community engagement, supported by community health care workers who play a pivotal role in facilitating patient interactions and streamlining access to health care services, particularly for individuals presenting with elevated prostate-specific antigen (PSA) levels or in need of screening.

After a year of operation, the clinic has yielded promising outcomes, serving a considerable patient cohort and achieving notable rates of successful visit scheduling and cancer diagnoses. Collaborative endeavors with an array of stakeholders, including institutional partners, patient advocacy groups, and health care insurers have been pivotal in achieving these outcomes, according to Taplin.

®, Taplin discussed how the clinic’s initiatives exemplify a pragmatic approach to mitigating health care disparities in prostate cancer care and detailed future directions for the center. Taplin is the chair of the Executive Committee for Clinical Research and

institute physician at Dana-Farber Cancer Institute, and professor of medicine at Harvard Medical School in Boston, Massachusetts.

: What are some of the main elements that create health care disparities in prostate cancer? How has the prostate cancer outreach clinic in Boston helped combat these issues?

: Health care inequities in prostate cancer are a well-established challenge for us in the field. [There are] many barriers to equitable health care, including access to health insurance, access to medical centers, and access to physicians. But in addition to access, there’s also inequities in care delivery. To combat that barrier to care delivery in Boston, my colleagues in urology, Dr Quoc-Dien Trinh and Dr Adam Feldman, have worked for several years with many stakeholders to build a clinic for men who are at risk for prostate cancer, because of elevated PSA or who need PSA screening. The key to the success of that clinic is [community engagement]. To facilitate community engagement, community health care workers were trained and integrated into this clinic.

So, when patients are referred for prostate cancer screening, or because they have an elevated PSA, the first introduction is to a community health care worker, who then works with the patient to evaluate [whether] their insurance is consistent with getting care at one of the Mass General Brigham [MGB] hospitals. Then the community health care worker takes the next step and schedules the appointment and helps the patient get to the appointment. If the insurance is not compatible with an MGB institution, then the community health care worker will work with the financial assistance teams that are available to get the patient health care or an appropriate referral. This clinic has been in operation for about 1 year, but they’ve had over 220 patients within the system and almost 100 new referrals. Moreover 54% of patients were successfully scheduled for visits and of the patients with an elevated PSA 25% were diagnosed with prostate cancer.

I am very proud of my colleagues. Working with many stakeholders, from the institutions to patient advocacy groups, community practices, and health care insurers they were able to make a practical approach to breaking down the barriers to equitable care. Many important initiatives are underway, including working on improving access to getting to the medical practice because of issues with public transportation and how far away from the hospitals some patients live, as well as building bigger and more comprehensive coalitions, which will set the priorities for continuing this work and extending its outreach.

Which populations of patients are most vulnerable to these disparities?

[The population of patients who are most vulnerable to health care disparities] will differ by region. Patients who live in rural communities, patients who have poor health care literacy, patients who have no or poor health insurance, patients of different ethnic groups, especially if they have other risk factors, such as being far from medical practices [may be more at risk of not receiving adequate care]. It really depends on the area of the country. Since prostate cancer is very common in black men, we are concerned that black men are not getting equitable care, and that’s been shown in Dr Trinh’s research and others.

Could this clinic serve as a blueprint for other institutions nationwide?

I do think that [this outreach clinic] could be a model, and that was one of the reasons I wanted to discuss it so I could spread the word. In talking to Dr Trinh, part of his success was that he’s been with MGB for 15 years, so he had developed relationships with new people in many pockets of a very big health care system. That was key to being able to work with the different components to set this up.

Also, Dr Trinh, 10 years ago, approached it from an academic standpoint and had funding from the Department of Defense, the American Cancer Society, and the Prostate Cancer Foundation. [Because of that] he was able to, through academic work and publications and training, develop key metrics that then could be applied in a practical way with consensus from many listening sessions and by being open to taking the community feedback and engaging with the community. His team is not just going to show up once and talk about prostate cancer. [By] going [to] event after event after event, you develop a trust with the community that allows you to then open avenues of referrals for patients at risk, because you’ve met the community health care workers and the advocates [who are part of] running different groups and community practices. I think it can be used as a model, but it has to come with a deep commitment to breaking down the barriers, which are long established and sometimes unrecognized.

Did your colleagues face any challenges in getting the clinic off the ground?

