 demonstrated that men with positive pelvic lymph nodes or a prostatectomy Gleason score of 8 to 10 with disease extending beyond the prostate benefited from adjuvant radiation therapy and that the treatment was associated with a significant reduction of all-cause mortality in this population.

After investigators excluded patients with adverse pathology who had persistent prostate-specific antigen (PSA) expression, the reduced risk of all-cause mortality (ACM) associated with adjuvant radiotherapy remained significant vs early salvage radiation therapy. The association was maintained regardless of whether patients had pelvic nodal involvement (HR, 0.33; 95% CI, 0.13-0.85; 

 = .02) or not (HR, 0.66; 95% CI, 0.44-0.99; 

“We found that among men with adverse pathology at radical prostatectomy including pN1 or prostatectomy Gleason score 8-10 and pT3a or higher PC, adjuvant compared with early salvage radiotherapy was associated with a significant reduction in ACM risk,” the authors of the study wrote. “This association of reduced ACM risk with adjuvant compared with early salvage radiotherapy is strengthened given that men who underwent adjuvant compared with early salvage radiotherapy had less favorable prostate cancer prognostic factor distributions, which should have placed them at higher risk for needing salvage androgen deprivation and dying.”

Patients with prostate cancer who have adverse pathology at radical prostatectomy continue to be at a high risk for recurrence.

 This includes patients with pelvic node–positive disease, prostatectomy Gleason scores of 8 through 10, and extra-prostatic extension or seminal vesicle invasion or invasion into neighboring organs. When this patient population experiences recurrence, their PSA is found to rapidly increase, rising from the trigger PSA level of 0.1 ng/mL or 0.2 ng/mL to 0.4 ng/mL, signifying progression; this can happen while salvage radiotherapy is being planned and delivered, and before PSA response to salvage radiation therapy can be evaluated.

This results in men experiencing progression earlier while on salvage radiotherapy vs adjuvant radiotherapy. Due to this, investigators set out to determine whether those with adverse pathology at radical prostatectomy could derive benefit from adjuvant treatment vs salvage.

The study had a cohort of 26,118 men who had a median age of 62 years (range, 57-67) with pT2-4N0 or N1M0 prostate cancer that had been consecutively treated between June 23, 1989 and July 26, 2016. This treatment needed to include radical prostatectomy and pelvic lymph node assessment, after which patients were followed for possible treatment with adjuvant or early salvage radiotherapy.

The study took place at several institutions, including University Hospital Hamburg-Eppendorf; Charité University Hospital; University Hospital Ulm; University of California, San Francisco; and Johns Hopkins Medical Institution. Patients included in the study were stratified based on the presence or absence of adverse pathology.

Of the patients who were included in the study, 3.14% (n = 819) received adjuvant radiotherapy generally within 6 months of radical prostatectomy and 17.72% (n = 4601) received salvage radiotherapy. The 2 groups had PSA levels of less than 0.1 ng/mL and a median of 0.30 ng/mL, respectively. Among those in the salvage radiotherapy group, 14.24% (n = 655) had persistent PSA levels, defined as a postoperative PSA of 0.1 ng/mL or greater, and were categorized into the early salvage radiotherapy group. Additionally, adjuvant and salvage androgen deprivation therapy were administered in 1.35% and 9.69% of patients, respectively.

After receiving radical prostatectomy to the prostatic bed at a median dose of 68.4 Gy and pelvic lymph nodes (45.0 Gy), adjuvant radiotherapy was delivered a median of 3.55 months. Moreover, adjuvant androgen deprivation therapy was administered for a median of 9.17 months. In total, 5.71% (n = 1491) of the study population had pelvic lymph node–positive disease, of which 21.4% were treated with adjuvant radiotherapy and 16.16% received adjuvant androgen deprivation therapy. Notably, salvage androgen deprivation therapy was administered following PSA failure and clinical or radiographic evidence of progression following adjuvant or salvage radiotherapy.

“Men who received neither adjuvant radiotherapy nor early salvage radiotherapy never experienced PSA failure during the conduct of the study or were treated with salvage androgen deprivation therapy alone at progression,” wrote the authors of the study.

Those with adverse pathology who underwent adjuvant radiotherapy over salvage radiotherapy had a notably higher proportion of pT3a or higher (97.90% and 94.48%, respectively; 

 = .002) and margin-positive disease (82.71% and 45.68%, respectively; 

< .001). Additionally, those who received adjuvant therapy had a significantly higher proportion of patients with margin-positive disease (88.07% and 45.17%; 

< .001) and less use of salvage androgen deprivation therapy (35.78% and 45.84%; 

 = .06) vs early salvage radiotherapy with adverse pathology excluding pN1.

After a median follow-up of 8.16 years (range, 6.00-12.10), investigators reported that 8.06% (n = 2104) of the study population had died, 25.62% (n = 539) of whom passed from prostate cancer. Other findings from the study indicated that there was a significant association identified wherein adjuvant treatment decreased risk of all-cause mortality in men with positive margins (HR, 0.55; 95% CI, 0.34-0.90; 

 = .02) over salvage radiotherapy, although the significance was lost when excluding men with persistent PSA (HR, 0.67; 95% CI, 0.37-1.001; 

 = .0504). No significant association was observed in men without adverse pathology at radical prostatectomy (

Among those with adverse pathology including pN1 who received adjuvant radiotherapy, no radiotherapy, and salvage radiotherapy, investigators reported a 10-year adjusted point estimate for all cause morbidity of 13.78% (95% CI, 8.43%-22.12%), 27.32% (95% CI, 22.54%-32.88%), and 21.98% (95% CI, 18.30%-26.27%), respectively. When excluding pN1, the estimates were 5.13% (95% CI, 2.00%-12.82%), 25.32% (95% CI, 18.95%-33.34%), and 22.15% (95% CI, 17.55%-27.74%), respectively. Moreover, when excluding patients with adverse pathology, the estimates were 7.82% (95% CI, 4.55%-13.28%), 8.81 (95% CI, 7.35%-10.54%), and 7.95% (95% CI, 6.82%-9.24%).

“In conclusion, three randomized trials and a meta-analysis found no difference in progression-free survival for adjuvant compared with early salvage radiotherapy use. However, a benefit might have been missed in men with adverse pathology at radical prostatectomy because of inadequate power and the presence of immortal time bias,” the authors concluded.

Tilki D, Chen Ming-Hui, Wu J, et al. Adjuvant versus early salvage radiation therapy for men at high risk for recurrence following radical prostatectomy for prostate cancer and the risk of death. 

