Clinical trials play a central role in oncology. The existence of solid, evidence-based disease management would not be possible without well-designed and well-conducted studies.

However, the publication of the objectively meaningful outcomes of such efforts in high-impact peer-reviewed medical journals does not necessarily result in the observations being implemented into routine clinical care. Several reasons may explain the substantial delays noted between the publication of highly relevant data and uptake of the results into practice.

The results alter well-established, widely accepted approaches to disease treatment.

Changes may lead to potentially complex, unproductive, and expensive training for clinicians and staff.

Changes may add time to a routine clinical encounter without adding remuneration.

There may be a lack of local resources or supportive personnel to implement a new practice.

Implementation may negatively affect personal and practice finances.

Conversely, if essential training is provided by a source outside the practice on the evidence-based treatment approach, effectively marketed clinical trial results that suggest a new approach to disease management may lead to a greater willingness to carefully evaluate and subsequently employ the tactic. Further, if such implementation is associated with a favorable financial return, a practice will almost certainly show more interest.

If a new anticancer agent demonstrates meaningful activity for new clinical indications in initial registration trials or in subsequent studies leading to regulatory approval, a drug manufacturer may be willing to spend considerable time (and money) to inform oncologists of this development. This may include providing assistance in obtaining third-party insurance coverage for individual patients or any required training related to drug administration and safety.

However, the situation is likely to be quite different if the trial is not associated with a sponsor or any other form of support necessary to optimize meaningful implementation. In the opinion of this commentator, an increasing number of critically relevant observations and important study results published in peer-reviewed medical and oncology literature stagnate because there is no implementation plan or subsequent effort at encouraging clinical uptake.

Investigators of such projects may win awards for the quality of their research, subsequently obtain precious peer-reviewed grant funding, achieve promotion at their institution or elsewhere, or be awarded membership in prestigious national organizations, but their research findings themselves sometimes go nowhere. To be clear, there is no suggestion that this was ever the investigator’s intent, but it may be the result of the absence of an effective implementation plan.

There is a critical need in the oncology community for meaningful, focused efforts in implementation research. Consider the following: A recent study looked at adherence to established guidelines for venous thromboembolism prophylaxis following pancreatic surgery. The study’s results revealed that among 888 patients deemed eligible to receive such therapy upon hospital discharge, only 3.8% (34 individuals) “filled a prescription for venous thrombotic prophylaxis within 5 days of hospital discharge.”

 This is rather concerning considering that data from both clinical guidelines and trials support the use of such prophylaxis after major surgery involving the abdominal cavity.

How might surgeons be encouraged to use and inform patients of a known effective and safe measure to reduce the risk of this serious surgery complication?

A second example within the realm of cancer surgery suggests the need to understand and positively affect findings from thoracic oncology studies. A specific example is a retrospective cohort analysis of individuals with stage IB to IIIA non–small cell lung cancer (NSCLC) in the ALCHEMIST Screening Trial (NCT02194738) who did not subsequently participate in an adjuvant therapy trial and who had a cancer measuring at least 4 cm in diameter, with or without positive lymph nodes.

Among 2833 patients (53% women), 95% were underwent surgical resection, but only 53% were found to have had “adequate lymph node dissection.”

 A similarly low percentage of individuals (57%) received any adjuvant therapy, with only 44% receiving a minimum of 4 cycles of platinum-based chemotherapy, despite solid evidence revealing the value of such treatment. Although the authors of this provocative and concerning analysis appropriately conclude that “efforts are needed to optimize the use of proven therapies for early-stage NSCLC”

 the question is how do we effectively implement efforts to change what for many oncologists appears to be current routine surgical practice?

It is not difficult to find documented evidence outside the realm of surgical oncology that challenges the oncology community to focus research on strategies to more effectively improve outcomes or enhance patients’ quality of life. Topics highlighted in recent publications include disparities in electronic screening for cancer-related psychosocial distress

 and inadequacies in performance guideline–recommended geriatric assessments.

In the opinion of this commentator, there must be a more prominent role in our community’s investigative agenda for implementation research designed to discover and activate strategies to encourage widespread use of new, effective approaches to cancer management.

Perry LM, Bateni SB, Merkow RP, et al. Evaluation of adherence to venous thromboembolism prophylaxis guidelines among US adults after pancreatic cancer surgery. 

. Published online July 13, 2022. doi:10.1001/jamasurg.2022.2590

Felder S, Rasmussen MS, King, et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. 

. 2019;11(11):CD004318. doi:10:1002/14651858.CD004318.pub3

Vedovati MC, Becattini C, Rondelli F, et al. A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. 

. 2014;259(4):665-669. doi:10.1097/SLA.0000000000000340

Kehl K, Zahrieh D, Yang P, et al. Rates of guideline-concordant surgery and adjuvant chemotherapy among patients with early-stage lung cancer in the US ALCHEMIST Study (Alliance A151216). 

