Blood-based markers are the key to better understanding the biology of various breast cancer subtypes, said Mark E. Burkard, MD, PhD.

One of the most prominent markers in breast cancer is circulating tumor DNA (ctDNA), which is being used to measure tumor burden and detect potentially targetable mutations.

“[ctDNA] is of interest because it's a way of doing a simple blood test to get a sense of how much tumor burden is in a person, especially with metastatic disease,” said Burkard. “It also can tell you what particular genetic characteristics that tumor has. ctDNA can be very helpful for a specific selection of treatment.”

Alterations such as NTRK, PIK3CA, AKT, and ESR1 are also helping to drive treatment decisions.

“There are definitely emerging targets, and some of these only happen at the time of recurrence,” he added. “You may not find [these targets] in the breast cancer tumor that the surgeon resected; you may only find them after in the metastatic setting.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Breast Cancer, Burkard, an associate professor of medicine in the Hematology/Oncology section of the University of Wisconsin (UW) School of Medicine and Public Health, and a member of the UW Health Breast Center, discussed the significance of utilizing markers in the blood and highlighted emerging actionable mutations in breast cancer.

OncLive: What is the significance of ctDNA in breast cancer?

Burkard: In terms of measuring residual tumor burden, one area this is useful is in triple-negative breast cancer. We know that when we treat these patients with neoadjuvant chemotherapy, we can get a sense of how well that [approach] worked and whether it eliminated tumors based on their surgical response.

There are standard ways to assess for that. For the patients who failed to have a good response, there are some recent data from a group of researchers at Indiana University suggesting that you can also stratify patients [to determine which ones are] most likely to have recurrent breast cancer by doing blood biomarkers. Patients who have a high level of ctDNA in their blood are the ones who are most likely to have their cancer return. That's a nice way to potentially better identify patients who would benefit from more therapy.

Another use [for ctDNA] in the metastatic setting would be for genomic or precision oncology. We are selecting patients more and more in breast cancer based on the genes in an individual tumor. In the past, we focused on HER2 exclusively, but we now know more about how patients with BRCA mutations can benefit from PARP inhibitors. We know there are very rare patient cohorts who can benefit from FDA-approved drugs for genetic translocations of the TRKA/B/C genes or who have microsatellite instability-high (MSI-H) tumors.

We were just hearing about the new evidence that PI3K inhibitors may be useful in patients with PIK3CA-mutant breast cancer. Usually, the way we figure out if a patient has [these mutations] is by doing a biopsy on the tumor. Looking at the DNA in the tumor is another way to do this. In many of our patients—especially those with estrogen receptor (ER)—positive breast cancer&mdash;this isn't feasible, because they may have bone-only disease or the metastatic disease is in inaccessible sites. Cell-free DNA (cfDNA) is another way to determine [if there are molecular abnormalities]. It's a good adjunct for patients with metastatic breast cancer in whom you want to take a precision medicine approach.

What is the frequency of patients with MSI-H breast cancer?

[The prevalence is] very low. In one of the studies by Luis A. Diaz, Jr., MD, of Memorial Sloan Kettering Cancer Center, [the prevalence of those patients] was determined to be as high as 2% based on results from a retrospective analysis; that's on the high end.

However, with most of the MSI-H assays, it's far less than 1%. Other estimates are as low as 0.3%. Therefore, these [markers] are very rare, and NTRK is probably even more rare. Frankly, it may be hard to pull those out of blood tests, but those are [markers for] which you have actionable drugs, if you can find them.

Are there any other promising targets under investigation?

We have AKT mutations; A17K is the most common activating mutation. Although there are no FDA-approved AKT inhibitors today, there are several in clinical trials. There are also the PIK3CA mutations that I mentioned.

Another emerging target is FGFR, which are very rarely mutated or translocated; however, FGFR1 amplification is very common as a mechanism of resistance to hormone therapy in ER-positive breast cancer. The final one which we don't have a drug for are the ESR mutations—ESR1 is the gene; it’s mutated in almost 25% of breast cancers after they develop resistance to hormonal therapy. Therefore, there are many active drug developments but no FDA-approved drugs. People have tried high-dose fulvestrant (Faslodex), and there is some evidence suggesting that this may be promising, but there are newer drugs coming out. Many emerging targets are out there.

What are some trials evaluating the use of blood-based markers in breast cancer?