. Published online June 4, 2021. doi:10.1200/JCO.20.03714

Markowski MC, Chen Y, Feng Z, et al. PSA doubling time and absolute PSA predict metastasis-free survival in men with biochemically recurrent prostate cancer after radical prostatectomy. 

. 2019;17(6):P470-475. doi:10.1016/j.clgc.2019.08.002

Suissa S. Immortal time bias in pharmacoepidemiology. 

. 2007;167(4):492-499. doi:10.1093/aje/kwm324

Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. 

. 2020;396(10260):14131421. doi:10.1016/S0140-6736(20)31553-1

This article was originally published on OncLive as 

“Adjuvant Radiation Therapy Could Yield Reduction in All-Cause Mortality in High-Risk Prostate Cancer”

Articles

Adjuvant radiation therapy treatment yielded strong results in reducing all-cause mortality in patients with high-risk prostate cancer. 

Adjuvant Radiation Therapy Associated with Reduced Risk of Death in High-Risk Prostate Cancer

Clinicians must consider factors like prophylactic medications and optimal fluid administration when they are administering the 4-drug treatment regimen of carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone, and daratumumab (Darzalex; KRd-D), according to C. Ola Landgren, MD, PhD. 

“[We need] to really be on [the top of our] game and know what is needed. If you are going to deliver these good drugs, you need to have the right supportive drugs,” Landgren underscored. “[It’s] the same thing [with fluid]. If you give half a liter of fluid before and after the infusions with carfilzomib, you are going to run [the risk of] congestive heart failure…You have to give the optimal fluid and have the right prophylactic medicine. Attention to [these details] is very important.”

In an interview with Oncology Nursing News' sister publication, 

®, Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, Miami Health System, discussed key safety considerations with a novel carfilzomib quadruplet regimen in patients with newly diagnosed multiple myeloma, the clinical implications of the phase 2 MANHATTAN trial (NCT03290950), and next steps for this research.

®: What was the tolerability of the 4-drug regimen examined in MANHATTAN and what factors should be considered to ensure the appropriate management of patients who receive it?

: One thing that is sometimes a little bit overlooked is the attention to detail [that is needed] for [optimal] clinical management; [this includes] how [drugs] are delivered and all the other surrounding [factors], such as the different types of prophylactic medications, as well as fluid administration, and careful assessment of patients. Many times, people tend to forget about this. The older drugs were less effective, but they were, at the same time, potentially a little bit easier to give. The newer drugs are more effective and better, but many of them [require] more attention. You have to have good anticoagulation if you are going to use good drugs.

Are any next steps planned for this research?

Yes. These results are the best we have ever seen in the newly diagnosed setting. Beyond the efficacy [observed], in terms of the high rates of minimal residual disease [MRD] negativity, we also did not see the high rate of peripheral neuropathy that you see with bortezomib [Velcade]. That is also one thing that we get used to; no one is hiding it [or] lying about it, because it happens all the time, but we kind of stop thinking about it. If you go back and look through the data, the bortezomib studies have been around for 15 years or so. Many patients who are treated with this therapy, maybe up to half, experience chronic peripheral neuropathy in [their] fingers and toes, which is something they will have to manage for the rest of their life; it impacts [them] every day. [Patients] have to be on medications and some even require a walker. Not every patient will experience this effect, but it is not a trivial proportion of patients [who] do.

With the regimen, you do not see that because carfilzomib does not cause peripheral neuropathy; that is important. For that reason, we felt that this [regimen] has to go forward to be validated and tested in a large study. We have already launched the large, randomized 2 ADVANCE study [NCT04268498]; this is open to newly diagnosed patients and compares this new therapy with the standard of care.

What are the clinical implications of the MANHATTAN trial? What should be taken away?

[These data] show that you can achieve very deep responses in patients with a modern therapy in the absence of a bone marrow transplantation. Once-a-week dosing is a very reasonable schedule for a defined period of time. I do not know that going forward every patient will need 8 cycles. If you look at the time to reaching MRD negativity, [some] patients reach negativity after just 1 to 6 cycles. The median time [to MRD negativity] is around 6 cycles. As such, thinking about getting an injection and infusion once a week—3-weeks-on and 1-week-off for this number of cycles—compared with other options like bone marrow transplantation and all the toxicities [that come with it], such as sustained peripheral neuropathy, [this approach is worth it]. If you look at the value proposition of receiving a modern 4-drug combination with such a high rate of MRD negativity, it really pushes the field forward and provides a new option for patients with newly diagnosed disease.

Data demonstrate that if you use the best drugs in every line of therapy, that means that you will lose fewer patients for the next line [of treatment]. If the disease relapses and comes back [because] patients were not treated properly, some will have so much disease that they will not make it to the next line [of therapy]. The emphasis on using optimal drugs in every line is there, and it starts with the first line.

The last thing I want to say is that this is not for every patient; unfortunately, [this regimen is] not for every doctor either. [To give this,] you must pay attention to detail. You have to be on top of the anticoagulation and the intravenous fluids. In my practice, I do an echocardiogram of the heart and an electrocardiogram for every patient before I start [my patients] on therapy. I would also assess the blood pressure and would adjust that, [if needed]; if it is too high, I would treat that. If there are any concerns, I would be more careful with these types of therapies. However, if you do not see [these issues], which is true for many patients, and no other underlying comorbidity [is observed], this is an excellent therapy.

This article originally appeared on OncLive as, "

Landgren Spotlights Safety Considerations for Carfilzomib Quadruplet in Newly Diagnosed Myeloma

Consider options like prophylactic medications and optimal fluid administration when giving a 4-drug regimen to treat patients with multiple myeloma, one expert says. 

Expert Talks Safety Considerations in 4-Drug Myeloma Regimen

Disparities in cancer incidence and outcomes by race and ethnicity continue to exist in the field of oncology, but cultural competence, multidisciplinary efforts with diverse faculty, and high-risk screening programs could help to address critical gaps, according to Anita Johnson, MD, FACS.

“We know that prostate cancer is very common in Black men, and when we look at breast cancer detection in Black women, we know they present at a later stage; [however], that has not been done is really enforcing high-risk screenings at the primary care level.” Johnson said. “We oftentimes see women who come in [who] have several family members with breast cancer, but they have never been sent to a high-risk clinic. That is where I believe we could have a significant impact.”

