Cancer's New Horizon: Promising Developments for a Brighter Future
Peter J Sciavolino, PhD, Director, Medical Writing and Scientific Content, Total Health
In my 25 years working as a freelance medical writer and consultant in medical education, the words ‘hopeful’ and ‘cancer’ have not frequently gone together in a sentence, but over the past two years, more than one of our esteemed faculty contributors at Total Health has described the outlook in their subspecialty of oncology as just that, hopeful. While the specter of cancer and its fearsome implications will undoubtedly continue in our lifetimes, and the thought of an absolute ‘cure’ or living in a world free of cancer remains about as probable as world peace, there is indeed much to be hopeful about. Over the past 2 years, we have witnessed remarkable advances that are unquestionably helping to lengthen life, and perhaps more importantly, improve quality of life, for individuals living with, and after cancer. As such, it behooves us to review and reflect on how just far the field has come from just a decade or two ago, when chemotherapy, more often a cure that is worse than the disease itself, was the rule, as opposed to the exception.
Cancer became all too real to me two years ago, when my wife of 20 years was diagnosed with a stage I breast cancer, and while her prognosis is excellent, and her course of treatment far less complicated than others, I felt extremely fortunate to have the knowledge and experience in oncology to be with her for all the pivotal appointments, and ask all the right questions when appropriate. Indeed, those individuals living with and after cancer today need to be more educated and informed about their disease than ever, and in a fair and unbiased manner. At Total Health, we believe that knowledge is power, and, while the medical education field has typically been about educating the oncology healthcare team, we are also striving in our ongoing initiatives to raise the largely unheard patient voice.
What Was New at Total Health
The past 2 years of medical education conferences at Total Health have featured our regular lineup of review sessions for the annual American Society of Clinical Oncology (ASCO) meeting, and our second year hosting the official review conferences in the United States for the European Society of Medical Oncology (ESMO) Congress. We also continued our local Community Oncology Educational Dinner Series (COEDS) program in South Florida, and our annual conferences with the West Oncology group, the University of Kansas Breast Cancer Year in Review, and the Oncology Nursing Society, Metro Denver Chapter (MDONS). Our Best of Breast and Best of Lung conferences, and our Community Cases programs also featured not only didactic content, but interactive case-based clinical discussions for community oncologists across several major cities, including Atlanta, Tampa, and Memphis. Highlights from many of these discussions can be accessed for free on our YouTube and Facebook pages. In addition, we featured several new educational initiatives over the past 2 years, the SEEK Color certificate program, focusing on strategies to address and reduce disparities in cancer care in minority populations, and T-Talks, a thrice-weekly program presented live on LinkedIn featuring a wide range of guests including leading experts in cancer care and survivorship, patient advocates, and cancer survivors.
One of our new initiatives over the past 2 years has also been what we call the “plain language summary”. With these summaries, we hope to convey some of the highlights from our clinically focused conferences in a more patient-friendly tone, and provide the oncology care team with language that promotes better engagement and patient understanding, and facilitates shared decision making. From that perspective, I review some of the most important developments in oncology over the past 2 years, with a focus on “the big five” – the five most prevalent subtypes of cancer across the world.
Hot Topics in Cancer 2022 - 2024: A Brief Overview
Some of our most important recent developments in cancer can be broadly grouped into categories, including immunotherapy, a class of therapies designed to help the body’s immune system more efficiently recognize cancer cells and target them for destruction, targeted therapies, which are designed to specifically inhibit a molecular alteration in the cancer cell that drives its uncontrolled growth and proliferation, antibody-drug conjugates (ADCs), which combine a cancer cell-targeting antibody molecule with a cytotoxic drug payload, and what are known as “biomarkers”, or molecular tests which can be used to assess some of the critical parameters in cancer treatment, such as risk for recurrence (and therefore a need for treatment escalation and/or the use of adjuvant therapy to reduce the risk for recurrence) as well as the likelihood that a given patient will respond to a specific type of therapy. Biomarkers can also be useful to determine whether a patient might have an inherent (“de novo”) resistance to a specific type of therapy, or to determine whether they have developed resistance to a given therapy during treatment (“secondary resistance”). Poly ADP ribose polymerase (PARP) inhibitors, have also been a hot topic of discussion recently. PARP inhibitors are used in cancer patients who have specific genetic mutations, such as those in the BRCA genes and others, which are involved in DNA homologous recombination repair (HRR), and as such, tumors in these individuals can be very specifically targeted by PARP inhibition.