Many of these studies are observational; they are built on as adjuncts to the existing trials. What we've learned from them is more about the biology of the disease. For example, one thing we learned that's slightly frightening is that when patients develop resistance to hormonal therapies in ER-positive breast cancer, often the resistance is polyclonal. Therefore, if you biopsy a tumor and look for the ESR1 mutation, you find it. If you look for the FGFR1 mutation, you might find it in a different tumor. With a blood sample that is collecting DNA from every tumor in a person's body, sometimes you can find both of these resistance mechanisms happening simultaneously. This reveals that when resistance develops, it can develop at many places and in many cells simultaneously, which is very interesting biologically.

Practically, this poses a very unique challenge; you're not going to reverse that [resistance] by only targeting FGFR1 or only ESR1 mutations. You have to do something a little more strategic to get around that. The other place where this is being implemented into clinical practice is through measuring residual disease. We've had protein biomarkers like CA27-29 and CA15-3 for a long time. We also have circulating tumor cells, which are measured in cell-search assays and other tests. [With this approach,] people count the number of cells they find in the bloodstream that came from the cancer; as the tumor burden increases, [the number of these cells] increases, and as [the burden] decreases, they often go back down.

cfDNA is another way of accomplishing that, although it's not clear if that [approach] will be better. It poses some advantages and disadvantages compared with the other methods. In terms of advantages, [this approach] is potentially more sensitive because there are technologies for DNA amplification that could see as little as 1 molecule of DNA with a mutation.

There are also challenges [with this method] because people have other DNA floating in their bodies, and sometimes, we find out that those DNA are mutated for other reasons. For example, there's a group of people who have p53 in their bone marrow, which you can pick up this way. In this case, it doesn't come from the tumor at all, it's a [genetic alteration] in their bone marrow. It's hard to distinguish those things.

There are various other challenges with measuring disease burden by quantitating the amount of DNA harboring a particular mutation in the blood. That's another area of interest, and I suppose it has different advantages and disadvantages against the pre-existing measures of tumor burden.

Could you expand on the challenges faced with understanding these genetic alterations?

Almost every breast cancer is unique in its genetic characteristics. One of the major challenges is that the most common mutations in breast cancer are PIK3CA and p53, which occur in up to 25% of breast cancers. Everything else is less common. Capturing the diversity [of these genetic alterations] is a challenge. If you want to quantify the amount of tumor burden by measuring the DNA in the blood, you have to accept that diversity and say, "I don't even know what mutations I'll find in this particular patient." You need to just quantify the amount of DNA in each mutation. That is a special challenge, and it's particularly difficult when one is trying to measure deletions and amplifications of genes.

For example, HER2 amplification happens in 20% of breast cancer. Usually, you would capture that by doing a biopsy, taking the DNA out, and measuring the number of times you get DNA sequences from the HER2 gene versus everywhere else. If you had a lot more in the HER2 gene, it's amplified.

In the blood, that poses a challenge, because now you've mixed DNA from the tumor with DNA from many other blood and non-blood cells. It may be hard to capture that amplification in the setting of that deletion. What was a 200-fold amplification might only show up as maybe 10-fold, and what is a 10-fold amplification might not show up at all.

Articles

By better understanding the subtypes of breast cancer, clinicians can create more personalized and effective treatment plans for patients with breast cancer.

Blood-Based Markers Improve Precision Medicine in Breast Cancer

Monoclonal antibodies, proteasome inhibitors, and targeted agents are among the many options in the crowded treatment landscape of relapsed/refractory multiple myeloma, and the emergence of drugs, such as venetoclax (Venclexta) and selinexor, could add to the complexity of this paradigm, said Cristina Gasparetto, MD.

Although both the BCL-2 inhibitor venetoclax and the XPO1 inhibitor selinexor have shown promise in previously treated patients with myeloma, they are not without safety concerns. In March 2019, the FDA announced that it was placing a partial hold on all clinical trials evaluating venetoclax in multiple myeloma. The decision followed a review of data from the phase III BELLINI trial (M14-031; NCT02755597), in which there was a higher rate of death observed in patients in the venetoclax arm compared with those in the control arm.1Specifically, the rate of reported deaths in the venetoclax arm was 21.1%, with 6.7% considered to be treatment-emergent. Of the 13 treatment-emergent deaths, 8 were associated with infection.

“I have been using venetoclax for several years, and I was surprised because I have patients on single-agent and combination venetoclax who are doing phenomenally,” said Gasparetto, an associate professor of medicine and director, Multiple Myeloma Program at Duke Cancer Institute. “[I'm not seeing] increased signals of immunosuppression or risk of infection. I don't know if these adverse events are due to the proteasome inhibitor or something else, but we are now waiting to re-open some important studies.”

