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In recent years, cellular immune therapies such as chimeric antigen receptor (CAR) T-cell therapy have significantly improved response rates for various hematological malignancies. The Multiple Myeloma and Amyloidosis Multidisciplinary Team (MDT), Bone Marrow and Stem Cell Transplant MDT, and the Hematologic Oncology MDT at Barbara Ann Karmanos Cancer Institute in Detroit, Michigan, have helped drive many treatment advancements in cellular immune therapies for cancers.

Karmanos offers all approved CAR T-cell therapies for non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). The institute also continues to support research into new treatment indications for which CAR T-cell therapy could be used. CAR T-cell therapy is at the cutting edge of treatments for certain cancers, wherein the patient’s T cells, an integral part of the immune system, are genetically modified to recognize and kill the cancer cells.

Cancers Show Promising CAR T Response Rates

The outcomes of CAR T-cell therapies have been remarkable, especially because most patients receiving this immunotherapy have faced difficulties in controlling their disease despite multiple rounds of chemotherapy. The Karmanos team collaborated with leading cancer centers around the country on various pivotal clinical trials leading to the FDA approval of CAR T-cell therapy.

The complete response rates for ALL are approximately 60% to 70%.

 Regarding NHL, the FDA has approved CAR T-cell therapy to treat diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma and transformed lymphoma. Patients with these diseases must meet specific requirements to receive CAR T-cell therapy including that their cancer does not respond to initial chemotherapy and relapses within 1 year or there is relapse after 2 previous lines of chemotherapy.

The long-term complete response rates in patients with DLBCL in the third-line setting are around 40% to 50%.

 For patients with DLBCL whose disease does not respond to initial therapy or relapses within 1 year of completing treatment, CAR T-cell therapy significantly improved the chance of being cured compared with standard salvage chemotherapy.

With CAR T-cell therapy, we can also target mantle cell lymphoma. For this disease, we have seen a complete response in two-thirds of patients whose disease had relapsed or not responded to multiple chemotherapy regimens.

 CAR T-cell therapy also showed very high response rates in patients with follicular lymphoma whose disease had relapsed after 2 prior lines of chemotherapy.

 The response rate for patients with MM whose disease relapsed after 4 or more prior lines of chemotherapy was 80% to 95% after CAR T-cell therapy treatment.

Some patients may develop unique adverse effects (AEs) that should be monitored closely for the first few weeks after infusion. AEs include cytokine release syndrome (CRS), which may manifest as high fever, low blood pressure, low oxygenation, neurological toxicity, confusion, word-finding difficulty, and rare cases of seizure or coma. The most severe AEs usually occur within the first couple of weeks after infusion of CAR T cells. Patients can also be at risk for low blood counts and a weakened immune system. If this happens, the patient may need antimicrobial treatments to prevent severe infection.

In the recent years, research has also focused on strategies to reduce the AEs of this unique therapy. Karmanos participated in a clinical trial in which patients with DLBCL received steroids for 3 days at the time of infusion of CAR T-cell therapy, which led to less risk of CRS without compromising efficacy of the treatment.

 This approach is now used for patients at a high risk of developing severe AEs from CAR T-cell therapy.

We have an ongoing clinical trial in which we give an antibody treatment to patients undergoing CAR T-cell therapy, which may help reduce risk of related neurological toxicity. Our team is also participating in clinical trials investigating allogeneic CAR T cells. With this treatment, patients receive genetically modified CAR T cells from a donor. This method may hasten therapy compared with waiting on the patient’s manufactured immune cells. We are also collaborating with Karmanos experts specializing in solid tumor oncology for clinical trials with CAR T-cell therapy. These trials involve other cellular treatments for breast, lung, prostate, head and neck, and gynecologic cancers.

Karmanos specialists have experience in providing commercially approved and investigational cellular therapies. As a National Cancer Institute–Designated Comprehensive Cancer Center, we work closely with investigators developing novel strategies to make this therapy safer, develop pathways toward new indications, and ensure more accessibility to CAR T-cell therapy. With our robust clinical trials program and experienced team, we are committed to further improving outcomes for patients who are candidates for these therapies and to overcoming challenges associated with them.

