Robert L. Ferris, MD, PhD

This monthly article is usually devoted to highlighting particular discoveries arising in the major journals or the highest-impact oncology meetings throughout the year. But this month, I would like to address the topic of how all these new fi ndings and exciting new data get transmitted into clinical practice for the oncology community at large. Two somewhat interrelated but also different methods are the comprehensive “guidelines” from the National Comprehensive Cancer Network (NCCN) and “clinical pathways.” 

These 2 approaches are similar in that they refl ect the most recent data and trial results but begin to diverge in terms of application because NCCN guidelines often permit multiple and sometimes many different therapeutic options, without a particular advocacy toward one approach or modality over the other. Surgical therapy may be equally permitted as well as nonsurgical-, radiation-, or chemotherapy-based regimens. 

Clinical pathways, on the other hand, are more instructive and try to distill the available therapeutic or diagnostic options down to one primarily recommended treatment selection. Usually, 3 parameters in the prioritization hierarchy determine the most-recommended approach: oncologic effi cacy, toxicity, and cost.

Pathways are very useful for health systems and cancer centers to monitor quality, and compensation may be—to some degree—linked with quality metrics, such as the “on pathway” rate. These decision-support tools are often mandated or incentivized by health insurers and major clinical networks. Some standard-of-care recommendations, such as cellular immunotherapies, may be on a pathway but require referral to another specialized center, adding complication because a referral to another center may create a negative impact on the established physician-patient relationship.

Nonetheless, the value of pathways is inarguable and permits health systems to stimulate a periodic conversation with their oncologists if they fall below the 80% or 90% on-pathway rate. It also may facilitate clinical research by permitting the oncologist to write a free text explanation for why the clinician went “off pathway,” and this may lead to the development of clinical trials in the phase 4 or pragmatic arena.

Thus, there is a role for these overlapping entities—guidelines and pathways—and each permits fl exibility for the oncologist for available treatment options in the level and quality of data. The public expects and demands that we are held to externally verifi able treatment algorithms. This does not mean that we practice cookbook medicine, but rather, that we can defend and justify our decisions with suffi cient fl exibility to personalize and individualize our treatment choices with the patient at the center of the relationship.

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There is a role for these overlapping entities—guidelines and pathways—and each permits flexibility for the oncologist for available treatment options in the level and quality of data.

Guidelines vs Pathways and Their Place in Oncology Practice

It is well accepted that for most cancers across settings, the use of combination therapies is the standard of care to maximize outcomes. Indeed, clinical trials evaluating conventional modalities such as chemotherapy with or without radiation in the definitive or postoperative adjuvant setting have focused on most efficacious combinations. Using combination treatments in the concurrent setting with chemotherapy, radiation therapy, or small molecule oncogene and pathway inhibitors may yield positive data in one setting but not another. 

Innovative developmental trial designs are necessary and results often get presented at disease-specific meetings like the recent 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers (GI) Symposium or the ASCO Genitourinary (GU) Cancers Symposium. The proliferation of trial acronyms that companies use to develop their trial portfolios (TOPAZ, HIMALAYA, CIRCULATE, etc.) reflects the many phase 2 and phase 3 clinical trials. These symposia focused on combinations of PD-1 inhibitors with radiation, chemotherapy, or targeted inhibitors in the preoperative neoadjuvant setting or postoperative setting for high-risk disease. Furthermore, findings were widely presented in locally advanced or recurrent, chemotherapy-refractory disease. 

Overall, trials discussed at these 2 symposia, and detailed in this issue, have reported novel findings using various combinations of IO and small molecule inhibitors, showing that the promise of targeted immunotherapy and genomeguided oncology drugs is rich with new findings and trial designs. 

Quite reassuringly, positive data are being seen in early-phase combinations, which bodes well for clinical outcomes in GU and GI cancers. Indeed, improvements in survival with add-on strategies—which are additive or synergistic—are needed to harness the power of greater biological understanding of disease, addressed through cancer immunotherapy and precision oncology. 

I recommend reviewing the results of phase 2 and phase 3 randomized trials from the recent disease-specific GI and GU symposia, which are well reported in this issue. These trials contain a wealth of exciting findings and provide a paradigm across other cancers for integrating these novel biologically driven therapies with the conventional regimens and modalities we have used for years. 

As we appear to be emerging from the pandemic, it is reassuring that scientific advancements and clinical investigation have kept up and are continuing the progress forward for our patients.

Using combination treatments in the concurrent setting with chemotherapy, radiation therapy, or small molecule oncogene and pathway inhibitors may yield positive data in one setting but not another. 