®, Johnson, a breast surgical oncologist and the Breast Cancer Program director at Cancer Treatment Centers of America, discussed existing disparities in cancer, studies that have helped to shed further light on the issue, and ongoing efforts being made to improve outcomes in all patients.

®: What disparities have you observed within the breast cancer field?

: I have been a breast cancer surgeon for over 25 years and I have seen disparities even before I became a surgeon. I trained at one of the foremost indigent hospital systems, Grady Hospital System, and observed patients coming in with late-stage diagnosis, whether it be cancer or advanced hypertension. We oftentimes see patients who are underinsured, who do not [typically] have access [to care], present with late-stage disease. [This is something that] has been going on for hundreds of years.

What are some of the studies that are looking into these disparities in cancer?

Several studies have been done, [but] one study done by the National Cancer Institute last year [specifically] reviewed disparities in oncology. As we know, when we compare death rates among several cancers, the rates are significantly higher [with] African Americans compared with Caucasians. Breast cancer is one of [these cancers in which this is the case].

We know that when we look at the incidence of breast cancer rates, it is equal among Black and White women, but when we look at the death rates, [they are] significantly higher for African American women stage for stage. The same [goes] for prostate cancer. The good news is that the death rates [associated with prostate cancer] are declining, but the bad news is that Black men have twice as high of a chance of dying from prostate cancer than White men. When we look at cervical cancer, Hispanic women and Black women have higher incidence rates, but Black women continue to die at a higher rate. Those are [some of the] disparities [we see] when we look at oncology, [overall].

What steps are currently being taken within your own institution to overcome these challenges and ensure equal care and outcomes for patients with cancer?

[With our] hospital system, our model is multidisciplinary. I actually submitted an abstract about 2 to 3 years ago to the Society of Surgical Oncology that looked at whether there] was a difference in treatment when it comes to patients with breast cancer, and there was no known difference. In our hospital system, all the patients are offered the same treatment. We do not have an isolated group. We review all our patients before they arrive and we follow national guidelines, [which] do not necessarily discriminate with screenings. We offer all our patients standard-of-care treatment options.

We still struggle as a hospital system because it is not only the treatment that is needed; [we also need to have] providers who are culturally competent and are able to have t difficult conversations. As we know, some ethnic groups look at cancer care or being diagnosed with cancer as being fatal. We know that the diagnosis, the treatment, and the surgery [approaches in this disease] have changed.

How might multidisciplinary efforts within the oncology community help to close the gap?

When it comes to oncology care, we are all humans. Being culturally competent is really important. It needs to start with medical school, [as it] depends on where you train and whether you are used to a diverse population. When we talk about hiring oncologists, we must make a sincere effort to hire those who will represent those populations.

[This also holds true for] advanced nurse practitioners and healthcare leadership, such as hospital chief executive officers. [We need to make] a significant effort [in this regard]. It also comes down to employers. Patients who are gainfully employed and who are well insured have more access to screenings, diagnosis, and early detection, which definitely impacts overall survival.

With the 2021 ASCO Annual Meeting fast approaching, how do you anticipate health equity in oncology to be highlighted?

ASCO is going to reiterate the disparities that are being seen among different groups and it will also shine a light on the COVID-19 pandemic. With the work environment being different, with some individuals being underemployed, we expect to see more patients present with late-stage disease. At this point, when it comes to healthcare among all specialties, telehealth will have a huge impact, [as well as] access to screenings. We need to step that up and become advocates of policy changes. [For] patients who have significant family histories, we need to ensure that they are placed in a high-risk program so that they are screened more frequently than those who do not have a significant history.

This article was originally published on OncLive as, "

Johnson Shines a Light on Racial Disparities in Breast Cancer, Prostate Cancer, and Beyond

Cultural competence, multidisciplinary efforts with diverse faculty, and high-risk screening programs could help to address critical gaps and cancer disparities.

Tackle Racial Inequalities in Cancer Care

Whole-genome sequencing in patients with precursor multiple myeloma conditions such as smoldering myeloma or monoclonal gammopathy of uncertain significance (MGUS) may help predict which patients will go on to develop the disease, according to study authors Ola Landgren, MD, PhD, and Francesco Maura, MD.

“In the past 2 or 3 years, we have shown that whole-genome sequencing has the potential to [identify] most myeloma-defining genomic events,” Maura, an assistant professor and principal investigator of the myeloma genomic lab at Sylvester Comprehensive Cancer Center, told 

. “If you [can] define events, you can see which patients with precursor disease have these events, and which do not. You can see that the presence of these events is associated with different clinical outcomes.”

, Landgren, Maura, and colleagues, explored the utility of whole-genome sequencing in patients with MGUS and smoldering myeloma to see whether they could identify genomic signatures that could predict progression to multiple myeloma. Results indicated that clinically stable cases of these 2 precursor conditions are characterized by different genomic landscapes and by variations in the temporal acquisition of myeloma-defining genomic events vs progressive entities.

One genomic signature of interest in the study was APOBEC, which has previously been observed in patients with relapsed multiple myeloma, according to Maura. Investigators noted that the patients who eventually progressed on the study already had this signature when they had MGUS, while those who did not progress did not have this signature.

“All of a sudden, we were able to lift off the lid on the Pandora's box of MGUS and see [those who will progress to] myeloma vs [those who will] not,” Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, told 

. “Many questions still need to be addressed. For example, [we know that] if a patient has [a specific] signature, that is a bad thing. However, if they do not have it, could they still develop it later? What is the rate of conversion? We do not know.” A large follow-up study is planned to examine this further, Landgren added.

, Landgren and Maura highlighted the evolution of genomic testing in multiple myeloma, further discussed their research with whole-genome sequencing in patients with precursor conditions, and spotlighted next steps for research.

What inspired this research to further examine myeloma precursor conditions?

: For a very long time, it has been recognized that some individuals who have proteins in the blood that are monoclonal do not have multiple myeloma. Others have multiple myeloma, [which] is the second most common blood cancer in adults. [This disease presents] in 35,000 people every year in the United States, and over 130,000 people are living with this disease without a cure. Years back, in the 1960s, there was a debate [regarding these] proteins; 1 group thought that there was no association between these proteins and the cancer, while others felt that maybe there was. In the 1970s, the consensus was that [the question remained open and up for debate].

