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TP53-mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) represent a molecularly distinct, poor-risk patient subgroup frequently associated with complex karyotypes, high propensity for relapse, and inferior overall survival.

Across TP53-altered MDS and AML, standard therapies for wild-type disease have been of minimal benefit, but a wave of investigational agents currently in development offers promise for patients with TP53-altered malignancies, which affect 8% to 12% and 5% to 10% of patients with MDS and AML, respectively.

 In contrast with wild-type, FLT3-, and IDH1/2-mutant MDS and AML, at present, no agents are indicated specifically for TP53-mutant disease.

TP53 gene mutations or chromosome 17 loss resulting in TP53 deletion impair function of the TP53 tumor suppressor protein, which regulates DNA repair and cell division.

 TP53 mutations are the most common genetic alteration in oncology, presenting in approximately 50% of all invasive malignancies, and are the most powerful negative prognostic covariate in hematological cancers specifically.

While the tendency is to think about MDS and AML as 2 different entities, the clinical features of TP53-mutant MDS and AML frequently overlap, according to Guillermo Garcia-Manero, MD, professor, chief of the Section of Myelodysplastic Syndromes, and deputy chair of Translational Research in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. “The characteristics of patients with AML with a TP53 mutation are very, very similar to those of patients with high-risk MDS with the same molecular and cytogenetic characteristics,” Garcia-Manero said in an interview with OncologyLive®.

To be classified as MDS, disease must meet 1 of the following decisive criteria: dysplasia (≥ 10% in 1 or more of the 3 major bone marrow lineages), a blast count of 5% to 19%, or an observable MDS-associated karyotype, such as deletion 5q (del[5q]), del(20q), +8, and or -7/del(7q).1 Notably, del(5q) is the most commonly observed aberration in complex karyotypes.

 Whether the chromosomal abnormality is isolated or part of a complex karyotype in MDS or AML, del(5q) is strongly associated with concomitant TP53 mutations.1 Existing evidence has shown that TP53 mutations are predictors of poor outcomes with lenalidomide (Revlimid) in higher-risk patients with MDS and del(5q).

 Lenalidomide was approved in December 2005 for patients with transfusion-dependent anemia to low- or intermediate-1–risk MDS associated with a del(5q) abnormality with or without additional cytogenetic aberrances.

Diagnoses of AML are generally made in the presence of 20% or more blasts in the marrow or peripheral blood, per the 2016 World Health Organization classification of AML, but diagnoses can still be made when blasts below 20% are seen in patients with recurrent cytogenetic abnormalities created by reciprocal translocations (t) or inversions (inv) such as t(15;17), t(8;21), t(16;16), or inv(16).

 However, the phenotypical similarity of TP53-mutant MDS and AML has led the field to perceive bone marrow blast percentage as an arbitrary mode of distinction, Garcia-Manero said. Further, many clinicians now view these 2 molecularly specific malignancies as “a homogeneous disease entity,” according to Hunter et al.

TP53-altered MDS and AML are jointly associated with 3 main characteristics: low response to chemotherapy, chromosomal complexity, and dismal prognosis.

 “Finding this mutation is very important to treatment selection because we tend to use lower-intensity approaches that are often better tolerated and more effective than conventional higher doses of chemotherapy,” Garcia-Manero said. “We see that patients with this mutation [are typically] more sensitive to lower-intensity type of chemotherapy, such as hypomethylating agents.”

Hypomethylating agent (HMA) therapy is the standard of care (SOC) for patients with higher-risk MDS. However, TP53-mutant disease treated with HMAs infrequently achieves durable clonal suppression and typically has poor OS.6 The efficacy of standard treatment is commensurately lacking in AML. For decades, induction chemotherapy with cytotoxic agents, including anthracyclines and cytarabine, has been the SOC for patients with AML who are healthy enough to receive systemic treatment.

However, TP53 mutations, which confer resistance to cytotoxic therapy, strongly correlate with inferior responses to induction chemotherapy. The complete response rate for TP53-mutant, induction chemotherapy–treated AML is from 20% to 40% with high relapse rates; median OS ranges from 4 to 9 months. Despite minimal responses and short survival, patients with TP53-altered AML tend to fare even worse than those who received standard systemic therapy, indicating that SOC treatment should still be considered for these patients, despite the therapeutic prognostic trends observed in the presence of a TP53 mutation.

Beyond HMAs and chemotherapy, TP53 alterations also complicate the pursuit of allogeneic hematopoietic stem cell transplantation (allo-HSCT).

 Across de novo MDS and therapy-related MDS, TP53 is the only somatic gene mutation to predict not only inferior OS but also suboptimal benefit from allo-HSCT.

 Poor long-term outcomes seen with allo-HSCT in TP53-mutant AML have discouraged its use in this patient subgroup, with available data demonstrating posttransplant relapse rates of 40% and 50% at 6 months and 100 days after allo-HSCT, respectively.

“The rate of relapse is significantly higher in patients with TP53 mutations. This is an important point because the toxicity [as a result of the transplant] could be potentially severe. When you [perform transplants in] patients with TP53 mutations with the standard of care, the relapse rate posttransplant is also very, very high, which suggests that we’re not just talking about resistance. Perhaps the TP53 mutation affects the stem cell–like part of the disease that is very difficult to control with chemotherapy,” Garcia-Manero said.

TP53-mutant MDS and AML are also marked by chromosomal complexities, including complex karyotype (CK), which refers to the presence of 3 or more cytogenetic abnormalities. CK is regarded as a highly adverse prognostic marker that is identified in approximately 10% of MDS diagnoses and has been associated with MDS progression to AML and inferior OS.6,11 TP53 mutations are frequently found in tandem with a CK in MDS and AML and are associated with the worst prognoses when they co-occur.3 “Because the TP53 gene has a role in maintaining the integrity of the genome, when the function of the gene is disrupted, it’s not uncommon to see multiple chromosomal aberrations that are associated with poor prognosis and resistance to therapy,” Garcia-Manero said.

Eprenetapopt (APR-246), an experimental small molecule manufactured by Aprea Therapeutics, Inc and magrolimab (formerly Hu5F9-G4), an anti-CD47 monoclonal antibody developed by Gilead Sciences, Inc, are 2 agents under investigation for TP53mutant MDS and AML.

 “Eprenetapopt is a drug that binds to the TP53 protein and seems to be stabilizing its function. Early reports from clinical trials here in the United States and Europe are showing a high response rate with eprenetapopt in combination with decitabine,” Garcia-Manero said.