Yes, many. Establishing trust within the communities at risk was a challenge [because we are] working with different aspects of a large healthcare system where people turn over in their jobs. You may have had a meeting six months ago with a group and then six months later, the people that you met with are gone, so you have to start over with new employees in that part of the group. So, [there are] lots of challenges.

The first year [the clinic was open], the number of patients who had a follow-up appointment scheduled was less than ideal, [it] was about 54%. [There are] a lot of reasons for that, such as transportation, unstable housing, and medical literacy. A future goal is to increase the proportion of patients who come to the initial [appointment] and then follow through with the follow-up appointments. But this is just the first year and I think it’s a tremendous accomplishment.

We’ve had other Dana-Farber initiatives, such as PSA screening vans that go into the community that have had some success, but this practice of establishing streams of referrals for patients who might otherwise go unconnected to health care is not going anywhere.

Are there any other prospective avenues that are being considered to improve the success of the clinic?

It’s been identified that black men in Massachusetts are five times more likely to take public transportation to the practice and four times more likely to live at extended distances from the practice. Developing a program with rideshare vouchers is one of the future initiatives that [the clinic] has. Other future initiatives are going to come from the community, [so that we can continue to] develop this coalition and expand it and listen to the voices of the communities. Expanding the community health care worker network and program [has] proven successful and impactful. [I think we’ve shown that] was a missing link to the hospital systems and the practitioners.

Prostate cancer outreach clinic. Mass General Brigham. Accessed March 22, 2024. https://www.massgeneralbrigham.org/en/patient-care/services-and-specialties/prostate-cancer-outreach-clinic

Articles

Mary-Ellen Taplin, MD, discusses ways to mitigate health care disparities in the treatment of patients with prostate cancer. 

Taplin Tackles Equitable Treatment in Prostate Cancer 

Investigators have not been able to replicate the success seen with cellular therapy in hematologic malignancies. However, clinicians are hopeful that this therapy could prove to be a meaningful treatment option for patients in need with refractory solid tumors, according to Jay Spiegel, MD.

CAR T and cellular therapy has made extraordinary advances in hematologic malignancies in the past five years. We’ve been able to, I hope we can say, cure patients who would otherwise have not been able to be cured with these therapies. Solid tumors represent in some ways the next frontier. Although the days are still early, some of the advances that we’ve seen with tumor-infiltrating lymphocytes [TILs] in melanoma suggest that we may eventually be able to cross that frontier and bring these therapies to patients who are in need in the solid tumor space,” Spiegel explained.

 Spiegel, an assistant professor at Miami Miller School of Medicine and a transplant and cellular therapy physician at Sylvester Comprehensive Cancer Center in Florida, discussed the status of CAR T-cell therapy in solid tumors, highlighting challenges such as tumor microenvironment complexities and target antigen limitations.

: What jumpstarted interest in CAR T-cell therapy for solid tumors?

: CAR T-cell therapy is approved for the treatment of [patients with] lymphoma, leukemia, and myeloma. These agents have proven surprisingly effective for patients with refractory cancer and have had multiple approvals since 2017. But there’s huge unmet need in patients with refractory solid tumors. There’s been a lot of recent interest in trying to bring these types of therapies into the solid tumor space to see if they can [lead to more] cures or [simply] responses in patients who have highly refractory solid tumors.

What have been some of the challenges with cellular therapy treatment in solid tumors?

The stance of CAR T-cell therapy in solid tumors [is] that it’s been difficult. Everything remains in relatively early-phase [study]. CAR T involves taking somebody’s own T cells and genetically reengineering them to find cancer. An approach that is much older for the treatment of solid tumors is to [use] TILs that are immune cells that are already present in the cancer. [TILs are] able to get [into the tumor], which is a big problem with CAR T. [TILs are] already resident in the tumor, they may already recognize neoantigens or unique presentations of the tumor that might not be easily targetable with CAR T. And those [cells] are taken out, processed, grown, and turned into a cell therapy product, [which is] then given back to the patients.

FDA approved the first ever cell therapy for solid tumors

, the TIL therapy lifileucel [Amtagvi] in melanoma. That’s really the approach that’s had the most success. CAR T has some limitations in that it can only target an extracellular protein, whereas TILs can target intracellular antigens, which give it a wider scope.