Abhinav Deol, MD, is a medical oncologist and member of multidisciplinary teams including Bone Marrow & Stem Cell Transplant, Hematology Oncology, and Multiple Myeloma and Amyloidosis at Karmanos Cancer Institute in Detroit, Michigan.

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Articles

In recent years, cellular immune therapies such as chimeric antigen receptor T-cell therapy have significantly improved response rates for various hematological malignancies. 

CAR T-cell Therapy Establishes Prominent Role Across Hematologic Malignancies

Although tumor mutational burden burden (TMB) is established as a clinically informative feature of tumors, its optimal use in therapeutic decision-making faces many challenges, and we are only beginning to fully understand its strengths and limitations. Development of biomarkers that can be readily applied in the clinic to identify patients most likely to respond to groundbreaking immunotherapies has become a priority in immuno-oncology.

Next-generation sequencing (NGS), used to estimate the number of somatic mutations within a tumor specimen, is among the leading candidates for TMB detection. The pinnacle of its success arrived in mid-2020 with the tumor agnostic FDA approval of the immune checkpoint inhibitor (ICI) pembrolizumab (Keytruda) for patients with high TMB.

 New studies evaluating the pancancer role of TMB as a predictive biomarker of response to ICIs have revealed some of its limitations, raising doubts about its broad applicability and the appropriateness of a universal TMB cutoff.

In non–small cell lung cancer (NSCLC), the predictive power of TMB is perhaps best characterized, these challenges present a hurdle to clinical implementation of TMB assays. A supplemental biologics license application for the dual checkpoint inhibition in patients with NSCLC who had high TMB was subsequently withdrawn by the drug developers when a phase 3 trial failed to demonstrate an overall survival (OS) benefit in this population.

 Ongoing research is focused on finding ways to unleash the true potential of TMB, including efforts to standardize its measurement, define better cutoffs, and understand its role in common cancer types that have been largely overlooked.

Ongoing research is focused on finding ways to unleash the true potential of TMB, including efforts to standardize its measurement, define better cut-offs, and understand its role in common cancer types that have been largely overlooked to date.

In 2017, pembrolizumab received an historic tumor agnostic approval for the treatment of tumors with high levels of microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) after these biomarkers were shown to identify patients with improved outcomes.

The theory behind the efficacy of ICIs in this patient population was that tumors with greater numbers of mutations provoke a stronger antitumor immune response because they increase the presence of neoantigens, which activate cytotoxic T cells, on the tumor cell surface.

Mismatch repair (MMR) is a mechanism through which cells repair types of DNA damage that typically occur within areas of short, repetitive DNA sequences known as microsatellites. Abnormalities in the MMR pathway lead to inability to repair damaged DNA and accumulation of mutations, as well as a characteristic variability in the lengths of microsatellites; thus, MSI-H is an indication of dMMR.

Although dMMR/MSI-H is more common in some tumors than others, it is observed in a small proportion of patients overall.

 Although almost all tumors with MSI-H have high mutation rates, less than one-fifth of highly mutated tumors display MSI-H, suggesting that other mechanisms drive some tumors to acquire more mutations.

Assessment of TMB using whole-exome sequencing (WES) allowed investigators to capture highly mutated tumors irrespective of cause; although TMB varies, a subset of patients with high TMB can be observed in almost every cancer type.

 Initial retrospective studies in NSCLC and melanoma demonstrated that higher levels of TMB were associated with improved outcomes following ICIs.

 Since then, TMB has emerged as a powerful predictor of response to ICIs across different cancer types.

Targeted NGS panels, which are faster and less expensive than WES, provide a comparable estimate of TMB and are widely used.19-21 Most measure TMB from tissue biopsies, but liquid biopsies that use circulating tumor DNA isolated from the blood are being developed.

A growing number of prospective trials have been initiated to validate the relationship between TMB and ICI outcomes. Most notable is the phase 2 KEYNOTE-158 trial (NCT02628067), in which pembrolizumab monotherapy was evaluated in patients with multiple types of advanced solid tumors that had progressed following prior treatment. Among 102 patients with high levels of TMB (≥ 10 mutations [mut]/Mb), the overall response rate (ORR) was 29.4% (95% CI, 20.8%-39.3%), with complete responses in 4 patients and 57% of responses lasting at least 12 months. Responses were observed across 8 tumor types. An ORR of 6.3% (95% CI, 4.6%8.3%) was observed in patients with TMB lower than 10 mut/Mb (n = 688).