Breast Cancer
The key biomarkers in breast cancer which must be assessed at diagnosis are estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Patients with breast tumors that are hormone receptor positive (HR+) have detectable levels of ER and/or PR, and as such are candidates for endocrine therapy, which is aimed at reducing estrogen levels and/or blocking the growth promoting actions of estrogen. Tumors that are HER2 positive (HER2+) have an alternative pathway for growth, which can be inhibited by anti-HER2-directed therapies such as trastuzumab (Herceptin) and other therapies. Most breast tumors are HR+/HER2- (luminal A subtype), about 10% are triple positives, with both hormone receptors and positive HER2 expression (ER+/PR+/HER2+) and about 10-15% are triple negative (ER-/PR-/HER2-). In the past, triple negative breast cancers (TNBCs) were, by definition, the subtype least amenable to treatment, but fortunately, treatment options have expanded dramatically over the past few years. Another recently appreciated aspect of breast cancer is the so-called ‘HER2-Low’ subtype which has lower, but still detectable levels of HER2 expression, as defined by specific molecular criteria. While the biologic characteristics of HER2-Low breast tumors have yet to be fully elucidated, we now have treatments that have shown efficacy for patients with this subtype of breast cancer, and this has been an important advancement, paving the way for newer and more individualized treatment paradigms.
Talking breast cancer in one of our 2023 T-Talks with Dr Elyse Lower, Emerita Professor from University of Cincinnati.
For patients with HR+/HER2- early breast cancer, the principal types of endocrine therapy (ET) are the aromatase inhibitors (AIs) and tamoxifen, a selective estrogen receptor modulator (SERM). Secondary treatment resistance can occur after prolonged ET because of mutations in the ER gene, ESR1; this is particularly true for patients with metastatic disease who have already received ET using an AI. For patients who progress on ET, options also include the cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), such as palbociclib, ribociclib, and abemaciclib, as well as selective estrogen receptor degraders (SERDs) such as fulvestrant, which bind to the ER, and in so doing cause it to be degraded. In 2023, we saw the approval of elacestrant, an oral SERD which offers significant benefit in terms of route of administration over first-generation agents like fulvestrant, which need to be given intramuscularly. Importantly, elacestrant has shown efficacy in the clinically relevant group of patients with ESR1 mutations and in those with progression after ET + CDK4/6i, which has been a high unmet need. Other oral SERDs such as camizestrant are also under investigation in phase III trials with further approvals expected.
Dr Reshma Mahtani from Miami Cancer Institute discussed the oral SERDs at the 2023 Community Oncology Educational Dinner Series (COEDS).
For younger patients with early breast cancer, we have seen results from the POSITIVE trial which show that attempting pregnancy after a breast cancer diagnosis is safe; patients can interrupt their adjuvant ET for approximately 1 year, with similar outcomes including breast cancer free interval (BCFI) and distant recurrence free interval (DRFI) as compared to women who did not interrupt their treatment. In addition, there was no apparent impact on breast cancer recurrence for patients who did get pregnant versus those who did not. The findings offer hope for premenopausal patients who wish to bear children in the face of a breast cancer diagnosis.
Biomarker tests, such as the OncotypeDx recurrence score (RS) and others, continue to provide important prognostic information on a patient’s risk of recurrence, and, in combination with clinical factors such as tumor size, can be used to inform treatment decisions such as the need for adjuvant chemotherapy in early breast cancer. For patients with HR+/HER2- early breast cancer with high risk features, results presented this year found that the use of adjuvant CDK4/6i (abemaciclib) in combination with ET improved critical outcomes such as invasive disease free survival (IDFS) and distant recurrence free survival (DRFS), and importantly the benefit persisted after 4 years, even after the cessation of CDK4/6i treatment 2 years prior. The CDK4/6i + ET combination also plays an important role in HR+/HER2- advanced/metastatic breast cancers. In the SONIA trial, for example, the CDK4/6i + ET combination was more effective as a first line treatment than combination chemotherapy for patients with symptomatic visceral disease (e.g., lung or liver metastases), although to date, only ribociclib and abemaciclib have shown an overall survival (OS) advantage in this setting.