But CAR T also has to be able to get into the tumor, they have to deal with the tumor microenvironment, which is also true for TIL, but it can be particularly challenging in the setting of CAR T-cell therapy. And CAR T tends to only be able to target one antigen or even two antigens at a time. Solid tumors are more complex than hematologic cancers, so it may be hard to find an antigen that’s expressed on every cancer cell. Additionally, a lot of these targets are also present on normal tissues. So, for example, in hematologic malignancies, the main target in lymphoma is CD19, which is present primarily on B cells. You can lose your normal B cells and still survive [because] you can get replacements with IVIG. But for example, with mesothelin-targeting CAR T-cell therapy, mesothelinis present in the lung, and attacking the lung tissue can cause pneumonitis and [other] significant on-target but off-tumor toxicities. Those are some of the major issues confronting CAR T in the solid tumor setting.

Are there any current trials that you are keeping your eye on in this space?

The most advanced data that we’re awaiting is with the TIL therapy C-145 in cervical cancer, [which is developed by] the same company that produces lifileucel. We have the trial open at the University of Miami. [The investigators] last presented data in 2019, which everybody was excited about. But with changes to the cervical cancer landscape, namely the use of checkpoint inhibitors earlier on in lines of therapy, the FDA asked the trial to enroll more patients who had been treated previously with checkpoint inhibitors. That’s the most advanced therapy in gynecologic oncology that might lead to an approval.

There have been various other approaches using TCR-targeting MAGE, for example. But that trial was taken forward only for synovial sarcoma. It was studied in ovarian cancer, but we didn’t see the responses we would like. Similarly, there was a localized effort from Memorial Sloan Kettering Cancer Center with the MUC-16(ecto) CAR. They last presented [data with that agent] in 2020. They’ve been working on that, but I don’t think that’s necessarily close to the clinic in any appreciable way. We [have to go] back to the drawing board as far as using cell therapy in gynecologic malignancies outside of the TIL therapy I mentioned.

How will the approval of lifileucel inform the use of cellular therapy in other solid tumors?

in 2021, enrolled patients with metastatic melanoma post PD-1 and BRAF inhibition plus or minus a MEK inhibitor. Of the 66 treated patients the overall response rate was 36% with a median overall survival of about 18 months. We received the approval [about a month ago] and patients are already starting to undergo procedures for TIL harvesting. I don’t believe anybody has been treated commercially yet because it takes approximately 3 weeks to make the product. As far as what it holds for solid tumors, it will be important to see how the product is going to perform outside the clinical trial setting. We always have to think about the generalizability of trial results because patients outside of the clinical trial setting may not match [the description of those who participated in the trial].

The success of manufacturing the TIL product, which entails undergoing surgery and having the company successfully make the product, will be important to see. With some CAR products that manufacturing process has been more difficult than [with] other [therapies]. Regarding whether [the therapy is] directly applicable [to other solid tumors], melanoma is a disease that is famous for having great responses to immune-based therapies, which have not necessarily translated to every solid tumor. It’s hard to draw direct comparisons there, but as far as the functionality of a TIL product in practice in the general community, [lifileucel will] be something we can learn from.

What other types of cellular immunotherapy could emerge as a potential treatment modality in solid tumors?

The vaccine approach, which is kind of an old approach made new again, with some of the mRNA vaccine approaches is an exciting area to keep track of. I haven’t been part of any of those trials, but that might be another avenue of utilizing the immune system that we haven’t necessarily seen commercial success with. Ultimately, the thing about CAR T that may hopefully allow it a future in solid tumors is that it can be iteratively updated, because you’re already utilizing genetic modifications. In theory, that’s limitless, though it likely isn’t because of changes you can cause to the genome and secondary problems.

We’re in the early phases of learning how to make cell therapies work. CAR is an adaptable cell therapy in that we can continue to work on what makes the best receptor and what makes the best combination of targets, looking at gating strategies where you need to trigger on two targets, not just one to hopefully avoid on-target, off-tumor toxicities. The future is bright in that sense, but we still need that next jump in technology to be able to achieve success. Where we are now, I’m a little less bullish on. There needs to be some advances that will come into the scientific community before it can become a reality.

What does the future hold for these therapies?