Promising Approaches That Use Targeted Therapy Combinations Are Explored at GI, GU Symposia

We continue to observe the steady pace of drug development, which employs rational combinations based on preclinical science and biology paired with promising small developmental trials. Fortunately, innovative agents are still able to emerge, allowing for progress through further clinical evaluation even when early trial results are equivocal. From the European Society for Medical Oncology (ESMO) Immuno-Oncology (IO) Congress 2021, 1 particular trial deserves mention as an exemplar. In head and neck squamous cell carcinoma (HNSCC) there has been a drought of recent positive trial data. Although further IO combinations with doublet immune checkpoint inhibitor combinations continue to be tested, a different strategy targeting natural killer (NK) cells has shown promise.

Findings from the phase 1/2 clinical trial IPH2201-203 (NCT02643550) showed a confi rmed objective response rate (ORR) of 32.5% for all patients, regardless of PD-L1 status, and the unconfi rmed ORR was 50% [page 31]. This result compares favorably with the CheckMate 651 trial (NCT02741570) or pembrolizumab (Keytruda) plus chemotherapy in the KEYNOTE-048 trial (NCT02358031). The combined positive score of PD-L1 greater than 1 was 63% vs 80% in other trials, so this was not necessarily a cohort that was highly immune responsive. A combination of cetuximab (Erbitux) and monalizumab that blocks an inhibitory receptor in NKG2A on NK cells had previously shown activity in recurrent or metastatic HNSCC and in a separate cohort of patients who were PD-1 refractory. Given these exciting early data, the cetuximab and monalizumab combination appears to be enhanced with the addition of durvalumab (Imfi nzi). Indeed, durvalumab is not approved for HNSCC despite indications of its activity in first- and second-line trials that were negative overall. Durvalumab had “failed” in prior HNSCC phase 3 trials, though a glimmer of activity was observed. This example of developing new immunobiology translating to the clinic is innovative because it does not simply rely on a new T-cell targeted immunotherapy but rather on harnessed NK cells, long felt to be key antitumor immune effectors and helper cell.

Buttressed by the promising data from those trials of development of activity in HNSCC, AstraZeneca saw enough activity to remain enthusiastic about prospects for durvalumab, used here as a triplet IO regimen. This is a model for the fi eld to progress multiple antibody combinations and possibly re-introduce specifi c agents which had not succeeded alone in other trials but may leverage other target assets using rational biological combinations. 

According to Robert L. Ferris, MD, PhD, there is a steady pace of drug development for head and neck cancers despite modest findings with durvalumab triplet.

Lukewarm Outcomes for Durvalumab in HNSCC Don’t Deter Triplet IO Combinations

It's a time for reflecting from an academic and educational standpoint in the field of oncology and translational and clinical research. I recently attended 2 meetings, the Society for Immunotherapy of Cancer (SITC) and the 6th Annual International Congress on Immunotherapies in Cancer®: Focus on Practice-Changing Application, sponsored by Physicians’ Education Resource® (PER®).

SITC was held at the Washington, DC, convention center and the PER® meeting was held in New York City. In my view, as an attendee and invited speaker, both meetings were a success. A wonderful series of presentations was accompanied by the usual and enjoyable human interaction between colleagues and friends. The scientific presentations were focused on new cellular therapies and chimeric antigen receptor (CAR) cells using T cells and NK cells. We remembered the giants of immunotherapy, Thomas A. Waldmann, MD, and Martin “Mac” Cheever, MD, who had passed somewhat unexpectedly in the previous months. Crystal L. Mackall, MD, received the Richard V. Smalley Memorial Award and Lectureship.

I point out these details to indicate how important human interaction is to cancer research and treatment. But a whole generation of trainees has been missing someone walking by their poster or listening to their presentation and providing key feedback that they would never get without an in-person meeting.

The PER® immunotherapy meeting was focused on immuno-oncology advances across multiple cancers and was led by Drs Mario Sznol and Charu Aggarwal. I learned a great deal from the faculty and also from the attendees who posed questions from the floor microphones.

A number of attendees participated virtually, and I give great credit to the IT groups of both meeting organizers for the accommodations to expand participation in the hybrid portion of the meetings. However, I believe those attendees who have participated virtually in the past, myself included, are still missing something. What about our colleagues who may think that it is cheaper and easier to stay in Europe or Asia or even on the other side of our vast United States and open up a browser window to hear a single talk, as opposed to seeing an old friend, developing a new collaboration, or networking to advance their own or one of their mentees’ careers?

I really hope that we de-emphasize and, possibly, maintain some hybridformat conferences but offer, perhaps, a discount or some enticement to those who attend in person. These in-person interactions enrich and eventually improve the outcomes that we are able to provide to our trainees, and thus to patients and the field of oncology.

In-person interactions enrich and eventually improve the outcomes that we are able to provide to our trainees, and thus to patients and the field of oncology.