It is thought that about half of patients with metastatic breast cancer (mBC) may be categorized as ‘HER2-Low’ as mentioned earlier, and results from DESTINY-Breast04 presented in 2023 have now demonstrated efficacy for the ADC trastuzumab-deruxtecan (T-DXd) in this subgroup of patients. While interstitial lung disease (ILD) and pneumonitis are important adverse events to consider with T-DXd and other agents in the ADC class of drugs, with increasing use, clinicians are learning to better monitor and manage these events. In this regard, it is notable that the overall rate of serious ILD/pneumonitis with T-DXd has been decreasing. This year, we also saw results from a pooled comparative analysis of treatment-emergent Grade 3 or higher adverse events (TEAEs) in older (> 65) versus younger (< 65) patients treated with T-DXd. It was reassuring that, despite a trend toward more adverse events in those > 65, and > 75 years, T-DXd showed an acceptable safety profile when used in these older populations.
Sacituzumab govitecan (SG) is another ADC with a distinct target, TROP2. Results from the TROPiCS-02 trial have shown that SG is superior to treatment of physician’s choice (TPC) for both progression-free survival (PFS) and OS endpoints in a heavily pretreated population (up to 4 prior lines of therapy) of patients with HR+/HER2- mBC. It was also reassuring that a benefit of SG over TPC was seen even in patients with very low levels of TROP2 expression. ADCs are also improving outcomes for patients with HER2 positive disease. We saw additional results this year from the Destiny-Breast 03 trial with significantly improved PFS, as well as OS, with T-DXd over an earlier generation ADC, trastuzumab-emtansine (T-DM1). This has established T-DXd as the new standard of care as a second line agent for HR+/HER2+ breast cancer following 1 to 2 prior lines of chemotherapy and anti-HER2 therapy. In fact, it has been estimated by at least one expert that, based on the available data, a patient with HER2+ mBC might expect a median survival in excess of 8 years.
Dr Lee Schwartzberg from Renown Cancer Institute answered “Burning Questions in Breast Cancer“ at the 2023 Total Health Spring Oncology Review and Renew Conference
One of the central themes emerging for patients with TNBC is that different subtypes of TNBC are being recognized, which may have different biologic features. Approximately 40% of TNBCs, for example, have expression of the immunotherapy biomarker, programmed death ligand 1 (PD-L1) and as such, are candidates for treatment with immunotherapy in combination with chemotherapy. Other TNBC patients may have mutations in the breast cancer associated genes, BRCA-1 or BRCA-2, and these patients are candidates for treatment with PARP inhibitor therapy. Targeted therapies are also becoming available for metastatic TNBC patients with less commonly observed molecular alterations such as NTRK gene fusions and others. As such, molecular testing using next-generation sequencing (NGS) methodologies is becoming increasingly important to evaluate treatment options for patients with metastatic TNBC.
A novel ADC, datopotomab deruxtecan (Dato-DXd) has also shown promise for patients with advanced and heavily pretreated TNBC, based on findings from the TROPION-PanTumor01 study, and the TROPION-Breast-02 study which specifically evaluates the efficacy and safety of Dato-DXd as compared to chemotherapy in patients with metastatic TNBC. The BEGONIA study also examines the impact of combining immunotherapy (durvalumab) with various novel therapies, such as the ADCs T-DXd and Dato-DXd for first line treatment of metastatic TNBC. Results from BEGONIA reported thus far suggest that combining durvalumab-based immunotherapy with ADCs can enhance their efficacy and durability of responses without enhancing toxicity.