Eprenetapopt reactivates mutant TP53 proteins by restoring wild-type TP53 conformation and function to induce programmed cell death in patients with TP53-altered disease.5 The agent’s actionability in TP53mutant MDS is being tested in an ongoing randomized phase 3 trial (NCT03745716) of frontline eprenetapopt with azacitidine (Vidaza) versus azacitidine alone in 154 patients.

The pivotal study was initiated after eprenetapopt showed encouraging activity with an acceptable safety profile when coadministered with azacitidine in an earlier-stage trial. Data from the phase 1b/2 study (NCT03072043) that provided the impetus for the phase 3 investigation demonstrated the capacity of the eprenetapopt-containing regimen to induce high response rates across subpopulations. The overall response rate (ORR), assessed by 2006 International Working Group criteria for MDS, was 87% among the 45 patients evaluable for response. When stratified by MDS/AML and MDS/myeloproliferative neoplasm, the ORR was 88% and 75%, respectively. More than half of patients in the general population (53%) experienced a complete response (CR); 61% of the 33 patients with MDS achieved a CR. Further, a TP53 mutation, which was identified in 62% of enrolled patients, was predictive for a higher CR rate (69% vs 25%; P = .006) with a trend for higher ORR (93% vs 75%; P = .17). The study enrolled 55 patients with higher-risk MDS, MDS/myeloproliferative neoplasm, or oligoblastic AML who had not previously received an HMA.

Like eprenetapopt, which currently holds FDA breakthrough therapy, fast track, and orphan drug designations in MDS, magrolimab is also “showing very significant activity in TP53-mutant MDS when combined with decitabine,” said GarciaManero. “It’s possible that at some point maybe next year, we will have results for these 2 compounds, which could potentially improve cure rates in this group of patients.”

The potential viability of magrolimab in the TP53-altered MDS/AML treatment landscape is supported by phase 1b data (NCT03248479) demonstrating the tolerability and durability of the first-in-class therapy tolerability when added to azacitidine. Magrolimab exerts its anticancer activity by targeting CD47, an immune checkpoint on the surface of macrophages that is overexpressed in myeloid malignancies.13 Efficacy data presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed that the combination induced the same best ORR (75%) in the subgroup of 12 patients with TP53-mutant AML and a separate subgroup of patients with TP53-mutant MDS (n = 4).

Forty-two percent of patients in the AML cohort and 50% of patients in the MDS group achieved a CR. After a median follow-up of 8.8 months and 7.0 months in the AML and MDS subgroups, respectively, the estimated 6-month survival was highest among patients with MDS (91% vs 100%).

“The follow-up is not that long, so we don’t know the durability of these responses and the impact on overall survival, but we believe that these are very active compounds that could be used to treat patients with these diseases before and after transplant,” Garcia-Manero said. The phase 1b data have since led the FDA to grant magrolimab a breakthrough therapy designation for patients with newly diagnosed MDS.

If respective, ensuing trials of eprenetapopt and magrolimab confirm the benefit seen in earlier-stage studies, the TP53-mutant MDS and AML armamentarium could gain the first FDA-approved therapies indicated specifically for TP53-altered disease.

It is not unreasonable to speculate that either experimental agent could enrich not only the treatment portfolio but also combination strategies in this space, Garcia-Manero said.

“It’s likely that these compounds could be combined with hypomethylating agents and with other drugs like BCL-2 inhibitors such as venetoclax [Venclexta], so we may see triplets of these drugs that could be quite active,” he observed.

If approved, eprenetapopt and magrolimab could later become critical components of a concept that Garcia-Manero and colleagues refer to as “total therapy,” which involves improving pretransplant treatment to increase the response rate, propelling more patients to allo-HSCT, and administering posttransplant therapy in a manner akin to maintenance treatment that will “hopefully result in improved outcomes,” GarciaManero said. “We’re starting to think a lot about how to implement these kinds of therapies after transplant.”

Articles

TP53-mutant myelodysplastic syndromes and acute myeloid leukemia represent a molecularly distinct, poor-risk patient subgroup frequently associated with complex karyotypes, high propensity for relapse, and inferior overall survival.

Overcoming Clinical Challenges Associated With TP53-Mutant MDS, AML

In the past decade, immunotherapy has been incorporated into the standard of care for many malignancies. Agents have shown efficacy in malignant melanoma, kidney cancer, and non–small cell lung cancer, and investigators are examining the efficacy of checkpoint inhibitors in less immunogenic tumors such as colon cancer, particularly in tumors with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) genes.

The DNA MMR genes MLH1, MSH2, MSH6, and PMS2 are involved in correcting errors that occur in DNA replication. If these genes are deficient, the cells are unable to correct errors and they accumulate mutations that ultimately lead to malignant potential. Deficiency in these MMR genes is MSI or dMMR, and tumors with heavily mutated MMR genes are identified as MSI-H. Testing for MSI can be done by immunohistochemistry that stains for tumor expression, or polymerase chain reaction alone or within a next-generation sequencing panel.

MSI/dMMR mutations can be somatic or germline mutations and testing for them has been part of the standard of care for patients with colon cancer since around 2013.

The genes with germline mutations are present in familial colon cancer syndromes such as hereditary nonpolyposis colorectal cancer, or Lynch syndrome, which makes up approximately 2% to 4 % of all colon cancer diagnoses. Therefore, if MSI/dMMR is detected, it has implications for the patient’s treatment and prognosis as well as for the patient’s family members, who may have the same mutations.

Patients with MSI-H/dMMR colon cancer typically present with lower-stage disease and have a better prognosis. The availability of mutational status at diagnosis helps to determine if adjuvant therapy would benefit patients with stage II colon cancer. If a patient presents with stage II MSI-H colon cancer, the prognosis is better and clinicians typically do not recommend adjuvant therapy. Alternatively, patients with stage II microsatellite stable colon cancer have a less favorable prognosis and, in certain cases, clinicians recommend adjuvant treatment with a f luorouracil (5-FU)–based therapy.

Until recently, MSI-H/dMMR metastatic colon cancer was treated with standard cytotoxic 5-FU–based chemotherapy plus VEGF or EGFR inhibitors depending on the tumor mutational status. In 2017, data from the CheckMate 142 trial (NCT02060188) showed that the anti–PD-1 agent nivolumab (Opdivo) alone or nivolumab plus the anti–CTLA-4 agent ipilimumab (Yervoy) could be used as a second-line therapy in patients with metastatic colon cancer not believed to be candidates for intensive chemotherapy and who had not received prior immunotherapy agents, and whose cancer was MSI-H.