Additionally, selinexor will have to overcome regulatory obstacles before potentially becoming part of routine clinical practice. Despite yielding substantial response rates and encouraging survival data, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 5 against an accelerated approval for a new drug application (NDA) for the agent in February 2019.

The decision came on the heels of safety data released from the phase IIb STORM trial, which showed significant incidence of fatigue (72.4%), thrombocytopenia (71.5%), nausea (69.9%), and anemia (65.9%).2 Treatment-related adverse events also resulted in patient deaths in this study. In March 2019, the FDA announced it was adding 3 months to the review period for an NDA for selinexor in the treatment of patients with penta-refractory multiple myeloma, moving the new decision date to July 6, 2019.

, Gasparetto discussed the rapidly evolving field of relapsed/refractory myeloma.

What is some of the key research being done in relapsed/refractory myeloma?

Gasparetto: There have been some important studies focusing on combinations of pomalidomide (Pomalyst) and dexamethasone. In my presentation, I discussed the recent results of the ELOQUENT-3 trial. This was a phase III randomized study comparing pomalidomide plus dexamethasone with elotuzumab (Empliciti) plus pomalidomide/dexamethasone. It clearly showed that the addition of elotuzumab to therapy after first relapse improves overall response rate (ORR) and progression-free survival (PFS). It is very interesting to dissect this study; however, the most important takeaway was that the addition of elotuzumab did not cause any additional toxicity. This is a good combination for patients with early relapsed myeloma.

I also briefly discussed the OPTIMISMM study, which was another study reviewing the combination of pomalidomide, dexamethasone, and the proteasome inhibitor bortezomib (Velcade). The study was presented by Paul G. Richardson, MD, of Dana-Farber Cancer Institute, in 2018. Results showed that the combination was superior to the doublet [of pomalidomide and dexamethasone], with increased ORR and PFS. Even in the relapsed setting, triplets can have higher durability of response and response rates than the doublets. I also presented data from the ARROW study, which showed that weekly administration of carfilzomib (Kyprolis) was superior to the bi-weekly administration. Patients were probably able to sustain treatment longer with the lessened toxicity. They were also able to sustain a higher dose. We knew from the beginning that a higher dose of carfilzomib correlates with a better outcome.

I was also able to touch base on a couple of important studies for patients who have failed multiple lines of therapy—patients with penta-refractory disease. This patient population doesn't have many options left; they come to us seeking clinical trials and different targeted therapies. I had the fortune of working with 2 important drugs over the last few years; the first was selinexor, an XPO1 inhibitor. This can be a difficult drug if you don't know how to use it, and I was definitely a little intimidated at first. However, now I really love it. You learn to support the patients; I've had patients on selinexor for more than a couple years who are doing very well. There are a lot of dose modifications and reductions after the first few cycles. Selinexor is given orally, and in combination with dexamethasone, it is given twice weekly. Many patients also receive this combination once weekly and are doing quite well with good quality of life and sustained responses.

Venetoclax targets the t(11;14) population, which accounts for about 30% of all patients with myeloma. Responses are phenomenal in this patient population. When combined with dexamethasone, responses were about 60%. Then, we see with carfilzomib responses are nearly 100%. There was some concern with the increased risk of infection, so now all patients are receiving antibiotics and prophylaxis. I've had the good fortune of working with venetoclax for many years and I've seen great responses.

At the 2018 ASH Annual Meeting, we also saw updates on CAR T cells. The most established in the United States is bb2121,which is going for registration. Noopur Raje, MD, of Massachusetts General Hospital, presented the results at the meeting and there were incredible response rates. The durability of response was a little disappointing, so we're all seeking modifications and additional novel targets. All of these agents and targets have definitely impacted this patient population.

There have been some trials halted with venetoclax. Could you discuss this further?

Recently, there was a phase III randomized study in which patients in the relapsed setting were randomized to receive bortezomib and dexamethasone, which is a standard backbone, versus bortezomib, venetoclax, and dexamethasone. The primary endpoint was PFS, which was met. The improvement was statistically significant. Unfortunately, the overall survival was determined to be inferior because there were an increased number of deaths in the experimental arm primarily due to bacterial infections. That raised a lot of questions; we are all waiting for additional analysis with this drug.

How is selinexor being used in this space?