My old boss from fellowship used to say that this version of CAR T-cell therapy is like the Nokia phone from the 1990s. Looking at a lot of scientific advances that our colleagues are making in the field as far as how to learn more about why particular CAR T cells work, what makes the best T cells to turn into a CAR, those are the things that I have the most excitement about in terms of seeing how we evolve as a field, because we do need to evolve. We’ve had exciting successes, but these are still barriers we need to overcome. In the near future, it’s going to be [about] phase 1 clinical trials, and hopefully, we’re going to learn more, but I’m excited to see what we can come up with from the scientific perspective.

Peterson C, Denlinger N, Yang Y. Recent advances and challenges in cancer immunotherapy. 

. 2022;14(16):3972. doi:10.3390/cancers14163972

Jay Spiegel, MD, discusses advancing cellular therapies and challenges in gynecologic cancer treatment.

Advancing Cellular Therapies in Solid Tumors: Current Challenges and Future Directions

As advancements continue to unfold across the spectrum of radiation oncology, disseminating information on new treatment strategies, novel technologies, and ongoing research to up-and-coming oncologists is vital to keep the field moving forward, according to Steven Finkelstein, MD, DABR, FACRO.

“One of the things I strongly believe in is exposing our youth early to what we do as oncologists across the spectrum of oncology,” Finkelstein said in an interview with 

. “I love to see when young folks come [to these meetings], and they get here and bathe in all the excitement of what it means to help patients.”

During the interview, Finkelstein highlighted the significance of the 2024 ACRO Meeting, discussed unmet needs in radiation oncology that ongoing research endeavors aim to address, and explained the value of integrating potential oncologists into the radiation field early in their careers.

Finkelstein is the chair of Science and Education for ACRO and a radiation oncologist with the US Oncology Network at Florida Cancer Affiliates in Panama City.

: What is the significance of meetings such as the ACRO Summit for the field of radiation oncology?

: [ACRO] is a conference that brings together radiation oncologists from across the spectrum of academia and the community. [Approximately] 80% of patients with cancer get treated in a community setting, and it's important for us to disseminate education across our field. This is a meeting that brings doctors from all diverse backgrounds together—even in a multidisciplinary setting—to talk and see some of the advances in both care and research.

I'm happy to report that at the [2024 ACRO Summit], we had over 100 abstracts submitted, which were published and presented [over the course of the meeting]. In addition, as the founding editor of the new 

Journal of the American College of Radiation Oncology

, also known now as CURiE, we're excited to announce that we published both the first paper and the first sets of abstracts coming from the annual meeting. We're excited to bring these advances to the field of oncology to help patients.

What can community oncologists gain from attending meetings such as the ACRO Summit?

The importance of meetings like ACRO for community oncologists is that we need to continue to advance education. The field is moving so fast, and there is so much information out there. How can we see the important advances and incorporate them to help our patients? In meetings like this, we can present and cull the intense amount of information into digestible pieces. Presentations like we [saw at the ACRO Summit] can be seen across the platform of virtual media to help people who can't make the meeting. There is a lot of cross pollination between what we do here at ACRO on an educational basis. We have world experts and doctors show up, network, exchange knowledge and then have that knowledge go out to the world, whether it be from personal interactions or interviews like this.

In terms of ongoing or upcoming research initiatives in radiation oncology, is there anything specific you would like to spotlight?

I'm extremely excited about the continued advancement of radiation oncology research in the community setting. We do such a wonderful job in radiation oncology. Again, if 80% of [patients with] cancer get treated in the community, we need to continue to advance those research approaches so that community physicians have access [to the latest radiation technologies and methods] to be able to bring [these strategies] to their patients. For me, as a principal investigator, [it’s important to] be active in those initiatives. Within our center [at Florida Cancer Affiliates], we try to bring those advances [to patients], and some of those advances we brought as a presentation [at the 2024 ACRO Summit].

However, what I really want to bring home is this message that if you're a patient, your doctors are learning about what they need to learn, and hopefully [this allows them] to bring [patients] access to the most cutting-edge technologies and research protocols so that they can have the best outcomes possible.

What unmet needs in the radiation oncology realm would you like to see addressed in the future?

One of the key unmet needs in radiation oncology is the continued advancement of radiopharmaceuticals. As a national expert in radiopharmaceuticals, we're just scratching the surface of this [area]. With the advent of [radiopharmaceutical] therapies in prostate cancer, we're helping patients, and that's going to extend outside of the prostate cancer space to help people with all different kinds of diseases.