Results from the phase 2 study demonstrated an objective response rate (ORR) of 60%, a 12-month progression-free survival (PFS) rate of 77%, and an overall survival (OS) rate of 83% with the combination of nivolumab and ipilimumab.

 In addition, results from KEYNOTE-164 (NCT02460198) showed the anti–PD-1 agent pembrolizumab (Keytruda) to be an effective subsequent therapy in metastatic MSI-H/dMMR colon cancer. The ORR was 33%, and the 12-month OS rate was 76% for patients who had received more than 1 prior line of therapy.

Neither of these studies compared immunotherapy with standard of care. Immunotherapy did not show efficacy in patients with metastatic colon cancer that was MSI-low or with proficient MMR genes.

Until this year, there were minimal data to support immune checkpoint inhibitors as first-line therapy for patients with MSI-H/dMMR metastatic colon cancer. KEYNOTE-177 (NCT02563002) was a multicenter, open label, randomized control trial that evaluated pembrolizumab versus standard of care with 5-FU–based therapy plus bevacizumab (Avastin) or cetuximab (Erbitux) for metastatic MSI-H/dMMR colon cancer. The study findings showed a PFS of 55% with pembrolizumab versus 37% with chemotherapy at 12 months, and 48% versus 19%, respectively, at 24 months.

Investigators did not report OS as the study is ongoing; however, 83% of patients who received pembrolizumab continued to show response to therapy at 24 months. Patients tolerated pembrolizumab better than chemotherapy, in addition to its being more efficacious.

 On June 29, 2020, the FDA approved pembrolizumab for first-line therapy for patients with metastatic MSI-H/dMMR colon cancer.

The MSI-H/dMMR subset of patients with colon cancer is a special population that requires a nuanced approach to determine therapy. Immunotherapy with checkpoint inhibitors has a role in the treatment of these patients, specifically in those with metastatic disease. However, given that MSI-H/dMMR colon cancer has a unique tumor biology, immunotherapy may have a role in local disease as well. Studies are evaluating the efficacy of immunotherapy in both the adjuvant and neoadjuvant settings, as well as the efficacy of immunotherapy plus chemotherapy in this patient population. As investigators gather more data, it is likely that the role of immunotherapy will continue to extend into the other stages of colon cancer.

NCCN. Clinical Practice Guidelines in Oncology. Colon cancer: NCCN evidence blocks, version 4.2020. Accessed November 6, 2020. https://www.nccn.org/professionals/physician_gls/pdf/colon_blocks.pdf

Matloff J, Lucas A, Polydorides AD, Itzkowitz SH. Molecular tumor testing for Lynch syndrome in patients with colorectal cancer. 

. 2013;11(11):1380-1385. doi:10.6004/jnccn.2013.0161

Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. 

. 2019;16(6); 361-376. doi:10.1038/s41575-019-0126-x

Lonardi S, Andre T, Wong KYM, et al. Combination of nivolumab (nivo) + ipilimumab (ipi) in the treatment of patients (pts) with deficient DNA mismatch repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC): CheckMate 142 study. 

. 2017;28(suppl 6):VI3. doi:10.1093/annonc/mdx422.001

Lenz HJ, Lonardi S, Zagonel V, et al. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: clinical update. 

. 2020;38(suppl 4):11. doi:10.1200/JCO.2020.38.4_suppl.11

Lenz HJJ, Van Cutsem E, Limon ML, et al. Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). 

. 2018;29(suppl 8):VIII714. doi:10.1093/annonc/mdy424.019

Le DT, Kim TW, Van Cutsem E, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. 

. 2020;38(1):11-19. doi:10.1200/JCO.19.02107

Andre T, Shiu KK, Kim TW, et al. Pembrolizumab vs chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. 

 2020;38(suppl 18):LBA4. doi:10.1200/JCO.2020.38.18_suppl.LBA4

FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. FDA. Updated June 30, 2020. Accessed November 6, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-first-line-treatment-msi-hdmmr-colorectal-cancer

December 14, 2020 - Immunotherapy agents have shown efficacy in malignant melanoma, kidney cancer, and non–small cell lung cancer, and investigators are examining the efficacy of checkpoint inhibitors in less immunogenic tumors such as colon cancer, particularly in tumors with high microsatellite instability and deficient mismatch repair genes.

Biomarkers Drive ICIs in Colon Cancer

Historically, insurance companies have taken little action to manage oncology drugs and have left prescribing decisions largely up to provider preference, mostly because of the complexity and sensitivity of treating cancer. 

It appears, however, that the companies are beginning to indirectly manage prescribing to better manage costs. Namely, they are shifting financial risk to providers and, in doing so, are trying to push providers to consider cost effectiveness, as well as the efficacy and safety of treatments. If providers are forced to consider cost to a greater extent, payers reason, they may begin to do more robust clinical and cost-effectiveness analyses to inform their decision-making.

The cost of oncology treatment is high and rising in the United States. For example, the monthly price of novel oncology drugs increased on average by 9% annually, and the average monthly cost of oncology drugs more than doubled between 2006 and 2015, from $7103 to $15,535.

 This raises the question whether insurance companies will begin to employ new tactics to influence provider-prescribing decisions toward lower-cost treatment options. 

To this end, Two Labs conducted a survey of 120 oncologists practicing in the United States to better understand the extent to which insurance companies are placing financial pressure on them and how this influences their prescribing decisions.

As a follow-up, an oncologist at a large academic treatment center participated in a multidisciplinary panel that included representatives from an insurance company and from manufacturers of oncology medications. 

The survey findings suggest that across 6 major oncology indications—non-small cell lung cancer, chronic lymphocytic leukemia, breast cancer, colorectal cancer, acute lymphoblastic lymphoma, and diffuse large B-cell lymphoma—prescribers at large academic institutions believed that payers have increased the financial management of oncology therapies, making it more difficult to prescribe their first choice of therapy. (

In addition, the findings confirm that prescribers are feeling increased financial pressure. The participating oncologist, whom Two Labs is not identifying in this article, is aware of an increase in payer management in recent years, noting that she has had to change her first-choice medication about 20% of the time. 

Pathways of care are a new management tool that have emerged in recent years as an attempt to curtail the increasing costs of oncology drugs by recommending which ones to prescribe in early and late lines of thera-pies. Payers incentivize providers to follow pathways by either offering upside financial rewards for compliance or downside risks for deviating from recommendations.