There is also evidence in TNBC that adding immunotherapy to standard of care neoadjuvant (pre-surgery) chemotherapy (NAC) can improve the rate of pathologic complete response (pCR), which usually leads to better outcomes. For example, results from the KEYNOTE-522 trial show a significant improvement in event-free survival (EFS) for patients receiving immunotherapy with pembrolizumab in combination with NAC independent of PD-L1 expression, and regardless of whether they had achieved a pCR. Although many unanswered questions remain, such as the optimal duration of immunotherapy in patients who achieved a pCR, the integration of immunotherapy into neoadjuvant therapy provides an expanding range of options for TNBC patients with high-risk early stage and metastatic disease.
Prostate Cancer
The past 2 years have also seen strides in treatment for prostate cancer (PC), the second most commonly diagnosed, and the second most common cause of cancer death in men. Like breast cancer, PC is hormonally driven, and androgen deprivation therapy (ADT), or chemical castration, remains a cornerstone of treatment for prostate cancer. As such, PC can be broadly grouped into disease that is castration sensitive (CSPC), or castration resistant (CRPC), the latter of which has acquired resistance to subsequent anti-androgen treatment. Metastasis in PC (i.e., spread beyond the primary site) can also be grouped into disease that is synchronous, or present at the time of diagnosis, or metachronous, meaning developing at a later time in an initially treated PC patient. Patients with synchronous or “de novo” metastases at initial presentation, have a poor prognosis, and surgery is currently not recommended in these patients due to the risk of complications, as described below. Prostate-specific antigen (PSA) assessment remains the major method of screening for PC. PSA is also a biomarker for the overall disease burden, and an indicator of recurrence in PC (also referred to as a ‘biochemical recurrence’ or ‘PSA progression’). Treatment and staging of metastatic disease in PC has also been greatly impacted recently by the next-generation imaging technique of prostate-specific membrane antigen positron emission tomography (PSMA-PET). The purpose of PSMA-PET is to help stage prostate cancer patients with intermediate to high risk for metastases, to find early metastatic sites that may be amenable for treatment in the case of a biochemical recurrence, and lastly, to identify patients with early metastatic (‘M1’) prostate cancer who may be candidates for targeted treatments.
Dr Bruno Bastos from Miami Cancer Institute presents updates from the ESMO Congress at our first ESMO East review conference in 2022.
Combined ADT using “next generation” androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide, is indicated for patients with metastatic (M1) castration-sensitive prostate cancer (CSPC). Some of our case-based presentations in 2023 highlighted the use of metastasis directed therapy (MDT), which may be a better option than just observation for metastatic PC patients having a low disease burden (e.g., 1 or 2 metastatic sites), based on phase II data from the ORIOLE and STOMP trials. We also saw a case based discussion focused on younger PC patients (e.g., 63 years) with high risk features but without metastases (i.e., ‘M0’ patients). For such patients, results from trials such as STAMpede have suggested that combination ADT with leuprolide, in addition to abiraterone and prednisone, followed by definitive radiotherapy (RT) to the prostate gland significantly improves OS and metastasis free survival. The results established this regimen as the current standard of care, and an alternative to radical prostatectomy (removal of the prostate), which poses a significant risk for complications such as urinary obstruction and sexual side effects, particularly for a younger patient. The PEACE-1 trial also examined the impact of adding RT and abiraterone to standard of care (SOC) ADT in patients with “low volume” metastatic PC (defined as fewer than 4 bone metastases, and no visceral metastases). The results showed that RT improved radiographic PFS (rPFS) when added to abiraterone and SOC, but not when added to SOC treatment alone. Although not statistically significant, overall survival (OS) was also numerically improved with the triple combination.
One of the most effective treatments to emerge in recent years for prostate cancer is Lutetium 177Lu-PSMA-617 (Pluvicto), which specifically targets metastatic castration-resistant prostate cancer (mCRPC) which expresses PSMA. Results reported this year from the phase II ENZA-p trial compared the use of first line enzalutamide, an antiandrogen drug, and the current standard of care, in combination with 177Lu-PSMA-617, versus enzalutamide alone, in patients with mCRPC having poor risk features. The rationale for this trial was based on the finding that some patients receiving enzalutamide alone as a first line treatment are “early progressors” and progress within the first 3 months. In addition, it was known that enzalutamide causes an initial upregulation of PSMA expression on prostate cancer cells, which, in turn can be targeted and killed with 177Lu-PSMA-617. Results from ENZA-P showed a near doubling of the primary endpoint, PSA progression free survival (PSA-PFS) with the combination treatment versus enzalutamide alone. There was also a benefit of the combination on the PSA response rate (RR), and patients continue to be followed for PFS and OS endpoints.