That interplay between radiation oncology and industry partners to bring these new [radiopharmaceutical] therapies to research trials, both in academics and community settings, and then be able to have access [to these novel agents] for patients, is going to be a key piece of our future. I look forward to being part of [that initiative].

As new information continues to unfold in radiation oncology, what is the best way to keep pace in this evolving landscape?

A key takeaway I have for my colleagues across the field of radiation oncology and oncology [is to] be involved. It's not always easy to get away [from practice] to come to a meeting but find a way to be involved and get the information needed so that we can always do the highest quality work for our patients. We all fight the good fight every day. It's harder than ever [to keep up] with this incredible expanse of information. However, the kind of work that we're trying to do at meetings such as the ACRO Summit is to try to disseminate information that helps our patients.

What is the significance of involving students, trainees, residents, and younger individuals in research endeavors and conferences such as the ACRO Summit?

One of the things that is important is the future [of oncology]. Our future is our youth who decide that oncology is an important place to help the world and help patients. ACRO is at the forefront of engaging fellows, residents, and medical students. [Looking at] my background, I did surgery and surgical oncology. Then I went back to do radiation oncology because I never really had exposure [to this field]. I'm excited to get people [who have yet to become] medical students to see that radiation oncology is an exciting field with infinite potential. It is an honor to pay it forward in that way, and I'm excited to help in that role as chair of education.

Steven E. Finkelstein, MD, DABR, FACRO, discusses the importance of disseminating treatment advancements and ongoing research in radiation oncology. 

2024 ACRO Summit Underscores the Importance of Continued Education in Radiation 

Improving survival remains a key goal for the treatment of patients with metastatic colorectal cancer (mCRC); however, ensuring patients in this population maintain quality of life (QOL) during and after treatment is also paramount, according to Sebastian Stintzing, MD.

presented data from a post-hoc quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis

 of the phase 3 FRESCO-2 trial (NCT04322539), which evaluated fruquintinib (Fruzaqla) plus best supportive care (BSC) vs placebo plus BSC in patients with pretreated mCRC. Findings from the analysis showed that in the fruquintinib arm, the average Q-TWiST duration was 6.25 months (95% CI, 5.89-6.61) compared with 4.21 months (95% CI, 3.81-4.60) for patients receiving placebo plus BSC (difference, 2.04 months; 95% CI, 1.51-2.57; 

Furthermore, the mean TWiST from randomization until disease progression without toxicity was 4.06 months (95% CI, 3.75-4.36) for the fruquintinib arm compared with 1.92 months (95% CI, 1.75-2.10) for the placebo plus BSC group (difference, 2.14 months; 95% CI, 1.78-2.49; 

 < .05). The average time spent experiencing grade 3/4 treatment-emergent adverse effects (TEAEs) between randomization and disease progression (TOX) was 0.45 months (95% CI, 0.37-0.53) in the fruquintinib arm and 0.21 months (95% CI, 0.15-0.28) in the placebo plus BSC arm (difference, 0.24 months; 95% CI, 0.13-0.34; 

the FDA approved fruquintinib for the treatment of adult patients with mCRC

 who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if 

 wild-type and medically appropriate, an anti-EGFR therapy. The regulatory decision was supported by prior data from FRESCO-2.

“Fruquintinib is not only able to prolong the survival in patients with [pretreated] mCRC; it's also able to prolong the lifespan with a high quality of life,” Stintzing explained.

, Stintzing discussed data from a post-hoc Q-TWiST analysis and elaborated on the importance of maintaining QOL for patients with mCRC during later lines of treatment.

Stintzing is the head of the Department of Hematology-Oncology and Cancer Immunology at the Charité Universitaetsmedizin in Berlin, Germany.

 What was the rationale for conducting a Q-TWiST analysis for FRESCO-2?

 Fruquintinib is a selective inhibitor of all three VEGF receptors, and it has been shown in the pivotal FRESCO-2 study that it can prolong overall survival for patients with previously treated mCRC. [Fruquintinib plus BSC] has significantly prolonged progression-free survival [PFS] and overall survival [vs placebo plus BSC]

[At the 2024 Gastrointestinal Cancers Symposium], we presented a preplanned analysis of the Q-TWiST of this study. We know with this patient population [that is receiving later lines of therapy], you have the cancer and you have the treatment, which may impact QOL. Therefore, we wanted to show was, if we could prolong life, is this prolongation also meaningful for the patient? [In other words,] can you prolong life where the patient is without toxicity and without progression?