The survey findings suggest that pathways of care often strongly recommend or mandate the use of certain high-cost drugs over others, for example, a PD-1 inhibitor such as Keytruda (pembrolizumab) over nivolumab (Opdivo) or ipilimumab (Yervoy).

Although in theory care pathways may be useful in standardizing care, noted the oncol-ogist, in reality, each patient requires an individualized treatment approach. She has not seen any evidence that following such pathways leads to better patient outcomes and also suggests that pathways can quickly become dated and not accommodate the rapidly changing landscape in oncology. Initially, she was expected to adhere to pathways 70% of the time and there were only upside financial incentives. Then, adherence expectations increased to 80% and negative penalizations were introduced. 

Another challenge for providers is that they must often juggle multiple pathways from different insurance companies, and in some cases from their institution as well. In some cases, providers juggle more than 3 pathways. The panel’s oncology provider handles multiple pathways. This causes her to choose the “least common denominator” treatment option, the one most likely to be covered on all pathways. 

The survey results suggest that payers are shifting financial risk to providers, with 73% of providers suggesting they agree or strongly agree with the statement that insurance companies have been shifting financial risk to their hospital system/practice. This trend is even more marked among prescribers at large academic centers, with 78% of the providers agreeing with the statement. 

Of respondents who agreed or strongly agreed with the statement, 66% said that this caused them to reconsider prescribing decisions. The most common way providers experienced this is through bundled payments. Often, they also face cost penalties, and in some cases financial risk is shifted through upside bonuses (

The panel’s oncologist has also experienced the shifting of financial risk. Her institution participates in the Oncology Care Model (OCM), which was introduced in 2016 to help providers lower cost while improving quality of care. There are currently 138 practices and 10 payers participating in the OCM.

The oncologist notes that cost savings do not always capture the true value of care, as more effective therapies often have greater toxicities, which can be costly to manage.

Anne Runyon is a senior market access consultant at Two Labs, a pharmaceutical services company.

Insurance companies are beginning to indirectly manage prescribing to better manage costs. 

Oncology Providers Face Rising Pressures From Payers Over Therapy Choices

In the past 3 years, novel agents have shaken up the treatment landscape for patients with chronic lymphocytic leukemia (CLL). Deciding between agents in the first-line setting has become increasingly complex, as data for pathway inhibitors, specifically Bruton tyrosine kinase inhibitors (BTKis) and BCL-2 inhibitors, show promising therapeutic response. While individual patient risk factors such as comorbidities and age at diagnosis remain a key stratification factor, cytogenetic abnormalities including 17p deletions (del[17p]) and 

 mutations are reliable prognostic tools to identify patients with CLL who may be at a higher risk of early progression.

“Selection and choice of first-line therapy is an important decision to make for patients with CLL,” moderator William G. Wierda, MD, PhD, said. “We have options, and we have a lot of data to support our decisions. We also have prognostic factors to help us prioritize and select frontline therapy.” In a recent 

, a panel of hematologic experts discussed the paradigm shift in frontline therapy options for patients with CLL. The panelists focused on the latest data for novel BTKis and discussed progress in overcoming acquired resistance to BCL-2 inhibitors.

“There has been a very rapid shift in therapies for CLL. There have been many new approvals,” Nicole Lamanna, MD, said. She noted that FDA-approved BTKis now include ibrutinib (Imbruvica) and acalabrutinib (Calquence), which can be used as monotherapy or in combination with a CD20 monoclonal antibody in the first- and subsequent-line settings, and that she expects zanubrutinib (Brukinsa) to be approved as well.

The recently published follow-up results from arm C of the SEQUOIA trial (NCT03336333), in which treatmentnaïve patients with the high-risk cytogenetic marker del(17p) received zanubrutinib, showed an overall response rate of 94.5% at a median follow-up of 18.2 months, with 3.7% achieving a complete response or complete response with incomplete bone marrow recovery, 87.2% a partial response (PR), 3.7% a PR with lymphocytosis, 4.6% stable disease, and 0.9% progressive disease.2 The estimated 18-month progression-free survival (PFS) rate was 88.6%, and the estimated overall survival rate was 95.1%. Treatment was generally well tolerated, with only 4 patients (3.7%) discontinuing treatment because of an adverse effect (AE). The most common AEs, occurring in at least 10% of treated patients, included contusion, upper respiratory tract infection, decreased neutropenia/neutrophil count, gastrointestinal effects including diarrhea, nausea, constipation, rash, back pain, cough, arthralgia, and fatigue.

“We all would agree that for patients with a 17p or a 

 abnormality, these are patients who should receive a novel agent. Our longest data happen to be with BTK inhibitors in this subgroup, but certainly there are data for venetoclax-based combinations as well in this poor prognostic group of patients. That’s an important factor to know about prior to treating your patient,” Lamanna said.

She also emphasized that patients’ chromosomal abnormalities may change following various treatments, making it important to assess patients’ cytogenetic markers before starting any subsequent treatments.

Considerable progress has also been made with venetoclax, the first selective, orally bioavailable BCL-2 inhibitor. It has shown good therapeutic responses as a monotherapy in patients with CLL irrespective of the presence of adverse clinical or genetic features, including in patients with relapsed or refractory CLL.

 A challenge, however, has been that most patients ultimately become resistant to this treatment, which has led to the investigation of a variety of venetoclax combination approaches.

“Recently, we had the [approval of] the BCL-2 inhibitor venetoclax in combination with obinutuzumab,” Lamanna said (

 ). Approval was based on data from CLL14 (NCT02242942), a randomized, multicenter, open label, actively controlled trial, which randomly assigned 432 patients with previously untreated CLL with coexisting medical conditions 1:1 to venetoclax (Venclexta) plus obinutuzumab (Gazyva) (VenG; n = 216) or obinutuzumab plus chlorambucil (GClb; n = 216).

 The primary end point was investigator-assessed PFS. Data from an updated analysis presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed that after a median follow-up of 39.6 months, the median PFS was not reached in the VenG arm versus 35.6 months in the GClb arm (HR, 0.31; 95% CI, 0.22-0.44; 

 < .001). The estimated 3-year PFS rate was significantly higher in the VenG arm than in the GClb arm at 81.9% versus 49.5%, respectively. Benefit was observed regardless of high-risk cytogenetic features, including TP53 deletion/mutation or the presence of unmutated immunoglobulin heavy-chain variable region genes.