Are Virtual or Hybrid Meetings Now Permanent? The Virus Is Not Going Away

A saying frequently mentioned in oncology, often attributed to Hippocrates, is “Cure sometimes, help often, comfort always.” This sentiment has driven physician behavior for centuries and is even more true in an era of unprecedented success in cancer treatment. The issues related to the recently expanding field of survivorship exemplify what patients must endure because of the (successful) oncologic efficacy of curative therapy. These patients have come from different cancer types over the years primarily due to the identification of good prognosis disease subsets such as in breast cancer, HPV-positive head and neck cancer, and other types with a more indolent disease course. In those areas, the recognition of treatment-associated toxicity has motivated large-scale clinical trials aimed at maintaining high oncologic efficacy while de-escalating therapy in terms of less surgery, reduced radiation dose and fields, and substituting chemotherapies for less toxic agents.

Now, due to tremendous success of precision oncology and genomics-guided medicine as well as the highly successful cancer immunotherapy field, with durability of the survival tail on the Kaplan-Meier curve, survivorship has emerged in previously incurable patients with metastatic melanoma, advanced lung cancer, and renal cell carcinoma, as well as other cancer types. Thus, patients are now “afflicted” with the desirable, though no less difficult, challenges of survivorship. These include decreased function and quality of life in major organs, anxiety associated with cancer recurrence, and in some situations, death from other causes, sometimes treatment-related.

Due to these advances and the areas affected by survivorship, overlap with this emerging field, driven by sophisticated palliative care professionals has become commonplace. Palliative care itself has become a specialty measuring “outcomes” beyond providing comfort, pain management, and hospice care, as well as instructing clinicians on how to intervene and strategies to ameliorate some of these maladies associated with survivorship.

Further, oncologists and their patients may view successful oncologic therapy and improved survival outcomes differently if the quality of the life extended is not one associated with the expected quality or functional capabilities. However, this is a problem worth investigating and oncologists and palliative care experts now need to develop interventions and hopefully pre-habilitative strategies to ensure that our patients get the right treatment at the right intensity at the right time, since once the treatment-related chronic toxicities set in, they are difficult to reverse. Nonetheless, the field is bright because survivorship requires surviving one’s cancer, which is increasing encouragingly. The field is ripe for preventing the undesirable long-term effects of cancer treatment or reducing them altogether through de-intensification. Thus, survivorship is not a goal but rather a process and journey and will certainly lead to better quality of life and not just extended life spans.

The field is ripe for preventing the undesirable long-term effects of cancer treatment or reducing them altogether through de-intensification, according to Robert L. Ferris, MD, PhD.

Expanding Role of Survivorship Is Related to Increasingly Successful Treatment Approaches

In reviewing the recent progress from the European Society of Medical Oncology Breast 2021 Virtual Congress, a number of abstracts presented data that focused on diagnostic, therapeutic, or other biological investigations around the HER2 receptor and its associated growth factor pathway. It struck me as exciting and gratifying for the fi eld of biologically driven, precision oncology that the discovery of such a marker protein, the HER2 receptor and the ErbB family, is still a major area of investigation and fruitful benefit in the clinic for patients. 

The abstracts presented in this issue of 

 focus on neratinib (Nerlynx) as an irreversible HER2 inhibitor with therapeutic potential. Other research looked at the possibility of less intense trastuzumab (Herceptin), the anti-HER2 monoclonal antibody that has been approved for some decades, in the adjuvant setting.

Discoveries made in the mid-to-late 1980s by Drs Dennis Slamon and Stuart Aaronson involving the HER2 family have led to a number of advances: a subset of patients eligible for targeted therapies, biological tumor classification, and even antibody-drug conjugates, which deliver a payload using this targeted receptor for concentration of toxic chemotherapy. Indeed, genomic guidance based on mutations or copy number alterations is another way that we can diagnose and potentially track patients with circulating tumor DNA. So, looking back on the 30 to 40 years since the HER2 protein and its relevant oncogenic pathway were discovered, it is amazing that we are still actively investigating the therapeutic potential and the true evidence for precision oncology and biology-based cancer treatment.

It has taken some decades, but the identification of targets such as HER2 has enabled us to segregate cancers into different subtypes, develop novel therapeutic strategies, and eventually understand the biology distinguishing one group of patients from another. Furthermore, as we deploy our therapeutic weapons at the cancer cells, we need to have some specific target to shoot at—and this was one of the first. Understanding tumor heterogeneity and the role of individual pathways is commonplace now in the 2020s. However, thinking about how far we have come since the late 1980s reinforces that this is the correct path for translational science and many patients are benefiting. But what is equally intriguing is how much more we have to learn as clinical trials are still testing nuances of subgroups defined by HER2 in breast cancer and the ErbB family across many other solid tumors. The path is long, but progress is happening faster and faster.

It has taken some decades, but the identification of targets such as HER2 has enabled us to segregate cancers into different subtypes, develop novel therapeutic strategies, and eventually understand the biology distinguishing one group of patients from another, says Robert L. Ferris, MD, PhD.