Previous findings from the VISION trial showed that 177Lu-PSMA 617 improved the endpoints of both radiographic PFS (rPFS) and OS in patients with mCRPC who had received prior chemotherapy with docetaxel. Importantly, the trial showed a relationship between the overall PSA response and rPFS, such that for patients with a PSA decline of > 90%, the rPFS was increased more than 5.5-fold compared to those with no decline in their PSA. As such, a lack of PSA drop after 2 doses (12 weeks) of 177Lu-PSMA 617 provides an early indicator that the patient is not responding, and other treatments might be considered. The PSMAFore trial also examined the use of 177Lu‑PSMA‑617 for mCRPC patients who had not received a prior taxane chemotherapy for their disease (e.g., docetaxel). Results for the primary endpoint of rPFS reported at ESMO 2023 showed a significant benefit of 177Lu‑PSMA‑617 treatment versus changing their androgen receptor pathway inhibitor (e.g. changing from enzalutamide to abiraterone). There was also a benefit of 177Lu‑PSMA‑617 in overall response rate (ORR) and health related quality of life (QoL) measures and the overall safety profile was manageable.
Our 2023 Community Cases Conference held in Tampa, Florida featured case presentations focusing on different clinical scenarios in prostate cancer. The discussion was moderated by Dr Jingsong Zhang, MD, PhD, from the Moffitt Cancer Center, and also featured Dr Juskaran Chadha, DO, and Sarah Raymond, PA, from the Moffitt Cancer Center.
In 2022, just prior to their induction into the Rock and Roll Hall of Fame, the guitarist from one of my favorite 1980’s rock bands, Duran Duran, Andy Taylor, revealed he had stage IV prostate cancer, and he noted he was beginning treatment with 177Lu‑PSMA‑617 in 2023. For Taylor, and most others with de novo metastatic prostate cancer, they would typically progress through initial anti-androgen treatments and then move on to more advanced therapies once their disease had become resistant to hormonal therapy. As noted earlier however, for patients with PC and metastases at the time of diagnosis, outcomes are significantly worse, and as such, there has been an effort to incorporate more effective targeted treatments for metastatic disease earlier in the treatment plan. Results from these trials with 177Lu‑PSMA‑617 offer the possibility for de novometastatic PC patients like Andy Taylor to possibly incorporate life extending therapies for metastatic disease earlier in the course of treatment and may ultimately change treatment paradigms for patients initially presenting with metastatic PC.
Targeted treatment is also expanding options for patients with mCRPC and specific mutations. The TALAPRO-2 trial, for example, examined the use of enzalutamide (an oral nonsteroidal antiandrogen medication) in combination with talazoparib, a PARP inhibitor, in patients with mCRPC and germline mutations in HRR genes, such as the BRCA genes, ATM, and CDK12. Results reported this past year showed a significant benefit of the combination treatment over enzalutamide alone for the endpoint of rPFS. While a benefit was seen across all subgroups of patients, regardless of disease stage, and prior treatments, it was most prominent for those patients with BRCA1 or BRCA2 mutations. A three-year update of the phase III MAGNITUDE trial was also presented at ESMO 2023, which compared the use of first line niraparib (NIRA), another PARP inhibitor, in combination with abiraterone acetate + prednisone (AAP) for patients having mCRPC with HRR gene mutations and BRCA mutation positive (BRCA+) mCRPC. Previously reported primary analysis from MAGNITUDE demonstrated a significant improvement in rPFS with NIRA + AAP, as compared with placebo + AAP. The final analysis for OS showed a significant benefit of niraparib over placebo for patients with BRCA+ mCRPC. Based on the results of MAGNITUDE and subsequent FDA approval of the regimen for BRCA+ mCRPC patients, regimen is currently standard of care.