“The CLL14 study, in my opinion, is one of the most important studies for CLL,” Mazyar Shadman, MD, MPH, said. “Basically, it introduced time limits and chemotherapy-free treatment in the first-line setting. The benefit was seen in all the known risk groups for CLL, including those with 

 gene. So here, because we are talking about the fixed-duration therapy, the depth of response becomes very important and one of the secondary end points of this study was the rate of MRD [minimal residual disease] eliminations.” Three months after treatment completion, a higher rate of undetectable MRD (10

) was observed in the VenG arm (75.5%) versus in the GClb arm (35.2%; 

 < .001). Further, at 18 months after treatment, 47.2% of patients in the VenG arm had undetectable MRD compared with 7.4% in the GClb arm.

“This data is very impressive because we know from venetoclax-based therapies that the duration of response and progression-free survival are directly correlated with the depth of response, meaning that if you receive that undetectable MRD, the PFS would be longer,” Shadman said.

Additionally, venetoclax is showing promise combined with BTKis. “I should give credit to The University of Texas MD Anderson Cancer Center for publishing data that show for the first time the preclinical synergy between BTK inhibitors and BCL-2 inhibitors. We are seeing this now translate to clinical efficacy as well, not just additive properties between these drugs. We can utilize the modulation of different pathways and then hit them hard with both drugs,” John N. Allan, MD, said.

In a phase 2 study (NCT02756897) that assessed ibrutinib plus venetoclax in 80 previously untreated high-risk older patients with CLL who had del(17p), mutated 

, 88% had complete remission or complete remission with incomplete count recovery and 61% had remission with undetectable MRD after 12 cycles of combined treatment.

 Responses were observed across all risk groups. No new safety concerns were observed. Three patients had laboratory evidence of tumor lysis syndrome, but none developed clinical evidence of this complication or had to cease treatment because of it.

The panelists were particularly excited about upcoming updates from the phase 2 CAPTIVATE trial (NCT02910583), which they noted has 2 particularly well-designed cohorts that will enable cross-study comparisons to help answer some key questions in CLL.

 “We will find out if a patient population seems to benefit from maintenance. We’re going to start to learn what to do with MRD,” said Allan, who is an investigator on the trial. “The 25% of patients who don’t achieve MRD are randomized to monotherapy ibrutinib versus continuing the doublet of venetoclax and ibrutinib followed by a period of continual ibrutinib. That will be an interesting group to see who is not reaching MRD and then how well they do.” Allan explained this will help investigators determine if there is potential for MRD to deepen in those patients over time. “Right now, a lot of the data show that patients either reach MRD negativity or don’t within the first year or two. After the second year, MRD doesn’t seem to deepen. There is something about the biology of CLL that keeps MRD from deepening,” he said.

, data from CAPTIVATE supported the fixed-duration treatment regimen of ibrutinib plus venetoclax in patients who had confirmed undetectable MRD, defined as undetectable in both peripheral blood and bone marrow serially over at least 3 cycles. Patients 70 years or younger received 3 cycles of lead-in ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. The primary end point of disease-free survival (DFS) in these patients was defined as survival without progression or MRD relapse.

Of 149 randomized patients, 86 (58%) had confirmed undetectable MRD and were randomized to placebo (n = 43) or maintenance ibrutinib (n = 43). The 1-year DFS rate was not significantly different for patients who received placebo (95.3%; 95% CI, 82.7%- 98.8%) versus those who received ibrutinib (100%; 95% CI, 100%-100%; 

Full results will be presented at the 2020 American Society of Hematology Annual Meeting and Exposition. 

What makes the ibrutinib and venetoclax combination particularly exciting is that it is a completely oral, once-daily, chemotherapy-free regimen, which is convenient for patients. Thus far, results from the MRD cohort that received 12 cycles of ibrutinib plus venetoclax prior to MRD-guided randomized treatment discontinuation showed high rates of undetectable MRD in peripheral blood and bone marrow.

Other trials the panelists were excited about included A041702 (NCT03737981) and EA9161 (NCT03701282).

 A041702 is a randomized phase 3 trial led by the Alliance for Clinical Trials in Oncology comparing ibrutinib plus obinutuzumab with an ibrutinib, obinutuzumab, and venetoclax triplet in previously untreated older adults (≥70 years) with CLL in need of therapy.

 The trial is still enrolling patients through the National Cancer Institute’s National Clinical Trials Network. Similarly, EA9161 is a randomized phase 3 trial comparing the same combinations in younger patients (≤ 69 years).

“We are limited in terms of understanding the benefit of that anti-CD20, whether it is going to help or not. We’ll start to see MRD rates, and these are all very similar patient populations, so we will be able to make comparisons across studies to see if these MRD rates are any different or can have an additive effect,” Allan said, noting that these trials will help answer the question of whether patients can achieve an 80% bone marrow disease-negative state with the addition of an anti-CD20 to a BTKi and BCL-2 doublet.

The panelists agreed that choosing between BTKi and BCL-2 inhibitor therapy in the firs line are highly individualized decisions. “The choice in my mind is probably going to be a BTK inhibitor versus venetoclax/obinutuzumab,” John M. Burke, MD, said. “The choice for me doesn’t have as much to do with the disease, the biology, the gene mutation, etc. A lot of it comes down to 2 other factors related to the patient and the patient’s preferences. For example, venetoclax/obinutuzumab is a 1-year fixed duration therapy. That’s a big difference from indefinite therapy with a BTK inhibitor,” he said.

The other factor is a patient’s comorbidities, such as the presence of underlying cardiac issues, atrial fibrillation, or use of an anticoagulation therapy, which will play a role in therapeutic selection based on the toxicity profiles of the agents, Burke added. “For the patient who doesn’t have an obvious contraindication, it comes down to patient preference.”

One notable exception is in patients who receive a diagnosis under aged 65 years, are deemed fit, or have an 

 aberrancy according to fluorescence in situ hybridization results. “That is a group of patients that seems to have a particularly good outcome with FCR [fludarabine, cyclophosphamide and rituximab (Rituxan)] and chemotherapy,” Burke said. “A significant percentage of this subset of patients treated with FCR continue to be disease free well beyond 10 years now. So I think the FCR regimen or something similar to that still comes into play as an option for those patients.” 

NCCN Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic leukemia, version 1.2021. Accessed November 11, 2020. https://www.nccn.org/ professionals/physician_gls/pdf/cll.pdf 

Brown JR, Roback T, Ghia P, Azhar A, Baig M. Efficacy and safety of zanubrutinib in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): follow-up results from arm C of the SEQUOIA (BGB-3111-304) trial. 