Selinexor is not easy, and we need to do a lot of dose modifications and supportive care. However, as I mentioned, I do have patients on low-dose selinexor who are maintaining their response. I love selinexor now, but it does have some unusual factors, like the central nervous system penetration, which needs to be further explored. There is an additive effect with other drugs. I presented data at the 2018 ASH Annual Meeting on its combination with daratumumab (Darzalex). We saw an ORR of close to 80%; the duration of response is also significant. I really hope we can have more positive feedback from ODAC and the FDA in the future so that this agent can become more widely used. It is a real drug, and it works.

Is there anything that you would like to add?

In the relapsed/refractory setting, it is important to think about how to best sequence these drugs. We do have many options, and how we make a decision will be based on patients' comorbidities, type of myeloma, type of relapse, and how fast they relapse after induction. We are all learning about how we can apply what we learn from large studies to our patient populations.

FDA Grants Priority Review to Combination Regimen to Treat Multiple Myeloma

This article was originally published on 

Navigating the Complex Treatment Paradigm of Relapsed/Refractory Multiple Myeloma

1. AbbVie Provides Update on VENCLEXTA®/VENCLYXTO® (venetoclax) Multiple Myeloma Program [news release]. AbbVie. Published March 19, 2019. https://bit.ly/2Ogtt7M. Accessed May 24, 2019.

2. Chari A, Vogl DT, Dimopoulos MA, et al. Results of the pivotal STORM study (part 2) in penta-refractory multiple myeloma (MM): deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta-refractory MM. Blood. 2018;132:132-598. doi: 10.1182/blood-2018-99-116663.

Myeloma Treatment Landscape Continues to Change

The identification of molecular alterations has become essential in the treatment of patients with metastatic colorectal cancer (mCRC), said Michael J. Overman, MD, as this can inform which approach will provide the most benefit and result in the best outcomes.

For example, the identification of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) disease indicates that immunotherapy may serve as an effective treatment option, as this approach has been shown to induce dramatic, durable responses with curative potential in this rare subset of patients with mCRC.

“The numbers are fairly small on this front but it's clear that we are curing a fraction of [patients with] mCRC,” said Overman. “It behooves us as practitioners to identify these patients because it's a remarkable change in our standard approach. That's the most exciting thing about this MSI-H mCRC space.”

In the phase II CheckMate-142 trial, 119 patients with MSI-H/dMMR mCRC were treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy). Initial results showed an objective response rate (ORR) of 49% and the median duration of response had not been reached. These data led to the FDA’s decision to grant accelerated approval to the combination for the treatment of patients with MSI-H or dMMR mCRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan in July 2018.

Updated data from the CheckMate-142 trial, which were presented at the 2019 Gastrointestinal Cancers Symposium, showed that a median follow-up of 25.4 months, the combination elicited a 58% ORR, and the median progression-free and overall survival were not reached.

 Next steps for the regimen include further evaluation in the frontline setting.

, Overman, a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed this combination regimen in mCRC and highlighted existing challenges that still need to be addressed in future research.

: What does the treatment landscape of mCRC look like?

: The field of mCRC has become unique in that there are many different molecular subsets that we utilize. The first key statement in the mCRC landscape is molecular subset. [A patient] gets MSI testing, 

has emerged as an important [biomarker] as well. Clearly, there are a lot of exciting data with immunotherapy in MSI-H or dMMR CRC, so that's a subset we need to identify because we have therapies for them. We are utilizing this in the second- and third-line settings and beyond, and there are trials ongoing looking at the frontline setting. 

 V600E is a mutation where we have National Comprehensive Cancer Network (NCCN) guideline-based therapy of vemurafenib (Zelboraf), cetuximab (Erbitux), and irinotecan. There are potentially emerging data coming with the BEACON CRC study, a big ongoing phase III trial in this space.

 mutations, we've known for a while that they have to be 

 wild-type in order to benefit from anti-EGFR therapy, so that marker has to be collected as well. There are ongoing studies looking at the 

 space, but there is nothing in terms of guidelines right now. When we use combination approaches for HER2 targeting, we see a lot of activity. These are the key fundamentals you have to sort out to understand our unique approaches going forward. Our frontline setting still consists of the typical systemic chemotherapy of FOLFOXIRI, FOLFIRI, and others with a biologic depending on molecular profiling and sidedness.

What data have we seen with immunotherapy?