These results led the FDA to approve pembrolizumab in June 2020 for the treatment of adult and pediatric patients with unresectable or metastatic TMB-high (≥ 10 mut/Mb) solid tumors, securing another tumor agnostic win for the drug. The FoundationOne CDx assay, a 324-gene panel that estimates TMB based on a 0.8 Mb region of the exome, was approved as a companion diagnostic for use in this indication.

Although FoundationOne CDx is the only FDA-approved TMB assay, Memorial Sloan Kettering Cancer Center in New York, New York, developed MSK-IMPACT, which leverages a 468-gene panel covering a 1.1-Mb region of the exomet and has been authorized by the FDA through the 510K pathway. Numerous other TMB assays are commercially available for use in a research setting (TABLE).

The abundance of available assays has led to questions surrounding standardization of TMB estimation across different assays and tumor types. Friends of Cancer Research established a TMB Harmonization Consortium of stakeholders from pharmaceutical and diagnostic companies and scientific organizations, including the FDA, to conduct a comprehensive review of available data regarding TMB and response to immunotherapy. 

They found that some assays consistently underestimated TMB and others overestimated, compared with WES-derived TMB, with the size and content of the gene panel identified as key factors in assay performance. They developed consensus recommendations for standardization of NGS panels for TMB estimation and built a calibration tool to enhance the comparability of assays.

Doubts remain regarding the broad applicability of TMB as a predictive biomarker and over the use of a universal cutoff for determining high TMB. A criticism of KEYNOTE-158 is that it did not include more common tumor types, such as colorectal cancer, prostate, and breast cancer.

The predictive role of TMB is being explored in these settings. Prostate cancer is notable considering that ICIs typically offer little benefit to most patients. Preliminary data presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium demonstrated that a cohort of patients with advanced prostate cancer who received ICI therapy guided by blood-based TMB score experienced clinical benefit.

 In a separate real-world biomarker study, investigators showed that patients with metastatic castration-resistant prostate cancer who had high TMB (≥ 10 mut/Mb) derived greater benefit from ICIs vs taxane chemotherapy.

Another issue with KEYNOTE-158 is that among the tumor types enrolled, TMB appeared to be a better predictor of response in only some tumors. For example, the ORR in patients with endometrial cancer was 47%, compared with 7% in patients with anal cancer.

Additionally, the study measured ORR and not more clinically meaningful end points. Several subsequent studies have now evaluated the relationship between patient survival and TMB. Samstein et al analyzed the clinical and genomic data of 1662 patients with advanced cancer treated with ICIs whose tumors were evaluated for TMB using the MSK-IMPACT assay. High TMB (defined as the highest 20% in each tumor type) was associated with improved OS across most cancer types, although in some cases not statistically significantly.

A notable exception was glioma, in which high TMB was associated with poorer survival,3 possibly because the high TMB observed in glioma may result from treatment with DNA-damaging cytotoxic drugs and may not necessarily be associated with increased infiltration of T cells into the tumor microenvironment. Another study demonstrated an association between TMB and improved OS following ICI therapy, but only among tumors in which the levels of CD8-positive T cells correlated with predicted neoantigen load, such as melanoma, lung cancer, and bladder cancer.

In a third study examining the relationship between TMB and post-ICI OS, which used the approved cutoff of 10 mut/Mb, the median OS was longer only in patients with certain types of MMR-proficient cancer, such as head and neck cancer, NSCLC, and melanoma, with no benefit in patients with other cancer types.

 These results have led some to argue that the clinical benefit of high TMB as a biomarker has not been convincingly demonstrated across all tumor histologies.

Another challenge to the clinical application of TMB assays is how to define an appropriate cutoff for high TMB. In their study, Samstein et al found that the top 20% of TMB varied markedly between cancer types.

 In another study, investigators sought to determine how the FDA-approved cut-off performed in a realworld setting. They analyzed the outcomes of more than 1600 patients treated with ICIs. 

Overall patients with a TMB of at least 10 mut/Mb had better outcomes than those with a TMB below 10 mut/Mb; the universal cutoff did not reliably predict increased survival after immunotherapy across all tumor types. Notably, in patients with renal cell carcinoma, no cases met the high TMB threshold but many patients still responded.