 2022;8(5):717-728. doi:10.1001/jamaoncol.2022.0039

Sutton TL, Koprowski MA, Gold JA, et al. Disparities in electronic screening for cancer-related psychological distress may promote systemic barriers to quality oncologic care. 

2022; 20(7):765-773.e4. doi:10.6004/jnccn.2022.7015

Dale W. Why is geriatric assessment so infrequently used in oncology practices? The ongoing issue of nonadherence to this standard of care for older adults with cancer. 

. 2022;18(7)475-477. doi:10.1200/OP.22.00197

Articles

The publication of the objectively meaningful outcomes in high-impact peer-reviewed medical journals does not necessarily result in the observations being implemented into routine clinical care.

Implementation Research Takes On an Increasingly Essential Role in Oncology

CART-ddBCMA elicited an overall response rate (ORR) of 100% in patients with previously treated relapsed/refractory multiple myeloma (n = 31), according to data from a phase 1 trial (NCT04155749) presented at the 2022 ASCO Annual Meeting.1 Notably, patients achieved responses that were found to deepen over time, according to Matthew J. Frigault, MD.

Among those who responded to treatment, 94% experienced a very good partial response or better rate of 94%, and 71% experienced a complete response (CR)/stringent CR (CR/sCR). Of the 24 patients who had a minimum follow-up of 6 months and a median follow-up of 13.3 months, 92% still responded to treatment at 6 months. Of the 16 patients who had a minimum follow-up of 12 months and a median follow-up of 17.7 months, 94% had an ongoing response at 6 months and 69% were still responding at 12 months.

“CART-ddBCMA appears to be a highly effective, durable CAR T-cell therapy for highly refractory patients with high-risk features,” said Frigault, who is the administrative director of Cellular Therapy Service at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School. “It was [well] tolerated, and the pivotal phase 2 study [NCT05396885] should hopefully recapitulate the findings [we observed] from [the] phase 1.”

, Frigault discussed the findings from a phase 1 trial investigating the safety and efficacy of CART-ddBCMA in patients with multiple myeloma in whom all previous lines of treatment had failed and shared additional research opportunities for the CAR T-cell therapy.

: What was the design of the phase 1 trial evaluating CART-ddBCMA in patients with relapsed/refractory multiple myeloma?

: [At the 2022 ASCO Annual Meeting,] we presented data from the phase 1 trial of CART-ddBCMA; [this was] a first-in-human, dose-escalation study, where we we examined how CART-ddBCMA would work in relapsed/refractory multiple myeloma.

This was [done in] a patient population that had to have been exposed to all 3 major classes of multiple myeloma therapy: [a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody]. They had to have [received] at least 3 prior lines of therapy or be triple refractory, and they needed [to have] measurable disease at the time of treatment.

We [examined the therapy at] 2 dose levels: 100 x 10

 CAR-positive cells. The most impressive component of all this was that we saw an 100% ORR [with the therapy] across both dose levels. These were exciting data, and we look forward to expanding this into a pivotal [phase 2] study.

What else should be known about the population examined in the trial?

This was a heavily pretreated group of patients. They had [received] a median of 5 prior lines of therapy, and they had multiple high-risk features, including high disease burden. In particular, something that we know [correlates with] a poor prognosis for durability of responses, is extramedullary disease; 39% of patients had extramedullary disease at the time of treatment. [Furthermore], 68% of patients were penta-refractory, meaning that they were refractory to all 3 major drug classes, including 2 drugs from 2 of those classes.

Could you expand on the efficacy data reported during the meeting?

We saw impressive findings. [I mentioned that the therapy elicited] an ORR of 100%, [which included] a 71% CR/sCR rate. The interesting thing [to note] is that these responses continued to deepen over time.

Although we had a median follow-up of 12.1 months for the total patient population, if you looked at patients who [had] beyond 12 months [of follow-up], the 16 patients with a median follow-up of 17.7 months, half of those patients had extramedullary disease, which is a higher-risk prognostic factor. Despite that, [69% of those] patients were still in an ongoing response.

We are still waiting for the data to mature, but [this] is promising for these patients.

What were the safety data reported with CART-ddBCMA?

Something that was encouraging was the fact that [CART-ddBCMA] was very well tolerated. Only 1 grade 3 event of immune effector cell–associated neurotoxicity syndrome [(ICANS) occurred in someone who received the therapy at 100 x 10

 CAR-positive cells], which is our recommended phase 2 dose. All [cases of] cytokine release syndrome [CRS] was grade 1 or 2 [at 100 x 10

 CAR+ cells]. CRS [cases] were all managed with tocilizumab [Actemra] and steroids.

Importantly, we did not see any atypical neurotoxicity, [like] the Parkinson-like syndrome that we are seeing with some other BCMA-directed therapies. It is reassuring that this treatment was very tolerated and appeared to be safe.