That takes you into [the realm of] MGUS, which basically means we do not know. In reality, people show up with these proteins for various reasons. Doctors can order blood tests, and all of a sudden, you see these proteins. The patient wonders, ‘What is going to happen with me? Will I develop myeloma or not?’ People are living with this uncertainty. In the 1980s, [investigators were starting to realize that] some people have more protein than others; as such, they didn't fit with this terminology [of MGUS, so investigators] came up with the idea that they could call that smoldering myeloma. However, MGUS and smoldering myeloma are sort of the same thing; smoldering myeloma just has a little bit more of these proteins. For 40 years, blood tests [have been performed] every 3, 6, or 12 months and some people still develop myeloma, [while others] have [these proteins] and never progress. For many years, we have studied blood-based markers and other types of markers to determine whether we could identify those who are going to develop myeloma early on.

In 2009, I was the lead investigator on a study that definitively showed that any person who developed myeloma had these proteins in their blood years [in advance]. We had a collection of almost 100,000 blood samples that were drawn every year for many people. We identified all people who had myeloma, and then we went backward year by year and found [those proteins] in every person. That definitively showed that you need to have the protein to develop the cancer. However, the question that still puzzled us for more than 10 years was: Is there a better way to identify those who will [go on to] develop [the disease] vs those who will [not]?

To answer that question, we needed to first ask ourselves whether they were linked; the answer was, yes. There are [challenges to] doing these types of studies, because you need to have a lot of DNA if you are studying whole-genome sequencing. You need to have so many cells for the technology to work. You basically have people who already [are] halfway [to having] the disease. The real question is in those who have a very low level of disease, could you still address this question? Until now, that was not possible. This study takes advantage of a brand-new technology [that requires] low-input DNA. We were able to crack the code.

: This study aimed to answer 1 of the most important questions for the myeloma community. Some scientists [have] recently published very important studies showing that certain genomic drivers are associated with patients who progress. However, the limitation [in those] studies is that most of them are focused on smoldering myeloma because of the [number] of cells [they are able to collect]. [Others used] technologies that are focused on a small fraction of the genomes, so they are able to capture just a small fraction of events.

In the past 2 or 3 years, whole-genome sequencing has emerged and has shown the potential to reveal important myeloma-defining genomic events. [Whole-genome sequencing] is comprehensive and provides most of the answers that we were looking for, answers that the other previous studies could not; this is all possible with this technology.

Could you expand on the goals of this study and its key findings? What did the patient population look like?

: The study particularly focused on people with very low levels of disease; this is [those with] MGUS, which makes this study very unique. As you can imagine, if you study people with smoldering myeloma, they already have so many cells. If you have 1000 people, many will develop myeloma. However, if you have 1000 people with a MGUS, the proportion is going to be lower. For those individuals who are going to progress, [examining this is] equally important. This study, for the first time, focused on whole-genome sequencing, with a particular interest in people with very low disease burden.

What we showed was that we have an activation of certain genomic signatures. For example, a signature called APOBEC is known to be associated with aggressive, solid, and metastatic cancer. We have seen [this signature] in relapsed myeloma. However, when we look at these early disease cases, the patients who eventually progress already [had APOBEC] when they had the MGUS. The [patients] who did not progress, did not have [APOBEC]. That is a huge observation; that [shows us that we] can [predict] myeloma [before it occurs with these signatures]. Other single-variant hotspots, or templated insertions, [were also observed]. For example, chromothripsis also distinguishes these cases from each other.

The question now is [whether a person who does not have these genomic signatures now] can develop them later. [We need to know the rate of conversion.] To this end, we are already planning to open a large follow-up study, here, in Miami, where patients with MGUS and smoldering myeloma will be welcome to come for this test. [The study] will also allow them to come back on an annual basis if they have the low-risk signatures [so that they can] be tested longitudinally to] definitively answer this question. We are also working to develop early intervention studies to treat [patients] based on these signatures.

: Where we are now in the field is that the prediction of the risk of whether patients will progress is based on indirect measurement of disease burden. We have a different prognostic score that was developed by Mayo Clinic and the Spanish group, that is effective in identifying patients [who are] very high risk. We consider these patients to probably already have multiple myeloma; it is just a matter of time [for the disease] to expand and [cause] symptoms. In just a few months, less than 2 years, most of these patients will progress. These scores are less [effective in] predicting [those with] intermediate and low risk. That is [why] our study is important. All our patients enrolled, [those with] MGUS and smoldering multiple myeloma, were all intermediate and low risk. We did not have any high-risk [patients]. The [patients] who progressed were those who did so from an intermediate or low risk to multiple myeloma. That is another important consideration.

Despite the limited cohort, because we're talking about less than 50 patients, the data were clean; the cohort was not contaminated by high-risk patients or by [those with] multiple myeloma that was not yet diagnosed. It is important because this population of myeloma without symptoms is a big problem when you try to extrapolate or understand a large population, particularly [through] retrospective studies. That is another advantage. APOBEC, chromothripsis, templated insertions—all these events can only be detected in an accurate way using whole-genome sequencing. That is why whole-genome sequencing is important. You can detect APOBEC with exome data, but it is less accurate, and you [are left with] a lot of uncertainty.

Whole-genome sequencing is pretty robust; [either] you have [it] or you don't have [it], and if you don’t have it, then you’re sure you don’t have it. That is another advantage.

Finally, we performed a bit of a complicated analysis using mutations that are constant over time and we showed that the first genomic-defining events that we were able to time are acquired in multiple myeloma around the second decade of life. [Patients with] smoldering myeloma and MGUS who progressed [did so] in a similar time window: the second or third decade of life. What was interesting is that in the [patients with] MGUS or smoldering myeloma who did not progress, [events were acquired] in the fifth and six decades of life. We don't know whether these patients will progress, but we can also [hypothesize] that most of these patients, if they take the same path that multiple myeloma requires, will progress when [they are] more than 100 years [of age].

Oben B, Froyen G, Maclachlan KH, et al. Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities. 

. 2021;12(1):1861. doi:10.1038/s41467-021-22140-0

Whole-Genome Sequencing in Smoldering Myeloma and MGUS Could Predict Outcomes

Whole-genome sequencing may hold the answers for patients with myeloma precursor conditions.

Whole-Genome Sequencing Helps Predict MGUS and Smoldering Myeloma Outcomes

Offering patients with metastatic gastroesophageal tumors a more personalized and adaptable treatment approach using monoclonal antibodies matched to genetic profiles in combination with chemotherapy may result in higher rates of survival compared with historic controls, according to the results from the phase 2 PANGEA study (NCT02213289).