This [approach] is for the MSI-H or dMMR subset of mCRC, which represents about 4% to 5% of this disease. However, it's a group that has consistently shown good data with immunotherapy. We have seen data with pembrolizumab (Keytruda), an anti—PD-1 agent, nivolumab as a single agent, and now, the combination of nivolumab plus ipilimumab. This combination has also shown dramatic benefit. The CheckMate-142 study had 114 patients with relapsed mCRC treated with that combination. That demonstrated remarkable results of a 50% response rate and a progression-free survival benefit that appears consistent at about 70% at 1 year. It's a high level of activity that appears durable, so this is very exciting. The CheckMate-142 study had another part to it that was presented at the 2018 ESMO Congress, which asked the question of whether we could give this combination in the upfront setting. We saw similar activity of what you would see in the refractory setting.

In the frontline setting, we don't have any large randomized trials to look at presently, but there is one that is ongoing with pembrolizumab that will potentially read out either this year or next. This may help set the standard for the frontline setting with a randomized study behind it.

What is the clinical significance of these data in MSI-H mCRC?

The most significant thing is that we have these new options for patients with MSI-H mCRC. These drugs are approved after fluoropyrimidine, oxaliplatin, irinotecan-based chemotherapy. NCCN guidelines recommend [immunotherapy] as a second-line therapy. I think we should be identifying all of these patients to recognize the subset that [can benefit from] this effective therapy. In part, I say that because the early data with this therapy suggest that when it works, it can really be curative in a subset of patients. It is reducing the cancer and generating durable responses; patients can stop therapy and the cancer does not come back.

What are the biggest challenges that still exist in this space?

The biggest challenge is that we see a high level of activity when we look at monotherapy or combination therapy, but there's still a subset of patients that are not responding. This subset has a high mutation load and a lot of neoantigens. They have a lot of pro-immunologic components, so you would think that all MSI-H patients should be responding to immunotherapy. Clearly, there are other mechanisms at play that prevent our current therapies from working. The real open question that remains is what these other mechanisms are. Can we identify these clearly and then engage on them to move this great response rate even higher? There is a lot of hope that we can do this. Right now, it's a lot of sample translational analysis. There hasn't been a consistent answer to this, so it's a work in progress. 

Tailored Approaches Offer Curative Potential to CRC Subsets

Bristol-Myers Squibb’s Opdivo ® (nivolumab) + Low-Dose Yervoy ® (ipilimumab) is the First Immuno-Oncology Combination Approved for MSI-H/dMMR mCRC Patients Who Progressed Following Treatment with a Fluoropyrimidine, Oxaliplatin and Irinotecan. Published July 11, 2018. Access July 11, 2018. https://bit.ly/2uaofBD.

Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) in previously treated patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Long-term follow-up. 

Certain patients with colorectal cancer may see a cure thanks to new, tailored approaches.

Moving Toward a Cure for Colorectal Cancer

The PD-1 inhibitor pembrolizumab (Keytruda) has shown an overall survival (OS) advantage across 3 phase III clinical trials studying its use in patients with metastatic non—small cell 

 (NSCLC). These positive results led to a frontline indication as a single agent and in combination with chemotherapy for both patients with squamous and nonsquamous NSCLC.

Tracey L. Evans, MD, director of thoracic oncology research at Main Line Hematology/Oncology and a thoracic oncologist at Penn Medicine, discussed these trials in detail during a presentation at the

Pembrolizumab was initially approved by the FDA in October 2015 for the treatment of patients with advanced, PD-L1—positive NSCLC whose disease has progressed after other treatments. In October 2016, the agency granted the PD-1 inhibitor frontline approval for patients with metastatic NSCLC who have PD-L1 expression ≥50% and do not harbor ALK or EGFR aberrations.

This regulatory decision was based on data from the KEYNOTE-024 study, in which pembrolizumab demonstrated a 40% improvement in OS versus standard platinum-based chemotherapy (HR, 0.60; 95% CI, 0.41-0.89; 

 <.005). Results also showed a statistically significant advantage in progression-free survival (PFS) at 10.3 months compared with 6.0 months, favoring pembrolizumab.

FDA granted approval to frontline pembrolizumab

 in combination with carboplatin/pemetrexed for patients with nonsquamous metastatic NSCLC. This decision was based on data from the phase III KEYNOTE-189 study, said Evans, in which the combination had superior OS versus chemotherapy alone (HR, 0.49; 95% CI, 0.38-0.64; 

KEYNOTE-189 was a multicenter, double-blind phase III study with an active control arm. Importantly, patients with nonsquamous metastatic NSCLC were enrolled irrespective of PD-L1 expression. Patients had no prior systemic therapy and nor EGFR or ALK mutations. Their ECOG performance status was 0 or 1.