Could you expand on the methods utilized in the Q-TWiST analysis?

[The analysis included] all patients in this trial [enrolled in] the fruquintinib plus BSC [arm] vs placebo plus BSC. In a Q-TWiST analysis, you break down survival times into 3 different stages. One is [time spent with grade 3/4] toxicities for a patient [after the start of] treatment [and before disease progression]; then you have TWiST time, [meaning] time without toxicity and progression; and finally, there is relative [REL], which is the time a patient is surviving after progression.

By doing this [analysis], you can compare those times, and what we were able to show is that the TWiST times—the time without toxicity or progression—was prolonged by [2.14 months (95% CI, 1.78-2.49; 

 < .05) for fruquintinib vs placebo]. Therefore, [these findings] may be something you want to add when you discuss treatment options with your patients. The overall Q-TWiST time was 2.04 months (95% CI, 1.51-2.57; 

 <.05) longer [for fruquintinib vs placebo].

What is the known toxicity profile for fruquintinib in patients with mCRC?

Usually, fruquintinib is quite well tolerated. We [have experience with] other VEGF inhibitors, and no new toxicities were found [with fruquintinib]. Additionally, all toxicities [fruquintinib] were very manageable.

Looking into the future, what are the next steps for  FRESCO-2?

We will see more data coming up in more subgroup analyses. [With the Q-TWiST] analysis, it's important to show that we are prolonging QOL for those patients who are on treatment. This [analysis] may be also interesting for regulatory agencies because they are not only looking at the sheer prolongation of survival; they [are looking to see if this] is meaningful survival, meaning without toxicity. This is exactly what we were able to show with the Q-TWiST analysis.

Stintzing S, Tabernero J, Satoh T, et al. Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of fruquintinib + best supportive care (BSC) compared with placebo + BSC in metastatic colorectal cancer (mCRC): Results from the FRESCO-2 trial. 

. 2024;42(suppl 3):116. doi:10.1200/JCO.2024.42.3_suppl.116

FDA approves fruquintinib in refractory metastatic colorectal cancer. News release. FDA. November 8, 2023. Accessed March 11, 2024. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer

Sebastien Stintzing, MD, discusses a Q-TWiST analysis for fruquintinib vs placebo in pretreated metastatic colorectal cancer.

Q-TWiST Analysis Demonstrates Benefit of Fruquintinib Plus BSC in Pretreated mCRC

After osimertinib (Tagrisso) plus platinum-based chemotherapy was approved for the treatment of patients with advanced 

-mutated non–small cell lung cancer (NSCLC), determining if the regimen generates an overall survival (OS) benefit vs osimertinib alone will be the next key step, according to Pasi A. Jänne, MD, PhD, who added that additional research could help better identify subgroups of patients who would most benefit from the addition of chemotherapy to the EGFR inhibitor.

the FDA approved osimertinib in combination with platinum-based chemotherapy

 for patients with locally advanced or metastatic NSCLC harboring 

 exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

The regulatory decision was supported by data from the phase 3 FLAURA2 trial (NCT04035486), an open label, randomized trial that enrolled 557 patients with 

 exon 19 deletion– or exon 21 L858R mutation–positive locally advanced or metastatic NSCLC who received no prior systemic therapy for advanced disease.

Findings showed that osimertinib plus chemotherapy demonstrated a statistically significant improvement in progression-free survival (PFS) compared with osimertinib monotherapy (HR, 0.62; 95% CI, 0.49-0.79; 2-sided 

 < .0001). The median PFS was 25.5 months (95% CI, 24.7–not estimable [NE]) and 16.7 months (95% CI, 14.1-21.3) in the combination and monotherapy arms, respectively. OS data remained immature.

“[There are] several different types of benefits of the combination over osimertinib alone. We’re excited to see this move forward and have the combination available to treat our patients,” Jänne said.

®, Jänne expanded on the significance of the FDA approval of osimertinib plus platinum-based chemotherapy for patients with advanced 

-mutant NSCLC and discussed the key findings from the FLAURA2 trial that supported the decision.