 Many argue that a cancer type-specific threshold may be better, whereas others have suggested that an arbitrary threshold of high TMB is wholly inappropriate and that the use of ICIs should instead be considered in the context of the cause of the TMB.

The greatest preponderance of data showing an association between TMB and ICI response comes from NSCLC, but even in this setting its predictive role remains uncertain. Subgroup analyses from randomized clinical trials of ICIs in NSCLC in various settings demonstrated significantly improved response rates and progression-free survival (PFS) in patients with high TMB compared with those with low TMB when ICIs were used as monotherapy.

However, its predictive role in patients receiving ICIs in combination with chemotherapy appears more limited; in the KEYNOTE-189 (NCT02578680) study, high TMB was not significantly associated with improved OS, PFS or ORR in patients treated with pembrolizumab plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC.

Foundation Medicine’s blood-based TMB assay was being used in the phase 2/3 B-F1RST (NCT02848651) and phase 3 B-FAST (NCT03178552) trials, which evaluated the potential of TMB as a predictive biomarker for atezolizumab (Tecentriq) in the frontline treatment of advanced/metastatic NSCLC. High TMB (defined as 14.5 mut/Mb) was measured as 16 or greater in the blood TMB (bTMB) scale. 

InB-F1RST, the primary biomarker end point was investigator-assessed PFS at the cutoff of bTMB of at least 16. The median PFS was 5 months (95% CI, 1.6-10.8) in patients with high TMB compared with 3.5 months (95% CI, 2.6-4.3) for those with low TMB (HR, 0.80; 90% CI, 0.541.18; P = .35). The median OS was 23.9 months (95% CI, 8.8-not estimable) vs 13.4 months (HR, 0.66; 90% CI, 0.40-1.10; P = .18), respectively. Further, the ORR in the bTMB-high group was 35.7% (95% CI, 19.2%-55.5%) vs 5.5% in the bTMB-low group (95% CI, 2.2%-12.2%) (P < .0001).

 In B-FAST, in which atezolizumab monotherapy was compared with platinum-based chemotherapy in biomarker-selected patients with advanced NSCLC, results from cohort C, in which patients were selected based upon high bTMB levels, failed to meet the primary end point of PFS.

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Oncology Nursing News

Although tumor mutational burden is established as a clinically informative feature of tumors, its optimal use in therapeutic decision-making faces many challenges, and we are only beginning to fully understand its strengths and limitations. 

Tumor Agnostic Role of TMB  Biomarker Faces Challenges

CDK4/6 inhibitors have carved out a substantial role in the treatment of patients with hormone receptor–positive, HER2-negative breast cancer. The first approval of palbociclib (Ibrance) launched a series of trials examining the efficacy of agents in the frontline setting for these patients both as monotherapy and in combination with aromatase inhibitors (AIs).

During the panel discussion breast cancer experts contextualized how longer-term, retrospective, and realworld data presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and the European Society for Medical Oncology (ESMO) Breast Cancer Congress 2022 are continuing to drive clinical improvements for these patients. “It’s an exciting time to hear about the advances we’re making in this most common subset of breast cancer, the most common cancer worldwide in women,” moderator Hope S. Rugo, MD, FASCO, said.

CDK4/6 Inhibitors Hold Strong In First Line

The 2022 ASCO Annual Meeting featured updates from several key trials of CDK4/6 inhibitors for the treatment of patients with advanced hormone receptor–positive, HER2-negative metastatic breast cancer. Patient selection for this therapy accounts for several factors, but Anne P. O’Dea, MD, said that most of the patients she treats in this setting will receive a CDK4/6 inhibitor. “The overwhelming totality of data that was [is available] really supports the use of a first-line CDK4/6 [inhibitor],” she said. “It’s really a very rare patient in whom I’m not using that in the first line; perhaps an elderly patient in a skilled nursing facility where it’s very cumbersome for her to have laboratory monitoring. However, outside of a situation like that, I’m using a CDK4/6 [regimen] in all my patients.”

Although, cross-study comparisons and head-to-head trials are not feasible for these agents, investigators conducted a match- adjusting indirect comparison (MAIC) study of quality-of-life (QOL) outcomes for ribociclib plus an aromatase AI vs abemaciclib plus AI in the first-line treatment of this patient population.