A 1-year overall survival (OS) rate of 66% (95% CI, 54%-76%) was reported in the 68 patients who comprised the intent-to-treat population, meeting the primary efficacy end point of the trial (one-sided, 

 = .0024). The median OS was 15.7 months (95% CI, 13.4-17.7) in these patients; the median time to treatment failure (TTF) was 13.6 months (95% CI, 11.3-15.8). Moreover, the 2-year OS rate in this population was 29%, the 3-year rate was 14%, and the 5-year rate was 11%. The 1-year OS rate in the non-ITT population (n = 12) was 33.3%, with a 2-year rate of 8% and a median OS of 9.0 months (95% CI, 4.6-20.3).

“At first there was only chemotherapy for HER2-negative tumors in the first-line setting, but now other targeted therapies are coming out, including anti–PD-1, anti-FGFR2 and anti-claudin,” Daniel Catenacci, MD, an associate professor of medicine and director of the Gastrointestinal Oncology Program at the University of Chicago, as well as the assistant director of Translational Research in the Comprehensive Cancer Center, stated in a press release.

 “How does a physician decide which treatment to prescribe when a patient might be eligible for multiple options given known overlap in a tumor of the predictive biomarkers for each of these therapies? This study shows that using an algorithm such as ours could help with that prioritization to direct optimal care and may potentially lead to better outcomes for patients.”

Although advances made in genetic testing have created opportunities to better inform treatment strategies, heterogeneity can cause difficulties in identifying the best targeted therapy for each individual patient. To address this unmet need, investigators developed a new treatment strategy for this patient population.

The goal of the study was to optimize survival in patients through the use of sequential doublet chemotherapy in combination with an individually matched monoclonal antibody at baseline diagnosis, then again serially over up to 3 lines of therapy.

To account for the potential of several therapeutic approaches because of concurrent molecular alterations in a given patient’s sample, a predefined prioritized biomarker and treatment assignment algorithm was applied at each line of therapy. Investigators hypothesized that the individualized treatment approach, which comprised 8 biological subsets with 6 matched monoclonal antibodies, could address formidable hurdles presented by molecular heterogeneity, resulted in improved outcomes over historical controls.

From June 2015 through May 2019, investigators enrolled 80 eligible patients. The median age of the study population was 61 years (range 28-81), the majority of whom were male (80%; n = 64). Of the 80 total patients enrolled to the study, 43% (n = 34) had esophageal tumors and 30% (n = 24) and gastroesophageal junction tumors. Seventy-four percent of patients (n = 59) had signet ring cells absent.

In the total patient population, baseline metastases were noted in the lymph nodes (63%; n = 50), peritoneum (38%; n = 30), liver (36%; n = 29), lung (8%; n = 6), bone (5%; n = 4), adrenal gland (4%; n = 3), or another location (1%; n = 1). Additionally, 40 patients (50%) had a performance status of 0, 33 (41%) had a status of 1, and 7 (9%) had a status of 2.

The biomarker prioritization and treatment assignment algorithm utilized by investigators placed patients in 1 or 8 treatment arms based on genetic testing results:

PD-L1 IHC combined positivity score of over 10, who were microsatellite instability–high, had a tumor mutation burden less than 15 mutations/mb, and/or Epstein–Barr virus–positive received anti-PD-1 nivolumab (Opdivo)

-amplified received trastuzumab (Herceptin)

-amplified received anti-MET (no agents available)

In the ITT population, all patients received a first-line therapy, 87% (n = 53/61) went on to receive a second-line therapy, and 42% (n = 60) progressed and received a third-line therapy. Those who progressed on all 3 lines of therapy in the PANGEA study went on to receive a fourth line of therapy (12%; n = 8). No fifth-line or later therapies reported.

During the first cycle of treatment, 41.2% (n = 28) of patients in the ITT population received modified oxaliplatin, levofolinate, 5-fluorouracil (5-FU), and bevacizumab (Avastin; mFOLFOX7) without 5-FU bolus while the remainder were given leucovorin, 5-FU, and oxaliplatin (mFOLFOX6) with 5-FU bolus. Through the duration of their treatment, 20.6% of patients received palliative radiotherapy to the primary tumor, all of which were proximal esophagogastric junction tumors (28%; n = 14/50).

Additional findings indicated that 79% (n = 54) of patients in the ITT population and 83% (n = 10) of those in the non-ITT population had measurable disease. Four patients (7.4%) in the ITT population had a complete response (CR), 36 (66.7%) had a partial response (PR), 13 (24.1%) had stable disease, and 1 (1.9%) had progressive disease. No patients (0%) within the non-ITT population experienced a CR. However, 4 (40%) patients in the non-ITT population achieved a PR, 3 (30%) had stable disease, and 3 (30%) had progressive disease.

No diagnostic or treatment-related deaths were reported on the study, and only 1 patient required overnight monitoring due to abdominal pain following a baseline ultrasound-guided biopsy of a peritoneal nodule. The most frequent grade 3 or higher hematologic treatment-related adverse effects (TRAEs) reported across all lines of therapy included neutropenia (18%; n = 12), anemia (16%; n = 11), and white blood cell decrease (9%; n = 6). Other grade 3 or higher TRAEs included fatigue (13%; n = 9), as well as nausea and vomiting (9%; n = 6).

In the first-line setting, the most common high-grade hematologic toxicities included anemia (10%; n = 7), neutropenia (9%; n = 6), and thrombocytopenia (6%; n = 4), with other TRAEs including nausea and vomiting (6%; n = 4) and fatigue (4%; n = 3). Patients in the second-line setting experienced some neutropenia (8%; n = 4), fatigue (6%; n = 3) and diarrhea (6%; n = 3). Lastly, in the third-line setting, the most common TRAE was fatigue (16%; n = 4) with hematologic TRAEs including neutropenia (12%; n = 3), anemia (12%; n = 3), and thrombocytopenia (12%; n = 3).

“During the study, we learned that not only is it common to see genetic heterogeneity between the primary and metastatic tumor — about 40% of the time, the metastatic tumor differed substantially from the primary tumor — but also that about 45 or 50% of the time, patients had their therapies changed as the disease evolved,” Catenacci added. “By going after the metastatic site at the start of treatment, reassessing the tumor if and when there was clinical disease progression, and using the algorithm to prioritize therapy each time, the survival outcome was substantially higher than would be expected using standard therapies.”

Catenacci DVT, Moya S, Lommnicki S, et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): a phase II study evaluating an individualized treatment strategy for metastatic disease. 