Jänne serves as a senior physician, director of the Lowe Center for Thoracic Oncology, director of the Belfer Center for Applied Cancer Science, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, and the David M. Livingston, MD, Chair at the Dana-Farber Cancer Institute and is a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

: Why is the FDA’s approval of osimertinib plus chemotherapy for 

 The [FLAURA 2] trial demonstrated that the addition of chemotherapy to osimertinib, compared with osimertinib alone, as first line therapy for advanced 

-mutant lung cancer, led to an [8.8-month] improvement in PFS. That is a clinically significant and meaningful improvement in outcomes of patients. Although there were some added [adverse] effects [AEs] of adding chemotherapy to osimertinib, most patients tolerated the therapy very well.

In addition to the improvement in PFS, there was an also an improvement in patients who had brain metastases at baseline. There was an improvement in intracranial PFS, and more patients who received the combination of chemotherapy and osimertinib have had complete clearance of their brain metastases compared with those who have received osimertinib alone.

Osimertinib is a mutant-selective EGFR inhibitor, meaning that it’s more potent against the mutant form of 

 that's found in cancers and less potent against the normal form of EGFR, which is found in normal tissues. Hence, it has a pretty wide therapeutic index. Most patients tolerate the drug very well. It also crosses the blood-brain barrier and gets into the brain effectively. [Since] it's a fairly well tolerated medicine, it lends itself to study combinations like chemotherapy in combination with osimertinib.

Are there any safety signals to note regarding the combination of osimertinib and chemotherapy?

With the combination of osimertinib and chemotherapy, most of the added AEs of the combination occur early on in the treatment, because that's when combination chemotherapy is administered. Once patients transition into the maintenance part of chemotherapy, which is just pemetrexed by itself, the combination of osimertinib and pemetrexed it is well tolerated. Overall, the AEs lessen over time because of the changes from combination chemotherapy to maintenance chemotherapy with osimertinib.

Where do you see osimertinib plus chemotherapy fitting into the treatment landscape for patients with 

[Osimertinib monotherapy] is the standard of care for patients with newly diagnosed, advanced 

-mutant lung cancer. For patients who've had surgery for early-stage, 

mutant lung cancer, [single-agent osimertinib] is also given in the adjuvant setting. Chemotherapy adds to osimertinib, but we still need to continue to develop improvements in this field. It was too early in the trial to know if [osimertinib plus chemotherapy] improves patients’ OS. We are eagerly awaiting for that piece of information. If [the combination] does not [improve OS], we need to try to understand why and how to continue to improve upon this combination [to allow] patients with newly diagnosed, advanced 

-mutant NSCLC to live longer and better lives.

What is your view on making treatment decisions between osimertinib monotherapy and combination therapy with osimertinib and chemotherapy?

[Osimertinib plus chemotherapy] is more effective than osimertinib alone. It doesn't mean that everybody needs to receive chemotherapy and osimertinib, and one of the areas of future research for all of us is to try to understand which of our patients truly need the more intensified combination therapy and which patients can be treated with osimertinib by itself. However, the approval clearly demonstrates that there is a benefit to adding chemotherapy to osimertinib as initial treatment. We'll need to continue to study how patients do and try to better understand who needs chemotherapy, because it does come with some associated increase in AEs.

FDA approves osimertinib with chemotherapy with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed February 28, 2024. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer

Pasi A. Jänne, MD, PhD discusses the FDA approval of osimertinib plus chemotherapy for patients with EGFR-positive non–small cell lung cancer.

Osimertinib Plus Chemo Adds Combination Strategy to Advanced EGFR+ NSCLC Armamentarium 

Combined treatment with pembrolizumab (Keytruda) and chemotherapy has been shown to promote longevity in patients with advanced esophageal cancer as evidenced by results from the phase 3 KEYNOTE-590 study (NCT03189719), which continue to show persistent and proven benefits with the regimen vs chemotherapy alone.

 in San Francisco, California Manish A. Shah, MD, presented data from the KEYNOTE-590 trial which investigated the efficacy and safety of the combination in patients with locally advanced or metastatic esophageal cancer. Updated results from the trial, which were presented with a median follow-up of 58.8 months (range, 49.2-70.6), showed that patients who received pembrolizumab plus chemotherapy achieved a median overall survival (OS) of 12.3 months (95% CI, 10.5-14.0) versus 9.8 months (95% CI, 8.8-11.0) with placebo plus chemotherapy (HR, 0.72; 95% CI, 0.62-0.84).