“I thought this was an interesting paper because biostatisticians have always taught us not to do cross-trial comparisons, and yet they come up with this novel technique of MAICs. They can do just that using QOL data,” Mark Pegram, MD, said. “In this case, they use the EORTC QLQ-C30 [European Organization for Research and Treatment of Cancer QOL] metric as well as the BR23 [EORTC-breast-cancer specific QOL] questionnaires. Using this statistical method, they were able to compare the difference in adverse event [AE]/patient- reported outcomes with these metrics.”

Specifically, the trial compared outcomes from the phase 3 MONALEESA-2 (NCT01958021) and MONARCH 3 (NCT02246621) trials evaluating ribociclib and abemaciclib, respectively. Matching and weighting of individual patient data was performed and 205 and 149 patients in the ribociclib and placebo arms for MONALEESA-2 were matched to 328 and 165 patients in the corresponding arms of MONARCH-3. 

Time to first symptom deterioration (TTSD) was significantly better in terms of appetite loss (HR, 0.46; 95% CI, 0.27-0.81), diarrhea (HR, 0.42; 95% CI, 0.23-0.79), fatigue (HR, 0.63; 95% CI, 0.41-0.96) and arm symptoms (HR, 0.49; 95% CI, 0.30-0.79) in those who received the ribociclib-containing regimen vs the abemaciclib regimen. These AEs have been identified by patients as having a moderate to severe effect on their QOL.

“None of this comes as any surprise,” Pegram said. “It’s gratifying to see that the patient-reported outcomes match the investigator-reported data that’s already been published and approved by the FDA for both drugs. [The results] met what I expected, having used these drugs and heard my patients tell me about their experience. That’s gratifying, and I thought the methods were very interesting and novel to allow this kind of cross-trial comparison where a head-to-head trial is simply not available.” 

Rugo noted that overall survival (OS) outcomes for abemaciclib are still maturing, but that progression-free survival (PFS) data have demonstrated significant clinical benefit.

Updated OS results from MONALEESA-3 (NCT02422615), which evaluated ribociclib in the first line setting for postmenopausal patients with advanced hormone receptor–positive, HER2-negative advanced breast cancer, were presented at the ESMO Breast Cancer Congress 2022.

At a median follow-up of 70.8 months, patients who received ribociclib plus fulvestrant (n = 484) had a median OS of 67.6 months vs 51.8 months among those who were given fulvestrant/placebo (n = 242; HR, 0.67; 95% CI, 0.50-0.90). The 5-year OS rates were 56.5% vs 42.1%, respectively. The experimental combination also delayed time to second disease progression and improved chemotherapy-free survival vs placebo plus fulvestrant (TABLE).

“That [survival is] more than 5 years—an OS we’ve never seen before—as compared with the control group, which was about 51 months,” Pegram said. “This corresponded to a hazard ratio of 0.67. Clear OS advantage is seen with ribociclib plus fulvestrant in the first-line setting.” Dose reductions with ribociclib were another topic of discussion for the panel. Data from a poster presented during the 2022 ASCO Annual Meeting showed that dose modifications of ribociclib did not demonstrate a negative effect on OS in MONALEESA-2. Trial protocol allowed reductions to 400 mg or 200 mg per day to manage treatment related-AEs.

Among the 334 evaluable patients, 125 did not require a dose reduction (37.4%), 124 patients required 1 reduction (37.1%), 76 required 2 (22.9%), and 9 required more 3 or more (2.7%). The median OS among those who had at least 1 reduction 3 months into treatment was 63.1 months compared with 65.7 months among those with 0 reductions during that time frame (HR, 0.96; 95% CI, 0.68-1.36).

“In the poster discussion at ASCO 2022, [an audience member] asked, ‘Why don’t you just start at a lower dose? Why start at a higher dose, after all?’ ” Rugo said. “I thought: Why not just start at the full dose because you can dose-reduce so easily?” 

Pegram agreed, saying, “Unless we have randomized data, 400 mg vs 600 mg, I would not start with 400 mg. I would start with 600 mg, but if a patient has an AE, particularly neutropenia, I feel comfortable reducing to 400 mg.”