The 616 patients were randomized in a 2:1 fashion to receive pembrolizumab with chemotherapy or chemotherapy alone. Patients receiving the combination got 200 mg pembrolizumab plus 500 mg/m

 or carboplatin AUC 5 mg/mL. Patients received chemotherapy at 4 cycles every 3 weeks.

“If patients did not demonstrate disease progression, they moved on to pembrolizumab and pemetrexed at the same dose every 3 weeks until disease progression or unacceptable toxicity,” said Evans. “They could continue pembrolizumab treatment for up to 24 months.”

Of the 410 patients randomized to the chemoimmunotherapy combination, 206 were able to move on to the next cycle of treatment. Crossover to open-label pembrolizumab was permitted for patients in the control arm.

“Pemetrexed and platinum-based chemotherapy were chosen as the control arms because it is reasonable to say they were the standard of care for frontline treatment of these patients. I think thoracic oncologists were less than impressed with the survival advantage of bevacizumab (Avastin) given the toxicity we saw,” Evans said.

The primary endpoints of the study were OS and PFS assessed by blinded independent central review per RECIST v1.1 criteria; secondary endpoints were overall response rate (ORR) and duration of response. Patients were stratified by tumor PD-L1 status (TPS <1%; TPS ≥1%), cisplatin or carboplatin, and by smoking history.

Data showed a 51% reduction in the risk of death with the combination versus chemotherapy alone. Moreover, 1-year OS rates in the pembrolizumab arm was 69.2% compared with 49.4% in the control arm. Median OS was 11.3 months in the control arm and was not reached at time of data cutoff in the experimental arm, while the median PFS was 8.8 months versus 4.9 months, respectively, in favor of pembrolizumab.

ORR was 47.6% with pembrolizumab, with a median duration of response of 11.2 months. For patients treated with chemotherapy alone, ORR was 18.9% and a median duration of 7.8 months.

“Even the one-third of patients who had a PD-L1 expression of ≥1% derived an OS benefit with pembrolizumab,” said Evans.

In October 2018, pembrolizumab received another first-line indication, this time in combination with carboplatin and paclitaxel or nab-paclitaxel (Abraxane) for patients with squamous metastatic NSCLC. In KEYNOTE-407, the addition of immunotherapy to the chemotherapy regimen showed superior OS versus chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; 

KEYNOTE-407 was a double-blind, placebo-controlled, phase III study in which patients were again enrolled regardless of their tumor’s PD-L1 status. Patients with squamous metastatic NSCLC had to be previously untreated with an ECOG performance status of 0 or 1.

The 559 patients were randomized 1:1 to pembrolizumab at 200 mg every 3 weeks plus carboplatin AUC 6 mg/mL every 3 weeks plus paclitaxel 200 mg/m

 every 3 weeks or nab-paclitaxel 100 mg/m

 once weekly for 4 3-week cycles. Once patients completed 4 cycles of chemoimmunotherapy, they would move on to up to 31 cycles of 200 mg pembrolizumab every 3 weeks. In the control arm, patients would complete the same dose of chemotherapy before moving on to placebo every 3 weeks for up to 31 cycles.

OS, PFS, and ORR were the primary endpoints of the study. Median age of the patients was 65, with 55% of the cohort older than 65. About 60% of patients received paclitaxel and 40% received nab-paclitaxel. Fewer patients had brain metastases than in KEYNOTE-189, Evans said.

Results showed a 36% reduction in the risk of death with the addition of pembrolizumab to carboplatin plus paclitaxel/nab-paclitaxel. The 1-year OS rates were 65% and 48% with chemoimmunotherapy and chemotherapy, respectively. Median OS was 15.9 months with the addition of pembrolizumab compared with 11.3 months for chemotherapy alone. Median PFS in the experimental arm was 6.4 months versus 4.8 months in the control arm. The survival benefit was observed irrespective of PD-L1 status.

Common adverse events (AEs) associated with pembrolizumab are pneumonitis, colitis, hepatitis, nephritis, and severe skin reaction. Based on the severity of the AEs, Evans noted, pembrolizumab should be withheld or discontinued with the administration of corticosteroids if appropriate.

“It’s important to understand some of the downsides to this class of agents,” Evans said. “There are immune-mediated AEs associated with pembrolizumab, and some of these have been severe or fatal.”