. 2020;136(suppl 1):11- 12. doi:10.1182/blood-2020-134280 

Tariq S, Tariq S, Khan M, et al. Venetoclax in the treatment of chronic lymphocytic leukemia: evidence, expectations, and future prospects. 

. 2020;12(6):e8908. doi:10.7759/cureus.8908 

Al-Sawaf O, Zhang C, Tandon M, et al; CLL14 Study Investigators. Fixed-duration venetoclax-obinutuzumab for previously untreated patients with chronic lymphocytic leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized, phase III CLL14 trial. 

. 2020;38(suppl 15):8027. doi:10.1200/JCO.2020.38.15_suppl.8027 

Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. 

. 2019;380(22):2095-2103. doi:10.1056/NEJMoa1900574 

Wierda WG, Tam CS, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. 

. 2020;136(suppl 1):16-17. doi:10.1182/blood-2020-134446 

Woyach J, Ruppert AS, Perez G, et al. Alliance A041702: a randomized phase III study of ibrutinib plus obinutuzumab versus ibrutinib plus venetoclax and obinutuzumab in untreated older patients (≥ 70 years of age) with chronic lymphocytic leukemia (CLL). 

. 2019;134(suppl 1):1751. doi:10.1182/ blood-2019-127102 

EA9161 educational material. ECOG-ACRIN Cancer Research Group. Accessed November 11, 2020. https://ecog-acrin. org/clinical-trials/ea9161-educational-materials

In a recent OncLive Peer Exchange®, a panel of hematologic experts discusses the paradigm shift in frontline therapy options for patients with CLL. 

Evolving Data for CLL Set Stage for Frontline Therapy

Having patients go on drug holidays or intermittent therapy is a common strategy during treatment of prostate cancer and several other malignancies, whether to provide temporary relief from adverse effects (AEs) influencing quality of life (QOL), to prevent long-term health impacts, or to lessen drug resistance that would render the therapy ineffective. Now, however, the coronavirus disease 2019 (COVID-19) pandemic has made the decision to take a break from ongoing therapy more complicated and more urgent.

Before the pandemic, “there was a lot of anxiety from different patient groups” about interrupting their therapy, said Howard A. “Skip” Burris, MD, chief medical officer and president of clinical operations at Sarah Cannon Research Institute in Nashville, Tennessee, and a 2014 Giants of Cancer Care® award winner in the Drug Development category.

“I had some men who were older, in their 70s, who were worried about doing intermittent androgen therapy, and yet when COVID hit and they were more worried about coming to the clinic, they put themselves on a break,” Burris said in an interview with OncologyLive®. “I had women who were on maintenance trastuzumab [Herceptin] in remission for a long time who were worried about coming to the clinic, so they took their first break.”

The American Society of Clinical Oncology (ASCO) Survey on COVID-19 in Oncology Registry (ASCO Registry) is collecting data on how the epidemic is affecting the delivery of care and patient outcomes, including for those who paused treatment or switched therapies, noted Burris, who served as ASCO president from 2019 to 2020. “Everybody in the ASCO Registry has to be on treatment, either metastatic or adjuvant, or they have to have been within a year of completing therapies,” he said. “I think we’re going to learn a lot from these data.”

The data could prove illuminating in part because, as common as drug holidays are, their safety and efficacy varies in trials. Data are often contradictory, equivocal, or simply lacking for many scenarios, and it can be unclear why some patients benefit from therapy pauses while others experience progression.

Several research teams are now testing adaptive therapies that include holidays and dose modulation based on disease biomarkers or evolving tumor cell resistance, rather than uniform sequencing plans.

Regarding the definition of a “drug holiday,” Burris said the term means different things to different people. It can mean giving maintenance therapy intermittently, such as stopping chemotherapy and continuing only a checkpoint inhibitor administered once every 3 weeks, or stopping therapy in favor of active surveillance when a patient appears to be in complete or partial remission.

However, it can be difficult to gauge whether a patient still has active disease, and he said that he’s eagerly following adaptive therapy trials and other research that aims to inform intermittent dosing strategies.

“For the individual patient with cancer and metastatic disease, we’re closer to treating them as if they had a chronic disease. We need to then start thinking about alternative approaches, whether it be drug holidays, sequencing therapies, or whatever the terminology is,” he said. “We’ve had enough success with these drugs, and we’ve got patients living longer but not yet cured.”

In prostate cancer, “tons of studies in the past [have been] done on intermittent androgen deprivation [IAD]. Those roundly failed,” said Jacob Scott, MD, DPhil, a radiation oncologist at Cleveland Clinic Taussig Cancer Center in Ohio who studies evolutionary oncology. “One schedule doesn’t fit every person, and it might even be that the schedule that works for patient X stops working for patient X in 6 months because the cancer has changed. So it’s really about trying to understand the dynamics of an individual person’s cancer from some observables that we have.”

IAD may be the most thoroughly studied use of drug holidays. Continuous androgen deprivation (CAD) is the standard therapy for metastatic hormone-sensitive prostate cancer, but the resulting drop in serum testosterone levels is associated with sexual dysfunction, risk of cardiovascular disease, loss of bone and muscle strength, cognitive effects, and other AEs.

Stopping androgen therapy for some period of time to allow testosterone levels
to rise again is an important option for many men, said Nicholas J. Vogelzang,
MD, a clinical professor at University of Nevada School of Medicine in Las Vegas and a 2018 Giants of Cancer Care® winner in Genitourinary Cancers.

Prostate cancer treatment “is a bit of a rollercoaster ride for these patients, and they look forward to being off hormone therapy,” Vogelzang said. “I may be whistling in the dark, but I really hope and pray that for some of these men, they can get long periods of time when their testosterone can recover so they will be able to remain relatively normal. But I am regularly disappointed.”

Findings from the largest IAD trial (N = 3040) were published in 2013 by Maha H. A. Hussain, MBChB, a 2015 Giants of Cancer Care

 award winner, and colleagues, including Vogelzang. Investigators found significantly better erectile function and mental health (

 = .003, respectively) with intermittent therapy than with continuous therapy 3 months after randomization but not thereafter. Additionally, the overall incidence of grade 3 or 4 AEs was similar between the 2 therapeutic approaches: 30.4% for IAD and 32.7% for CAD.

Across the study population, median overall survival (OS) was higher in the continuous group at 5.8 years compared with 5.1 years in the intermittent group, representing a 10% relative increase in the risk of death with intermittent therapy (HR for death with intermittent, adjusted for stratification factors, 1.10; 90% CI, 0.99-1.23). The results “failed to show that intermittent therapy was noninferior to continuous therapy with respect to survival,” the investigators wrote. Additionally, they noted, findings suggested that intermittent therapy could hold
a 20% greater risk of death, but there were too few events to make a determination.