Data presented at the 2022 ASCO Annual Meeting did not demonstrate a significant improvement with palbociclib plus letrozole vs letrozole alone in the phase 3 PALMOA-2 trial (NCT01740427).

At the November 15, 2021, data cutoff, at a median follow-up of 90 months, patients who received the CDK4/6 inhibitor palbociclib plus letrozole (n = 444) had a median OS of 53.9 months (95% CI, 49.8-60.8) compared with 51.2 months (95% CI, 43.7-58.9) for patients who received placebo plus letrozole (n = 222; HR, 0.956; 95% CI, 0.777-1.777; P = .3378). However, in a post-hoc sensitivity analysis that adjusted for missing survival data, the median OS for patients treated with the combination (n = 385) was 51.6 months (95% CI, 46.9-57.1) compared with 44.6 months (95% CI, 37.052.3) for the 175 patients in the control arm (HR, 0.869; 95% CI, 0.706-1.069). The median duration of treatment was 22.0 months and 13.8 months, respectively. 

“We saw the long-awaited survival data from PALOMA-2 with disappointing results. There was no difference in the OS, but there were several unique characteristics of PALOMA-2 that are worth keeping in mind,” Rugo said. “One is it’s the only trial in the first-line setting that included patients who had a disease-free interval [DFI] from early- to late-stage disease of less than 12 months. That represented about one-third of the population. In that group of patients, when you look at a forest plot and divide the numbers up, they didn’t clearly have a survival benefit, but among those with a DFI of greater than 12 months—the OS numbers are close to first-line ribociclib and an AI, being well over 60 months.” Specifically, among patients with a DFI greater than 12 months, the median OS was 64.0 months (95% CI, 49.2-73.4) vs 44.6 months (95% CI, 37.0-53.2) with letrozole alone (HR, 0.736; 95% CI, 0.551-0.982).

Both arms of the trial had significant amounts of missing survival data, Rugo noted. Results were missing for 59 patients in the palbociclib plus letrozole arm and for 47 patients in the letrozole monotherapy. Most patients in both arms had died at the time of the analysis (62% and 60%, respectively). Patients were still alive at a rate of 25% and 19%, respectively. “A lot of patients withdrew consent for reasons that are unclear, and so they just didn’t have survival data on those patients, unfortunately,” she said. 

“PALOMA-1 [NCT00721409] opened the field of CDK4/6 inhibitors,” Aditya Bardia, MD, MPH, said. “Since then, we’ve had several studies. In terms of why the results of PALOMA-2 were negative [although] we are seeing positive results from MONALEESA-2, MONALEESA-3, MONALEESA-7 [NCT02278120], and MONARCH-2, I think this could be differences in study populations [or other causes]. The DFI [subset] was different, the results looked similar. The second possibility is what happened after the patients had disease progression on first-line therapy. That was not controlled, so there could be some imbalances in the placebo vs the palbociclib arm. The third possibility is that there are some differences in the drug; it’s just impossible to know without head-to-head trial comparison.”

O’Dea noted that in clinical practice she has observed patients exhibiting prolonged clinical benefit on palbociclib. “If we look at the entire PALOMA series, we see the dramatic efficacy of this drug; 10% of patients continue on palbociclib at 7.5 years,” she said. “I certainly have a couple of patients in my own clinic that started the drug in February of 2015 and remain on the drug today. Clearly, it’s an effective agent…. There are a lot of nuances to this.” 

Bardia agreed adding that although the PALOMA-2 data were not significant, if a patient is currently on palbociclib, he would feel very comfortable continuing treatment. However, for new patients with metastatic disease, he would consider the evidence from other trials in treatment selection.

Will Real-World Outcomes Inform Future Directions?

In selecting between agents in the first-line setting, Pegram said that there are 2 vantage points when reviewing the data: clinical vs scientific. “From a clinical perspective, we have level 1 evidence from a randomized, controlled phase 3 trial of an OS benefit that’s statistically significant in the case of the first-line ribociclib plus AI. That is the gold standard for clinical decision-making. For clinical decisions, that’s impactful to me,” he said. “The other perspective I like to look at this data set from is more from a scientific point of view. From that point of view, things are a little bit less clear.” 