Discussing the study’s impact, Shah explained, “Immunotherapy has been transformative in many cancers, and it is transformative in esophageal cancer. We need to test [for] biomarkers to [see whether] tumors express PD-L1. If they do, we should consider adding pembrolizumab to chemotherapy to maximize the benefit. The real message is that some patients may live quite a long time [on this regimen], even 5 years, which was previously unheard of.”

, Shah elaborated on the 5-year outcomes from the phase 3 KEYNOTE-590 study. Shah is the director of the GI Oncology Program at Weill Cornell Medicine and chief of the Solid Tumor Service Program as well as the codirector of the Center for Advanced Digestive Disease at NewYork-Presbyterian in New York.

What have earlier results shown about the efficacy of this regimen?

 KEYNOTE-590 was a practice-changing study of chemotherapy plus immunotherapy in esophageal cancer. We heard the initial results after about 2 years of follow-up where they suggested pembrolizumab plus chemotherapy was significantly better in terms of survival compared with chemotherapy alone for patients with esophageal cancer. The update from this poster was the five-year results.

This was a large study; about 700 patients were randomized to either receive chemotherapy plus placebo, or chemotherapy with pembrolizumab. The study [enrolled patients with] esophageal cancer, which included both squamous cancer and adenocarcinoma. The investigators looked at different subgroups of patients that had a high PD-L1 combined positive score (CPS) score of 10 or higher or 1 or higher and then in all-comers.

The upshot is that even throughout five years there was a significant benefit with the addition of pembrolizumab to chemotherapy compared with no pembrolizumab. The five-year survival rate with pembrolizumab was somewhere between 10% to 15%, depending on what subgroup you’re looking at, compared with about 3% with chemotherapy alone. Tripling to quadrupling the five-year survival rate was remarkable.

How has the addition of pembrolizumab to chemotherapy affected the immune response in patients with varying levels of PD-L1 expression?

Pembrolizumab is a PD-1 inhibitor. By finding PD-1 on the cancer cells and on the T cells, you can activate the immune response against the cancer. Squamous cell cancer as well as esophageal adenocarcinoma can overexpress PD-1, so by blocking that pathway, you’re effectively turning off the brake for the immune system to become activated. Tumors that have a higher PD-1 status are more sensitive to the addition of pembrolizumab. We measure that by something called the hazard ratio. [The hazard ratio equates the relative benefit of adding pembrolizumab versus not].

In the CPS 10 or higher group, which is the group that should benefit the most with pembrolizumab, the hazard ratio [for OS] was around 0.64. So, there was about a 36% improvement in survival with the addition of pembrolizumab to chemotherapy. Then, as the CPS score went lower and lower, the benefit was still there, but it wasn’t as striking.

How might these factors influence the interpretation of the study, and the application of it in real-world scenarios for patients?

With the long-term survival benefit, it’s well established now that pembrolizumab should be given to patients with esophageal cancer, along with chemotherapy. One of the key things that we found is that the people who had the longest survival had typical evidence of metastatic disease, including patients with liver metastases. The consistent, sustained benefit in both progression-free survival and OS, along with minimal increase in toxicity suggest that pembrolizumab should now be a standard with chemotherapy for esophageal cancer.

Shah MA, Sun JM, Shen L, et al. First-line pembrolizumab plus chemotherapy for advanced esophageal cancer: 5-year outcomes from the phase 3 KEYNOTE-590 study. 

. 2024;42(suppl 3):250. doi:10.1200/JCO.2024.42.3_suppl.250

First-line esophageal carcinoma study with chemo vs. chemo plus pembrolizumab (MK-3475-590/​KEYNOTE-590). ClinicalTrials.gov. Updated July 27, 2023. Accessed February 21, 2024. 

https://clinicaltrials.gov/study/NCT03189719?tab=results

Manish A. Shah, MD, discusses 5-year outcomes from phase 3 KEYNOTE-590 study of first-line pembrolizumab plus chemotherapy for advanced esophageal cancer.

Jax DiEugenio