Subsequent analyses have reached varying conclusions. A 2015 study
of data from 15 trials found support for the noninferiority of IAD, no difference
in OS for the 2 groups, and minimal differences in patients’ self-reported QOL, although there was some improvement in physical and sexual functioning with IAD.

Another 2015 study, by Hussain, Vogelzang, and colleagues, examined findings from 7 phase 3 trials and concluded that none demonstrated survival superiority of IAD compared with CAD. The trials that found IAD was not inferior were based on wide, prespecified noninferiority margins that likely would not be considered comparable by doctors or patients, they wrote.

Last year Hussain et al said findings from another meta-analysis showed the paradigm for IAD has “not lived up to expectations.”

 However, they noted that newer treatment regimens, such as CAD combined with docetaxel and abiraterone acetate (Zytiga) in patients with metastatic hormone-sensitive prostate cancer, have allowed patients with prostate cancer to live longer, making the impact of AEs and the need for deintensification strategies more prominent.

Other recent options include FDA approvals of the second-generation androgen receptor antagonists apalutamide (Erleada) and enzalutamide (Xtandi) in combination with androgen deprivation therapy (ADT) in metastatic castration-sensitive settings and darolutamide (Nubeqa) plus ADT in nonmetastatic castration-resistant disease.

Hussain and colleagues acknowledged that experienced clinicians recognize the benefits of IAD but that doctors and patients must understand its potential negative impact, especially given the lack of data on intermittent use of newer therapies.

The trials examined in the recent meta-analysis used several thresholds for pausing ADT: after 6 months; when prostate-specific antigen (PSA) levels fall below 4 ng/mL or reach 1 ng/ mL or lower; or when PSA decreases 80% or 90% below baseline levels.

Vogelzang said he looks for patients to possibly take a break after 18 months if their PSA is below 0.1 ng/mL. “When do you stop? The answer is, no one knows,” Vogelzang said. “I have arbitrarily taken the point that maybe 18 months is enough. That’s just my personal world view.”

Investigators at Moffitt Cancer Center in Tampa, Florida, have tried to lengthen time
to progression (TTP) by personalizing on-and off-treatment cycles in a way that slows the evolution of cellular resistance to ADT. Investigators developed a game theory model based on interactions of intratumoral subpopulations with testosterone.

When therapy is administered continuously at the maximum tolerated dose (MTD), investigators theorize, there is a rapid expansion of resistant T cells, whereas adaptive dosing allows the responsive cell populations to recover 

In a small trial, men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) were enrolled after they achieved a PSA reduction of 50% or greater with abiraterone as frontline therapy.

The study group comprised 15 men who were off the drug for at least 3 months before it was restarted for PSA progression. After more than 11 months of follow-up, 7 of the 15 had completed at least 2 adaptive therapy cycles at data cutoff in January 2019.

Investigators calculated that the median radiographic progression-free survival (rPFS) would be no less than 30 months (

 = .0068, Fisher exact test). Investigators said that result compared favorably with the 16.5-month median rPFS in the COU-AA-302 trial (NCT00887198) of abiraterone plus prednisone versus placebo in mCRPC.

The Moffitt trial also required much less of the drug, with patients using only 49% as much abiraterone as with continuous therapy.

Such adaptive strategies exploit competition between treatment-resistant and treatment-sensitive tumor cells. Rather than using a traditional MTD strategy that aims to eradicate as many cells as possible at the start, the adaptive therapy allows some sensitive cells to remain and “out compete” resistant cells, slowing their growth during treatment breaks. Although resistant cells eventually increase enough that the treatment fails, investigators say that in a number of cancers, this type of tumor control strategy extends TTP longer than MTD does.

“The crucial point here is, they’re doing dose modulation or holidays in response to how the tumor grows,” said Alexander Anderson, PhD, chair of the Integrated Mathematical Oncology department and senior member at Moffitt Cancer Center. “If you don’t see much growth or it doesn’t grow too quickly or return to the size it was within a period of time, they’re not treating or they’re continuing to deescalate the dose. When it eventually returns to the size it started at, that’s when they kick the treatment back in.”

That personalized approach contrasts with previous drug-holiday trials that randomly assigned patients to uniform dosing schedules, not only in prostate but also breast, melanoma, colorectal, and other cancers. 

Findings from one such trial were presented at the European Society for Medical Oncology Breast Cancer Congress 2019 in Berlin, Germany.

 The phase 3 STOP&GO trial (EudraCT 2010-021519-18; BOOG 2010-02) enrolled 420 patients with advanced HER2-negative breast cancer and randomized them to either 8 cycles of continuous chemotherapy or an intermittent schedule of 4 cycles, a break, and then 4 more cycles.

The combined median OS for patients receiving first-line therapy of paclitaxel plus bevacizumab (Avastin) or second-line treatment with capecitabine or nonpegylated liposomal doxorubicin was 20.3 months for those on intermittent treatment compared with 23 months for those on continuous treatment (HR, 1.93; 95% CI, 1.26-2.95).

 A separate analysis found that physical QOL declined more in the intermittent arm and that mental QOL improved slightly in both groups, but increased more in the continuous arm.

Serial holidays in melanoma treatment were explored in a phase 2 trial (NCT02196181) presented at the American Association for Cancer Research Virtual Annual Meeting 2020. The trial enrolled 242 patients with advanced 

 V600E/K– mutated disease. After receiving dabrafenib (Tafinlar) plus trametinib (Mekinist) for 8 weeks, 206 nonprogressing patients were randomized to continuous dosing with the combination or intermittent treatment on a 3-week-off, 5-week-on schedule. Median progression-free survival (PFS) was 9 months with continuous dosing versus 5.5 months with intermittent (

 = .064). Median OS was 29.2 months in both groups (

 = .93) at a median follow-up of 2 years.

Intermittent therapies have also been studied as ways to improve QOL for patients with metastatic colorectal cancer (mCRC). The OPTIMOX1 trial (NCT01023633), for example, randomly assigned patients to 2 different regimens of leucovorin and fluorouracil with oxaliplatin (FOLFOX). Arm A received continuous standard FOLFOX4 every 2 weeks until progression; arm B received FOLFOX7, a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin, for 6 cycles, followed by 12 cycles without oxaliplatin, and then FOLFOX7 again.