. Published online November 20, 2020. doi:10.1158/2159-8290.CD-20-1408

Dynamic, personalized treatment approach may improve outcomes in gastroesophageal cancers. News Release. University of Chicago Medicine. January 21, 2021. Accessed January 22, 2021. 

Personalized, Adaptable Treatment Strategies May Improve Survival in Metastatic Gastroesophageal Cancer

Personalized and adaptable treatment regimens seem to be the way forward in treating gastroesophageal cancer.

Individualized Treatment May Improve Outcomes in Gastroesophageal Cancer

Updated survival data from the phase 3 Short-HER trial (NCT00629278) presented during the ESMO Breast Cancer Virtual Congress 2021 confirm the promising long-term results obtained with 9 weeks of adjuvant trastuzumab (Herceptin) in patients with HER2-positive early breast cancer who have low and intermediate risk factors, a population that is representative of most patients seen in clinical practice.

After a median follow-up of 8.7 years, patients who received 1 year of trastuzumab had a 5-year disease-free survival (DFS) rate of 87.9% vs 85.8% those who received it for 9 weeks (hazard ratio [HR], 1.09; 90% CI, 0.88-1.35). Moreover, patients had a 5-year overall survival (OS) rate of 95.1% in both arms, respectively (HR, 1.18; 90% CI, 0.86-1.62).

“Patients classified as low/intermediate risk on the basis of [tumor] size and nodal status represent 84.6% of the Short-HER study population. In this patient population, long-term DFS and OS are superimposable between the 2 treatment arms,” Pier Franco Conte, MD, a full professor of oncology at the University of Padova, Italy; director of the Division of Medical Oncology at the Istituto Oncologico Veneto in Padova; and chairman of Rete Oncologica Veneta, said in a presentation on the findings. “Although 1 year of trastuzumab remains a standard, de-escalation of treatment is a reasonable option for a large proportion of a real-world population of [patients with] HER2-positive early breast cancer.”

The superiority of combining 1 year of trastuzumab with adjuvant chemotherapy over chemotherapy alone in patients with HER2-positive early breast cancer was demonstrated in the phase 3 HERA (NCT00045032), Joint Analysis B31-N9831, and N9831 trials.

 In November 2006, trastuzumab was approved by the FDA as an adjuvant therapy for patients with HER2-positive, node-positive breast cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel.

“It was very clear at the time that the choice of a 1-year duration of trastuzumab administration was based empirically and that a similar degree of benefit had already been reported with the small FinHER study with 9 weeks of trastuzumab,” Conte noted.

The Short-HER trial, which was an investigator-driven, noninferiority study, started off with an initial sample size of 2500 patients; however, as of February 2011, this was amended to 1250 patients. The study was conducted across 82 investigational sites in Italy and had a recruitment period that ran from December 2007 to October 2013. The primary analysis was completed after 189 DFS events at 5.2 years median follow-up.

The trial enrolled patients with HER2-positive, node positive, or high-risk node-negative disease. “Patients were then randomized to receive either 1 year of trastuzumab plus chemotherapy, which included 4 courses of doxorubicin and cyclophosphamide, followed by 4 courses of a taxane, vs 3 courses of docetaxel combined with 9 weeks of weekly trastuzumab followed by 3 courses of fluorouracil, epirubicin hydrochloride, and cyclophosphamide,” Conte said. Stratification factors included hormone receptor status and nodal status. Patients who were aged 65 years or older received docetaxel at 80 mg/sqm dose of docetaxel. Eleven percent of patients who received the longer duration of trastuzumab were given paclitaxel at 175 mg/sqm.

The overall patient population had a median age of 55 years (range, 25-78), and 64.0% were postmenopausal. Moreover, 40.6% of patients had stage I disease, 43.8% had stage II disease, and 15.2% had stage III disease. Most patients were node negative (53.5%), although 30.7% of patients had 1 to 3 positive nodes and 15.8% had at least 4 positive nodes. Additionally, 68.2% of patients had hormone receptor–positive status.

The DFS reported in the primary analysis of the trial showcased a HR of 1.13 (90%, CI, 0.89-1.42). Investigators reported that the probability that the shorter duration of treatment would be noninferior to that of the longer duration was 78% .

 Moreover, the primary analysis identified an association between a longer duration of treatment and a longer and higher incidence of cardiac events. The incidence of grade 2 or higher cardiac events was 13.1% in the long-duration treatment arm vs 4.3% in the short-duration treatment arm.

The updated results of the study had a median follow-up of 8.7 years with 237 DFS events and 109 deaths.

Investigators also examined DFS and OS outcomes with respect to risk category. “The high-risk group clearly has worse outcomes in terms of both DFS and OS, while both low- and intermediate-risk groups had very good DFS and OS estimates,” Conte said.

Patients in the low-risk group experienced a 5-year DFS of 91% in both treatment arms (HR, 0.91). In the intermediate-risk group, those who were treated with the longer duration of treatment had a 5-year DFS rate of 88% vs 89% with the shorter duration (HR, 0.88); the 5-year DFS rates in the high-risk group for the longer and shorter treatment durations were 82% and 64%, respectively (HR, 2.06).

Additionally, the 5-year OS rate for patients in the low-risk group who received the longer duration of treatment was 97% vs 99% with the shorter duration (HR, 0.57). In the intermediate-risk group, these rates were 96% and 95%, respectively (HR, 1.14), while they were 95% ad 91%, respectively, in the high-risk group (HR, 1.09).

Conte P, Frassoldati A, Bisagni G, et al. Nine weeks vs 1 year adjuvant trastuzumab: long term outcomes of the Short-HER randomized trial. Presented at: ESMO Breast Cancer Virtual Congress 2021. May 5-8, 2021; Virtual. Abstract 401.

Herceptin (Trastuzumab) in treating women with human epidermal growth factor receptor (HER) 2-positive primary breast cancer (HERA). ClinicalTrials.org. Updated April 27, 2017. Accessed May 7, 2021. https://clinicaltrials.gov/ct2/show/NCT00045032

Doxorubicin and cyclophosphamide plus paclitaxel with or without trastuzumab in treating women with node-positive breast cancer that overexpresses HER2. ClinicalTrials.gov. Updated April 29, 2021. Accessed May 7, 2021. 

https://clinicaltrials.gov/ct2/show/NCT00004067

Doxorubicin hydrochloride, cyclophosphamide, and paclitaxel with or without trastuzumab in treating women with HER2-positive node-positive or high-risk node-negative breast cancer. ClinicalTrials.gov. Updated August 2020. Accessed May 7, 2021. 

https://clinicaltrials.gov/ct2/show/NCT00005970

FDA approves Herceptin for the adjuvant treatment of HER2-positive node-positive breast cancer. News release. FDA. November 16, 2006. Accessed May 7, 2021. 