In KEYNOTE-189, pembrolizumab was discontinued because of AEs in 20% of the patients. The most common AEs in that study were pneumonitis (3%) and acute kidney injury (2%). AEs leading to interruption of treatment with pembrolizumab occurred in 53% of the patients, the most common of which being neutropenia and diarrhea.

Moreover, in KEYNOTE-407, treatment with pembrolizumab was permanently discontinued in 15% of the patients due to AEs. Thrombocytopenia and anemia were among the most common unacceptable toxicities. Pneumonia and urinary tract infection were also seen in 6% of patients.

“The factor to focus on in this study is that if you do a comparison with the addition of pembrolizumab versus chemotherapy alone, pembrolizumab really didn’t add much toxicity that we aren’t accustomed to seeing with chemotherapy alone or in patients with metastatic NSCLC,” Evans said. “The combination was very well tolerated.”

Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for  PD-L1—positive non–small-cell lung cancer. N

 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. 

. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.

Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). 

 2018;36 (suppl; abstr 105). doi: 10.1200/JCO.2018.36.15_suppl.105.

Thoracic Oncologist Highlights Recent Pembrolizumab Data in NSCLC

The PD-1 inhibitor pembrolizumab (Keytruda) has shown an overall survival advantage across 3 phase III clinical trials studying its use in patients with metastatic non–small cell lung cancer (NSCLC). These positive results led to a frontline indication as a single agent and in combination with chemotherapy for both patients with squamous and nonsquamous NSCLC.

Pembrolizumab's Journey to the Frontline in NSCLC

As the cost of cancer therapies continues to increase, the cancer community is looking to 

 as a potential alternative for treatment; however, experts wonder if factors besides cost need to be taken in to consideration.

For example, researchers need a better benchmark for what is said to be “clinically meaningful” in order to focus on the cost-effective treatment options with the greatest benefit, according to Sunil Verma, MD.

“We need to set up structures to assess things like overall response and other important data so we can ultimately provide the best possible treatment,” added Verma, professor and head of the Department of Oncology at the University of Calgary, and medical director of the Tom Baker Cancer Centre.

 Verma offered insight in to the benefits and unanswered questions that remain about biosimilars in oncology.

What impact would the implementation of biosimilars have?

There are a couple aspects to look at when we talk about global impact. One would be the cost of care. The second would be the integration of these new agents. In terms of cost of care, introducing biosimilars would reduce the burden of cost that's becoming an issue all over the world. This is especially true for biologic agents in cancer. The numbers [for biosimilar costs] are quite durable between what we've seen in North America and what we see across to Europe. Depending on what kind of cost reductions we get, this would have a significant impact.

The secondary impact would be our ability to then shift these walls and integrate these new therapies, so people can have access to them. We have to look at it in a way that allows any patient with cancer to have the option of a number of new, innovative treatments. If this comes to be, and we see an improvement in patient outcomes, that would be great for oncology. We're hoping this will be the case.

Why might there still be skepticism regarding biosimilars?

Mainly, the skepticism is that it remains to be seen what the cost reduction would look like. It is [unknown] how we are going to be able to collect real-world evidence to measure the integration of biosimilars. This has not been fully assessed yet. Also, there is skepticism because biosimilars would essentially replace therapies that have been providing significant clinical value to our patients. Any time you introduce a change, there's always this healthy doubt. Patients and oncologists want to be absolutely sure something works before they use it. Therefore, we need to make sure we're implementing new agents that are doing what they're labeled to do—and that is reducing cost and providing similar clinical benefit.

Do drug manufacturers pose a challenge in terms of implementing a more cost-driven solution?

It's hard to know. There will certainly be a competitive threat any time you want to introduce a new biosimilar. It is hard to say what this could mean for the drug companies, especially if a biosimilar could devalue one of their brands. In the clinical realm, we need to be supportive of methods that will lead to cost reduction. We need to have innovation in mind as the most important thing. Would biosimilars lead to greater innovation? That's something we still have to decide. One dogma might be that biosimilars would be stemming innovation just because they're driving down costs. I would argue that it would create greater innovation if we can divert some of those dollars to other newer therapies.

If the cost of treatment continues to rise, is the field of oncology sustainable without biosimilars?

It's a very provocative question. I would like to think that the field of oncology has a bright road ahead. The interest and investment that exists both from the industry, researchers, patients, and academia will lead to better therapy. The only way we can sustain and accelerate this is to address cost. Biosimilars would be one element, but it's not the only element. It's part of the approach.

A version of this article was originally published by 

Expert Highlights Evolution of Biosimilars in Oncology.