The 2 groups fared similarly: Median PFS was 9.0 months in arm A and 8.7 months in arm B, and median OS was 19.3 and 21.2 months, respectively. Arm B had somewhat fewer grade 3/4 toxicities (54.4% arm A vs 48.7% arm B). The investigators concluded that oxaliplatin can be safely stopped after 6 cycles in a FOLFOX regimen.

A 2013 review of mCRC rechallenge strategies discussed OPTIMOX1 and several other trials that had treatment holidays of a sort, but the overall implications were unclear due to varying study designs and results. The studies included the phase 3 COIN trial (ISRCTN27286448), which tested preplanned treatment holidays in 1630 patients with advanced colorectal cancer.

Patients were randomized to receive either a continuous oxaliplatin-fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (Erbitux; arm B), or intermittent chemotherapy (arm C).

In comparing results from arms A and C, investigators found that patients in the per-protocol population who received continuous therapy had a median OS of 19.6 months (interquartile range [IQR], 13.0-28.1) versus 18.0 months (IQR, 12.1-29.3) for those who had intermittent treatment. In terms of AEs, those in the continuous therapy arm experienced lower rates of nausea and vomiting (2% vs 8%) than those on intermittent therapy, respectively, but higher rates of grade 3 or worse hand-foot syndrome (4% vs 3%) and peripheral neuropathy (27% vs 5%).

In their review of multiple studies, Tonini et al concluded that the data do not clearly define an optimal role for a treatment holiday in which all therapy is paused and for chemotherapy-free intervals with maintenance. They did see the potential for a role for rechallenge therapy for fit patients in third-line or fourth-line mCRC treatment. “Intermittent treatment could be an important strategy in management of [patients with] mCRC when there is not the purpose of gaining an important tumor shrinkage,” they wrote.

Intermittent immunotherapy has also been studied. One small phase 2 trial (NCT03126331) used a partially personalized strategy. Fourteen patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy were treated with nivolumab (Opdivo) for 12 weeks. Of those, 5 achieved a 10% or greater reduction in tumor burden and entered a treatment-free observation phase with reimaging every 12 weeks. After a median 48 weeks’ follow-up, 1 patient had an increase in tumor burden of 10% or greater and restarted therapy. The remaining 4 patients had a sustained response for a median of 34 weeks (range, 16-53) off therapy.

Moving forward, investigators should seek to tailor therapy according to tumor composition rather than using one-size-fits-all schedules, holidays, and doses, Anderson and colleagues at Moffitt showed in a preclinical, mathematical modeling study.

They found that tumors made up of a mix of sensitive and resistant cells, such as breast cancers and melanomas, were best managed by an adaptive approach that exploits the fitness cost of resistance and cellular spatial dynamics. However, homogeneous tumors composed of sensitive cells, such as testicular cancer and some lymphomas, tend to respond better to MTD. Translating these findings to the clinic would require measuring initial variation in drug sensitivity using immunohistochemistry and then periodically assessing of tumor burden using systemic biomarkers, circulating tumor cells, cell-free DNA, or imaging, the investigators said.

Other preclinical studies by the Moffitt group showed how adaptive therapies could work in breast cancer. Investigators applied paclitaxel therapy to cell lines of metastatic triple-negative and estrogen receptor (ER)–positive breast cancer and measured tumor response with MRI. After initial intensive therapy achieved tumor control, it was maintained with progressively smaller doses. In 60% to 80% of animals, no treatment was necessary for intervals as long as several weeks.

A subsequent study investigated anti-estrogen therapy in which ER-positive xenografts were treated with continuous tamoxifen and cycles of estrogen suppression and stimulation. Brief interruptions in drug administration provided equal tumor control while using up to 50% less drug and maintaining high expression levels of ER and lower levels of MDR1, a glycoprotein.

One focus of adaptive therapy research has been tyrosine kinase inhibitors (TKIs), which inevitably stop working as resistance is acquired. Studies have demonstrated that some patients with non–small cell lung cancer (NSCLC) benefit from re-treatment with the same EGFR-targeted TKI after a holiday.

 However, preclinical work by Scott and colleagues revealed patterns or “maps” of collateral sensitivities that displayed cross-resistance to first-line ALK TKIs in 

-positive NSCLC, including after drug holidays, suggesting other strategies might provide optimal results in second-line settings.

 Another study tested resistance to a battery of drugs in Ewing sarcoma cells after chemotherapy and again found replicable patterns of sensitivity and resistance.

Due to the randomness of cell evolution, having sensitivity maps does not on its own allow predictions in individual patients, Scott said, adding that with his next study, of 

-positive lung cancer cells, he hoped to overcome that gap by gathering tumor genomic data linked to sensitivity patterns. “Once you have that map, the underlying hypothesis is that it’s fundamental.

Therefore, when a patient comes to you, you could biopsy their tumor, do next-generation sequencing, and then match that sequencing result up to your map of in vitro genotype-phenotype mapping.”

Those genetically informed maps could someday allow continuous therapy adjustments over the course of treatment, he said. That could prove useful not only during regularly scheduled care but also after unexpected breaks, such as those that have occurred during the COVID-19 pandemic. Patients would “come in and tell you, ‘Whoops, I took a month off,’ and you say, ‘OK, well, we need to reassess the state of the tumor,’ with the assumption that it has kind of wandered around evolutionarily a little bit. As soon as you know where it starts, you can calculate the future to a certain extent,” Scott said.

Burris noted that frequent next-generation sequencing testing is already technologically feasible but not practically accessible to many patients. “I’m hopeful that we will have price points around DNA sequencing,” he said. “That you could do sequential liquid biopsies, sequential blood-based sequencing, and try to see what patterns of resistance are emerging.”

Having patients go on drug holidays or intermittent therapy is a common strategy during treatment of prostate cancer and several other malignancies, whether to provide temporary relief from adverse effects influencing quality of life, to prevent long-term health impacts, or to lessen drug resistance that would render the therapy ineffective.

Vol. 21/No. 23 | Oncology Live®

Overcoming Clinical Challenges Associated With TP53-Mutant MDS, AML

Biomarkers Drive ICIs in Colon Cancer

Oncology Providers Face Rising Pressures From Payers Over Therapy Choices

Evolving Data for CLL Set Stage for Frontline Therapy

COVID-19 Sharpens Focus on Drug Holidays

The Therapeutic Toolkit for MDS-Associated Anemia Adds Luspatercept

Pandemic Heightens Stress of Cancer Diagnosis

Novel Tubulin-Targeting Therapies Make Headway