Conte P, Bisagni G, Frassoldati A, et al. Final analysis of the phase III multicentric Italian study Short-HER: 9 weeks vs 1 year adjuvant trastuzumab for HER21 early breast cancer. 

. 2017;28(suppl 6):vi1-vi2. doi:10.1093/annonc/mdx421

Shorter Duration of Adjuvant Trastuzumab Shows Long-Term Survival Benefit in Select HER2+ Early Breast Cancer.

A 9-week trastuzumab regimen may be favorable for patients with HER2-positive early breast cancer who have low and intermediate risk factors. 

Shorter Adjuvant Trastuzumab Has Long-Term Benefits for HER2+ Breast Cancer

The phase 3 IMpower133 trial (NCT02763579), which examined atezolizumab (Tecentriq) plus platinum-based chemotherapy and etoposide in patients with untreated extensive-stage small cell lung cancer (ES-SCLC) helped lay the foundation for the exploration of other novel immunotherapy combinations, according to Ravi Salgia, MD, PhD.

In the phase 3 CASPIAN trial (NCT03043872), investigators examined the use of first-line durvalumab (Imfinzi) plus the same chemotherapy backbone in patients with ES-SCLC.

 The combination yielded a durable improvement in overall survival, but the addition of tremelimumab (formerly ticilimumab; CP-675,206) did not appear to elicit any further statistically significant improvement.

Now, a phase 1 study (NCT04560972) will further build off of the IMpower133 regimen by examining the safety of the novel agent LB-100 in combination with carboplatin, etoposide, and atezolizumab in patients with untreated ES-SCLC.

Further exploration of immunotherapy regimens will be necessary, Salgia said.

“It is important for us to realize that the tumor mutational burden for SCLC is very high,” Salgia said. “We need to be able to [consider whether] immunotherapy [may] work even better [when used] in combination with chemotherapy or other therapeutic strategies.”

® during an Institutional Perspective in Cancer webinar on lung cancer, Salgia, a medical oncologist and Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope, discussed pivotal trials that have shaken up the small cell lung cancer treatment paradigm, novel immunotherapy regimens under investigation, and next steps for research.

®: What is your approach for selecting treatment for patients with limited-stage SCLC [LS-SCLC] vs ES-SCLC?

: SCLC is a difficult disease to treat. We have come a long way in terms of thinking about [the disease] and we know that there are 2 varieties of [the disease] that we consider in terms of the staging: LS-SCLC and ES-SCLC. For [patients with] LS-SCLC, we still [administer] chemotherapy and radiation therapy [with consideration] for prophylactic cranial radiation. For those with [ES-SCLC], we are changing the paradigm. Currently, we are using chemotherapy with immunotherapy. After the first line of therapy fails, [we have a] second-line option, which is lurbinectedin [Zepzelca]. Of course, we really try to emphasize [enrollment to] clinical trials, as well.

Starting in the frontline setting, how are you applying the findings from the pivotal phase 3 IMpower133 trial to clinical practice?

Results have [demonstrated] that platinum-based chemotherapy with etoposide in combination with atezolizumab does [yield] better survival. That is revolutionary for us and we are using that [agent] in our clinical practice. It is important to realize that the severity of the adverse effects were not worse than [what was reported in] the chemotherapy arm.

An ongoing study that is open at City of Hope is building off of the success seen with the IMpower133 regimen. Could you highlight this research and its potential implications?

For ES-SCLC, we are using carboplatin and etoposide with atezolizumab, as an example. However, we know patients can recur and relapse, so we wanted to make that better. In our laboratory, we had discovered that the PP2A pathway in SCLC is very important. We can inhibit that pathway with a drug called LB-100. We are using a backbone of the IMpower133 regimen—carboplatin and etoposide with atezolizumab—and combining it with LB-100. We are going to be publishing [these data] relatively soon. It is important to realize it is a phase 1 study, but we are quite hopeful that this [research] will [result in] revolutionary breakthroughs.

Does LB-100 have a safety profile that makes it amenable for use in a 4-drug combination?

The initial LB-100 study [that examined the] drug by itself was done here, at City of Hope, and that [research] was published by Vincent Chung, MD, and colleagues. The safety profile [of LB-100] was really good. [However], we do not know yet [what this will look like] in combination [with other agents] because this is a phase 1 study. Once we start the study, we are very much hoping that the toxicity is no different than [what we saw in] the IMpower133 study.

What has been learned from the phase 3 CASPIAN trial? How do you select which patients should receive this regimen vs the IMpower133 regimen in practice?

The CASPIAN study also gives us another [option] for our patients. Instead of utilizing atezolizumab, we utilize durvalumab. The study looked at durvalumab [plus platinum/etoposide and] with tremelimumab [vs platinum/etoposide alone]. However, the issue became that the [the addition of tremelimumab] did not [provide more benefit] than durvalumab [with platinum/etoposide]. We are using a platinum-based backbone, with etoposide and durvalumab. The difference is that in the context of the maintenance study, durvalumab was given once a month [while] atezolizumab was given once every 3 weeks. At the same time, we use it in our practice either way. I do believe [the decision] is really dependent on [factors like] tolerability. Both of the regimens are very reasonable.

In February 2021, the FDA approved trilaciclib (Cosela) to reduce chemotherapy-induced bone marrow suppression in adult patients with ES-SCLC who were receiving certain chemotherapy agents. How did this decision impact the paradigm?

Growth factor support has been always important for SCLC, especially [because of] the cytotoxic therapies that we give [to our patients]. We have used granulocyte colony-stimulating factor, and now, we have another option [in the form of] this new CDK4/6 inhibitor.

It was nice to see that [that the agent] did not affect the survival [of the patients who received it] in a negative way. We are very happy with that and [we will] be utilizing that [option] in our clinical practice. The more choices we have, the better it is for patients.

Shifting to the second-line setting, in June 2020, lurbinectedin was also approved by the FDA for use in patients with metastatic SCLC following progression on a platinum-based chemotherapy. How does the agent compare with standard topotecan?