Considering real-world data may shine a light on certain pathways forward for patients in this setting. “We talked about patient populations in clinical trials, which is always going to be contrived; there’s no way around it,” Rugo said, adding that inclusion criteria for different trials have a huge effect on outcomes. “You really are treating a different patient population [in the clinic] with a different biology of tumor in many situations. There’s quite a lot of real-world data on CDK4/6 inhibitors and then there’s also some data about how AEs are managed in routine clinical practice.” 

At the ESMO Breast Cancer Congress 2022, Rugo presented a poster on the real-world outcomes for patients treated with palbociclib plus endocrine therapy.

 In a retrospective analysis 1324 patients were identified for palbociclib plus endocrine therapy vs 1564 with an AI alone. The median OS was 53.4 (95% CI, 48.7-58.6) vs 40.4 months (95%CI, 36.3-44.9), respectively (HR, 0.67; 95% CI, 0.600.76; P < .0001).

“If you look at the results, they are quite similar to the other clinical trials with ribociclib and even abemaciclib in the sense that you see an improvement in OS,” Bardia said “We must be careful in terms of interpreting real-world data. It was not a randomized trial. But at least there’s evidence that it improved OS.” 

Data from another retrospective study, REACH AUT, showed that the efficacy of ribociclib was similar to outcomes observed in in the MONALEESA trials. At a median follow-up of 14.4 months, 283 patients treated with ribociclib plus endocrine therapy. The median PFS was 29.7 months, and the 12-month OS rate was 90.3%. Data for median OS were immature.

In reviewing all the data, treatment selection in clinical practice may lean heavier on the level 1 evidence and individual patient situations for the time being. “When we look at these trials, they were powered for the primary end point of PFS and if you look at the [Kaplan-Meier] curves they are nearly identical with identical hazard ratios,” Jhaveri said. “It’s very frustrating in some ways to then go back and say OK but now we’re not seeing OS benefit in one study but we’re seeing it in other. Are there significant differences that can explain the difference between the 2 agents?”

She added that there are differences in trial structure as well as toxicity profiles, but even with early MAIC analyses, it is not clear if that can translate into a significant clinical effect in terms of the difference in OS. “For me, I will have a patient in front of me, discuss the toxicity profiles, look at their comorbid conditions, what kind of medications they’re already taking concomitantly; and assess what would result in terms toxicity [with a given treatment].” 

“Ultimately, a good balance of tolerability, QOL, and the efficacy data as we have; we can have a discussion with our patient.”

Verzenio. Prescribing information. Eli Lilly and Company; 2021. Accessed August 9, 2022. bit.ly/3BUraOU 

Kisqali. Prescribing information. Novartis Pharmaceuticals Corporation; 2021. Accessed August 9, 2022. bit.ly/3PkgEHu Ibrance. Prescribing information. Pfizer, Inc; 2019. Accessed August 9, 2022. bit.ly/3BRKiAA 

Rodriguez C, Kaufman JL, Laubach J, et. al. Quality of life (QOL) with ribociclib (RIB) plus aromatase inhibitor (AI) versus abemaciclib (ABE) plus AI as first-line (1L) treatment (tx) of hormone receptor-positive/ human epidermal growth factor receptor–negative (HR+/HER2−) advanced breast cancer (ABC), assessed via matching-adjusted indirect comparison (MAIC). J Clin Oncol. 2022;40(suppl 16):1015. doi:10.1200/JCO.2022.40.16_suppl.1015 

Neven P, Fasching PA, Chia S, et al. Updated overall survival (OS) results from the first-line (1L) population in the phase III MONALEESA-3 trial of postmenopausal patients (PTS) with HR+/ HER2− advanced breast cancer (ABC) treated with ribociclib (RIB) + fulvestrant (FUL). Ann Oncol. 2022;33(suppl 3):S194. doi:10.1016/j. annonc.2022.03.280 

Hart L, Bardia A, Beck T, et al. Impact of ribociclib dose modifications on overall survival in patients with HR+/HER2– advanced breast cancer in MONALEESA-2. J Clin Oncol. 2022;40 (suppl 16):1017. doi:10.1200/JCO.2022.40.16_suppl.1017 