I am hoping that the pivotal [phase 2] study can begin enrollment by the end of 2022. We have a lot of patients who need highly effective BCMA-directed therapies. Currently, there are not sufficient slots for manufacturing, and there are many patients who would substantially benefit from CART-ddBCMA and other BCMA-directed CAR T-cell therapies.

This product can significantly impact access and could improve outcomes for patients, many of which are passing away prior to getting their slot allocation. I am optimistic to be able to enroll [patients to this] pivotal study and potentially see a new product on the block that can benefit patients.

Frigault MJ, Rosenblatt J, Cook D, et al. Phase 1 study of CART-ddBCMA in relapsed or refractory multiple myeloma. 

. 2022;40(suppl 16):8003. doi:10.1200/JCO.2022.40.16_suppl.8003

Matthew J. Frigault, MD, discusses the findings from a phase 1 trial investigating the safety and efficacy of CART-ddBCMA in patients with multiple myeloma in whom all previous lines of treatment had failed and shares additional research opportunities for the CAR T-cell therapy. 

CART-ddBCMA Generates Deep Responses in Relapsed/Refractory Multiple Myeloma

Pembrolizumab (Keytruda) plus concurrent chemoradiation followed by pembrolizumab maintenance did not lead to a statistically significant improvement in event-free survival (EFS) vs concurrent chemoradiation alone in patients with unresected locally advanced head and neck squamous cell carcinoma (HNSCC), missing the primary end point of the phase 3 KEYNOTE-412 trial (NCT03040999).

At the final analysis of the study, there was a numerical improvement in EFS in patients who received the addition of pembrolizumab, but the results did not meet statistical significance according to the prespecified statistical plan.

Full results from the study will be presented at an upcoming medical meeting.

“There have been limited advances for patients with locally advanced HNSCC and unfortunately, these results suggest that this disease remains very challenging to treat,” Eliav Barr, MD, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said in a news release. “We are proud of the significant role pembrolizumab plays in the treatment of certain later stages of HNSCC, and we are committed to investigating pembrolizumab-based regimens for this debilitating type of cancer in earlier stages of disease. We are grateful to the patients and investigators for their participation in this study.”

KEYNOTE-412 is a randomized, double-blind, phase 3 trial evaluating pembrolizumab with concurrent chemoradiation, followed by pembrolizumab as maintenance therapy for the treatment of patients with unresected locally advanced HNSCC.

 The trial enrolled approximately 780 patients with newly diagnosed oropharyngeal or larynx/hypopharynx/oral cavity squamous cell carcinoma. Eligibility criteria stipulated patients be eligible for definitive chemoradiation, provide tissue for PD-L1 biomarker analysis, and have evaluable tumor burden and an ECOG performance status of 0 or 1.

Patients were excluded if they were currently participating or had participated in a study with an investigational agent or had used an investigational device within 4 weeks of the first dose of study therapy, had received prior therapy with a PD-1, PD-L1, or PD-L2 inhibitor or with an agent directed to another co-inhibitory T-cell receptor; had received a live vaccine within 30 days prior to the first dose of study therapy, and had prior systemic therapy, targeted therapy, radiotherapy treatment, or radical surgery for head and neck cancer.

The primary end point of the study was EFS, and key secondary end points included overall survival and safety.

Investigators randomly assigned to 200 mg of pembrolizumab every 3 weeks in combination with cisplatin and radiation, followed by pembrolizumab as maintenance therapy for approximately 1 year or placebo plus cisplatin and chemoradiation, followed by placebo.

Investigators will continue exploring pembrolizumab alone and in combination with other agents, including in the phase 3 KEYNOTE-689 trial (NCT03765918). Investigators in that trial evaluating the agent for neoadjuvant and adjuvant treatment in patients with resectable locally advanced HNSCC.

Merck provides update on phase 3 KEYNOTE-412 trial in unresected locally advanced head and neck squamous cell carcinoma. News release. Merck. July 20, 2022. Accessed July 20, 2022. 

Study of pembrolizumab (MK-3475) or placebo with chemoradiation in participants with locally advanced head and neck squamous cell carcinoma (MK-3475-412/KEYNOTE-412). ClinicalTrials.gov. Updated July 1, 2022. Accessed July 20, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03040999

Pembrolizumab plus concurrent chemoradiation followed by pembrolizumab maintenance did not lead to a statistically significant improvement in event-free survival vs concurrent chemoradiation alone in patients with unresected locally advanced head and neck squamous cell carcinoma. 

Rapid Reviews in Oncology®: September 2022 | Supplements and Featured Publications

Implementation Research Takes On an Increasingly Essential Role in Oncology

CART-ddBCMA Generates Deep Responses in Relapsed/Refractory Multiple Myeloma

Pembrolizumab Plus Chemoradiation Misses EFS End Point in Head and Neck Squamous Cell Carcinoma