We know that in the first-line setting of SCLC, many of our patients relapse and/or recur. [Therefore], it is important to have [options in the] second-line setting. We have always said that clinical trials are incredibly important and lurbinectedin provides a potential [option] beyond topotecan. As we know, topotecan has been approved as a second-line therapy; however, lurbinectedin seems to be better tolerated and is showing [good] efficacy. [Moreover], topotecan is given on days 1 through 5, whereas [lurbinectedin] is really much easier to give. Having another choice makes a huge difference in practice.

How would you approach choosing between the 2 options?

Lurbinectedin is probably going to become the standard of choice; it has been in our practice. It is because of convenience—instead of days 1 through 5, it is [administered every] 21 days—as well as tolerability. I do think it has a huge role for us, and we will continue to utilize it. It [will be] important for us to explore this [agent] in the first-line setting [and learn] how we can overcome resistance in the second line.

The indication for pembrolizumab (Keytruda) in patients with metastatic SCLC who experienced disease progression on or after platinum-based chemotherapy and at least 1 prior line of treatment was recently withdrawn by the FDA. How do you foresee this impacting the use of the agent in this disease?

We has been excited about the approval of pembrolizumab, but it has since been withdrawn by the FDA, and very reasonably so— the end points [of the confirmatory trial] have not been met. If it does not help our patients, it is not worth it. [It begs the question], is pembrolizumab important? It could be very important in terms of early-stage disease, in the first-line setting, [and] in combination in other settings. We do not [currently] know and, clearly, we need to do more clinical trials.

Bispecific antibodies are going to be important, as well as bispecific T-cell engagers. Potentially even CAR T-cell therapies will be significant. All of those [options] will lead to significant advances in SCLC. Can one use immunotherapeutics with small molecule inhibitors? Can one [leverage] the genomics or alterations in SCLC [to improve outcomes]? That is to be determined, and that is where we need to [focus our] attention in [terms of] clinical trials.

Lung cancer is still a very tough disease to treat. We have some therapeutics that have revolutionized our way of thinking, but it is not good enough; we need to do better. We need to continue to [conduct] clinical trials [and encourage enrollment] so we can make a difference. It is important to do research in, and fund research [for], SCLC as we have done for non–small cell lung cancer, [where] many of the codes are being broken. We need to break the code even better for SCLC.

Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. 

. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8

LB-100, carboplatin, etoposide, and atezolizumab for the treatment of untreated extensive-stage small cell lung cancer. ClinicalTrials.gov. Updated March 15, 2021. Accessed April 29, 2021. https://clinicaltrials.gov/ct2/show/NCT04560972

Future of SCLC Treatment Lies in Innovative Immunotherapy Combos

New immunotherapy combinations are being explored in the small cell lung cancer space.

Next Up in SCLC: Immunotherapy Combinations

The EGFR TKI osimertinib (Tagrisso) has shaken up the treatment paradigm of advanced non–small cell lung cancer (NSCLC), and now the agent is under exploration in earlier-stage settings in an effort to further prevent recurrence and prolong survival, according to Edward S. Kim, MD, who added that the key to reaching patients earlier is to test for biomarkers earlier.

“In the early-stage setting, it is devastating when [patients experience] recurrence. Hopefully, [with osimertinib,] we can do something about it and treat them. Too many times, because of the nihilism that has built up over the years, we are just waiting for the recurrence to occur,” Kim said. “I hope we get to a point where recurrence is less common, and we are treating more patients with earlier-stage disease. Our paradigm has changed. We will continue to study other drugs and targets in these settings, as well.”

 during an Institutional Perspectives in Cancer webinar on lung cancer, Kim, physician-in-chief of City of Hope Orange County and vice physician-in-chief of City of Hope National Medical Center, highlighted the impact of osimertinib in the treatment of patients with 

-mutant NSCLC, next steps with the agent, and the importance of early genetic testing to provide personalized care.

: How has the emergence of osimertinib impacted the management of patients with

 has really been one of the pioneering biomarker pathways in lung cancer. Osimertinib is the preferred drug because it has very strong efficacy and a [favorable] safety profile. The newer-generation drugs penetrate the brain and the central nervous system much more predictably than older-generation agents; this has changed the paradigm of how we approach patients who have initially been diagnosed with brain metastases. If they are stable, then we do not jump right to radiation. Instead, we treat them [with these drugs] if they have a mutation and watch them in case we need the radiation. [However,] it is great to see even our radiation colleagues embrace these data.

What are some areas of focus in the realm of

Throughout our investigations, we have also found other mutations in 

; some are sensitizing, some are resistant, and some we are not sure about yet. We are developing drugs [to target] these specific mutations, which is exciting. That is what we dream [to do with] cancer [treatment]: identify a marker in the tumor that is unique to an individual and finding a [targeted] therapy that [that is efficacious and] will not cause many adverse effects [AEs].

 moving into the earlier-stage setting; this [development,] indeed, follows what we have seen in the breast cancer paradigm. You have drugs that [are initially used in the] metastatic [setting], like tamoxifen, that are now moving into the earlier-stage setting. [Patients] can take [these agents] for several years and [they are effective]. We are seeing that now with osimertinib, [which is under examination] in the early-stage setting, in patients who have stage IB through IIIA [disease].

 mutations. If you find one, then after you finish the surgery and/or give chemotherapy, [you can] then treat the patient with osimertinib for 3 years; this has been shown to greatly improve disease-free survival [DFS]. We are still waiting for overall survival [OS] data [with this approach]. However, the trial [that examined this strategy] was unblinded early because of its effectiveness, and patients are still being treated.

[Treatment has] really cascaded in the direction [where] we want to reach patients earlier—especially those who have curable disease or curative intent disease. [We want to] try to keep disease away as long as possible. I am really happy that biomarkers have made it into the clinic. I urge everyone out there to test [for] biomarkers. Ensure that you are testing for these before you initiate any treatment. It does not matter if you are using smaller panels or larger panels; just ensure that you are getting that information and utilizing it to inform decisions.

Looking more closely at the use of osimertinib in the adjuvant setting, how did the agent perform in the phase 3 ADAURA trial (NCT02511106)? What does this information mean for practice?

The primary end point of ADAURA was DFS, specifically in [patients with] stage II and IIIA [disease], although the trial did enroll [those with] IB through IIIA [disease]. DFS was the first reported outcome because you get those outcomes earlier. Data were revealed early because of the effectiveness [of the agent]; this [runs] parallel to what happened with tamoxifen.

Edward S. Kim, MD, highlights the impact of osimertinib in the treatment of patients with EGFR-mutant non–small cell lung cancer, next steps with the agent, and the importance of early genetic testing to provide personalized care.

Hayley Virgil