Finn RS, Rugo HS, Dieras VC, et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/ HER2− ABC): analyses from PALOMA-2. J Clin Oncol. 2022;40(suppl 17):LBA1003. doi:10.1200/JCO.2022.40.17_suppl.LBA1003 

Rugo HS, Brufsky A, Liu X, et al. Overall survival with first-line palbociclib plus an aromatase inhibitor (AI) vs AI in metastatic breast cancer: a large real-world database analysis. Ann Oncol. 2022;33(suppl 3):S202. doi:10.1016/j.annonc.2022.03.188 

Singer CR, Egle D, Greil R, et al. REACH AUT: efficacy and safety of first-line (1L) ribociclib (RIB) + endocrine therapy (ET) in HR+, HER2- metastatic breast cancer (MBC) from a real-world (RW) study: 3rd interim analysis. Ann Oncol. 2022;33(suppl 3):S217. doi:10.1016/j. annonc.2022.03.214

Oncology Live®

CDK4/6 inhibitors have carved out a substantial role in the treatment of patients with hormone receptor–positive, HER2-negative breast cancer. 

Long-term Data for CDK4/6 Inhibitors Solidify Role in Firstline HR+/HER2- Breast Cancer

When Weijing Sun, MD, FACP, started his career in oncology more than 30 years ago, the choice of medical treatment for patients with gastrointestinal (GI) malignancies was dominated by fluorouracil (5-FU), regardless of the tumor type.

“For treating all GI cancer, the only really effective drug was 5-FU,” Sun recalled in a recent interview with 

. “If you were treating colon cancer, it was 5-FU; stomach cancer, it was 5-FU. We tried to modify the regimen by prolonging infusion, with weekly infusion or daily infusion. We tried to maximize the benefit.”

Instead of becoming discouraged by such limited options, Sun was motivated to explore potential new treatments with drug development. He became a prolific investigator into novel agents and combinations across a range of GI malignancies, serving as an institutional principal investigator in more than 40 clinical trials involving hepatocellular carcinoma (HCC) and colorectal, esophageal, gastric, and pancreatic cancers.

Today, Sun is an internationally known GI cancer expert. He is the Sprint Professor of Medical Oncology and director of the Medical Oncology Division at The University of Kansas School of Medicine and associate director of The University of Kansas Cancer Center (KU Cancer Center), a National Cancer Institute (NCI)–designated comprehensive cancer center, both headquartered in Kansas City.

Although he retains an interest in research, some of Sun’s focus has shifted to serving as a physician leader seeking to foster discussion about optimal treatment strategies among practicing oncologists and mentoring the next generation of providers. In that capacity, Sun is helping to shape the agenda for the upcoming 

 Meeting of the International Society of Gastrointestinal Oncology

), which is scheduled to take place September 30 through October 1, 2022, in Nashville, Tennessee. Sun serves as president of ISGIO

“Our job is not just for ourselves but for the younger generation—to be their mentor, to encourage them, train them, and guide them,” said Sun, noting that many GI physicians have been practicing 30 years or longer. “We’re obligated to transfer the baton to the next generation.”

“Physician leaders are important,” he noted. “You do have some authority, you do have a voice in pushing or guiding research funding, finding resources, or using your expertise and knowledge to guide and help afford training for the younger generation. That’s one of the reasons why I am involved and interested in doing some administrative jobs.

“Of course, I’m still seeing patients in clinical trials,” he added. “Sometimes it seems like I have 3 jobs. Sometimes it’s overwhelming, sometimes it’s tiring. On the other hand, the reward is something you might not be able to see. . . You have a voice. If you’re not at the table, you don’t know what was discussed.”

At the start of his career, Weijing Sun, MD, FACP, was motivated to explore potential new treatments for gastrointestinal malignancies, and is now an internationally known GI cancer expert.

Vol. 23/No. 16 | Oncology Live®

CAR T-cell Therapy Establishes Prominent Role Across Hematologic Malignancies

Tumor Agnostic Role of TMB Biomarker Faces Challenges

Long-term Data for CDK4/6 Inhibitors Solidify Role in Firstline HR+/HER2- Breast Cancer

GI Cancer Expert Sets Sights on the Next Generation

Tumor Agnostic Approval Targets BRAF V600E–Mutant Disease

Unique Aspects of Maintenance Therapy in Oncology Require Careful Consideration