As the cost of cancer therapies continues to increase, the cancer community is looking to biosimilars as a potential alternative for treatment; however, experts wonder if factors besides cost need to be taken in to consideration.

Exploring the Global Impact of Biosimilars in Cancer Treatment

African-American and Caucasian patients with metastatic castration-resistant prostate cancer (mCRPC) demonstrated similar overall survival (OS) rates, according to study results presented at the 2018 ASCO Annual Meeting.

In the study, the researchers aimed to identify survival disparities between the two patient populations, for which they hypothesized that men in the African American population would have lower survival rates, but the opposite turned out to be true.

Delving further into the data, the research team conducted an adjusted analysis that factored in age, prostate-specific antigen (PSA) levels, and other variables. Results showed that risk of death was approximately 19% lower for African-American patients (HR, 0.81; 95% CI, 0.72-0.92; 

, Susan Halabi, PhD, professor of Biostatistics and Bioinformatics at Duke University School of Medicine, discussed the unexpected results of this survival disparity analysis in men with mCRPC.

We know that in the United States, African-American men are diagnosed at a much later stage of prostate cancer. In addition, they have higher incidence rates and higher mortality rates than Caucasian men with the disease. We know that African-American men [sometimes] do not have equal access to healthcare. Based on the population data, we were interested to test our hypothesis about OS outcomes in African-American and Caucasian men. Our initial hypothesis was that African-American men will have worse survival outcomes than Caucasian men.

In order to test this, we pulled data from 9 randomized phase II trials, which comprised over 8000 men. What was really interesting was that 85% of the men were Caucasian and only 6% were African American. Nevertheless, we went ahead with our study. In our initial analysis, we found no differences between the 2 subgroups; the median OS was 21 months.

However, when we did an adjusted analysis for important variables that might affect outcomes, like age, PSA levels, etc, we found that the hazard ratio was 0.81 in favor of African-American men. What does that mean? It means that the risk of death was about 19% lower for African-American men than Caucasian men. This is contrary to our initial hypothesis.

What was the breakdown of demographics in the study?

Out of the [total population], we know that 85% of them were Caucasian, 6% were African American, 5% were Asian, and 4% were other or unknown ratio groups. When we look at demographics between those patients, we found the following: African-American men were younger, had lower hemoglobin levels, had higher PSA levels, and had worse [ECOG] performance status. These were all statistically significant. Despite all the differences in terms of burden of disease, we found, to our surprise, that African-American patients did better.

This is an open question that we cannot answer definitively right now. This is a whole new area that requires further research. We can hypothesize or we can assume certain things. The first idea might be that African-American men have biological differences than Caucasian men. This could be why they're responding better. Remember, the patients we analyzed all received chemotherapy. It could mean that the African-American men were stronger and fitter.

It could also have to do with the patient selection. We know that to become involved with clinical trials, there is certain eligibility criteria. It could be that the clinician is using a tougher standard. Of course, we don't have data right now to support that claim. It could also mean that the African-American men generally respond better to chemotherapy than Caucasian men. No matter what, what's remarkable is the findings—and this will be a paradigm shift. When men have advanced and lethal mCRPC, we see that the African-American men are not only doing as well as Caucasian patients, but they're doing even better.

What are some additional analyses that will follow this study?

We have also accessed genomic data to see if there is genomic variability betweenthe 2 populations. What's also interesting—and it's important to know&mdash;is that out of these 9 trials, only 3 of them were conducted by the National Cancer Institute’s National Clinical Trials Network. When we looked at a subgroup of patients enrolled in the United States, we saw even more striking data that African-American men are 24% less likely to die from this disease than Caucasian men. Six of these trials were also conducted globally.

One of the take-home messages here is that we need to develop new methodology to enroll more African-American men in phase III clinical trials. We need to vigorously implement this methodology so that minorities are well represented. We are also looking at the original analysis and studying progression-free survival.

Are there any other demographics or tumor types where there might be disparity?

Next, we might look at Asian versus Caucasian patients and we're excited to look at that. Right now, though, we don't have access to other tumor types. It's important to emphasize that these results can't be applied to the general population because we know that only about 3% of patients with cancer in the United States enroll in clinical trials.

Halabi S, Dutta S, Tangen CM, et al. Overall survival between African-American (AA) and Caucasian (C) men with metastatic castration-resistant prostate cancer (mCRPC). 

Survival Disparity Analysis Yields Unexpected Findings in mCRPC