Lastly, updated results from RADICALS-RT were also reported at ESMO 2023. This was the largest trial examining outcomes following radical prostatectomy (RP) for patients treated with adjuvant (post-surgical) radiotherapy (RT) as compared to salvage RT (performed only after PSA levels start to rise). The results showed no significant difference in outcomes for critical endpoints such as OS and distant metastases with adjuvant RT after RP, relative to watching the patient carefully and performing RT only after PSA levels start increasing. By comparison, there was a higher incidence of events like cystitis, hematuria, and urethral stricture, as well as gastrointestinal events with adjuvant versus salvage RT. Results from RADICALS-RT thus offer the possibility for patients with PC to avoid these complications of RT after prostatectomy with equally favorable outcomes.
Lung Cancer
As a young child, I remember the image of my uncle, an avid smoker, essentially on his deathbed with advanced lung cancer - the profound weight loss, or cachexia, and visually striking hair loss - ravages not so much of the disease itself but the platinum-based chemotherapy that had been used to treat it. Today, while platinum doublet chemotherapy remains one of the principal treatments for advanced non-small cell lung cancer (NSCLC), the most prevalent subtype, the advent of effective and significantly less toxic treatments such as targeted therapy and immunotherapy have helped to dramatically improve survival. In many ways, lung cancer has become the model for targeted therapy, most commonly with small molecule tyrosine kinase inhibitors (TKIs), which are designed to inhibit a specific molecular alteration within the tumor that allows it to grow uncontrollably.
In the 1990’s, TKIs targeted to the epidermal growth factor receptor (EGFR) pathway became an essential component of treatment for patients whose tumors had mutations, or DNA changes in the EGFR gene (EGFRm). Today, third-generation, EGFR TKIs are more specifically targeted to mutant EGFRs, importantly, with less “off target” side effects. The result is better efficacy and greater long term tolerability with adjuvant treatment. This past year, for example, we saw updated results from the phase III ADAURA Trial, which examined the use of a third-generation EGFR inhibitor, osimertinib, or placebo, as adjuvant (post-surgical) treatment for three years in patients with successfully resected stage IB – IIIA EGFRm NSCLC. Results from ADAURA reported at ASCO showed that three years of adjuvant osimertinib significantly improved OS over placebo. Accordingly, osimertinib has become a new standard of care for first line treatment of patients with EGFRm NSCLC.
“Conversations for Change“: Dr Jason Porter from West Cancer Center discussed the importance of encouraging lung cancer screening at our 2023 Primary Care to Oncology DEI program in Memphis, TN.
This past year we also saw results from several trials examining the use of other novel targeted agents. Results from the CodeBreak 200 study, for example, examined the efficacy of sotorasib, a ‘first in class’ targeted therapy for patients with the KRAS G12C molecular alteration, which has been difficult to target with drug therapy. Patients in the study had relapsed on a prior therapy and were treated with sotorasib or chemotherapy (docetaxel). Results showed a more than doubling of PFS with sotorasib versus chemotherapy, and a benefit was observed across all relevant subgroups of patients. Important endpoints like overall response rate (ORR), disease control rate, and duration of response were also better with sotorasib, and there were fewer adverse events of Grade 3 or higher. The drug also offers substantive benefit over chemotherapy, being an oral therapy which can be taken at home and does not require an infusion. Also, in light of the practice-changing results from ADAURA mentioned above, a significant unmet need in the metastatic NSCLC setting has been what to do for patients who progress on first line anti-EGFR therapies such as osimertinib. In this regard, we also saw results from the INSIGHT-2 trial which examined the efficacy of another TKI, tepotinib, in combination with osimertinib, as treatment for those patients who progress after first line (1L) osimertinib and who also have a specific molecular alteration called MET amplification (METamp). While not yet FDA-approved, results of the trial showed that the combination therapy was an active oral regimen for patients with EGFRm and METamp who progress after 1L osimertinib, potentially allowing these patients to be spared chemotherapy.
Third generation TKIs targeting the anaplastic lymphoma kinase, or ALK pathway, such as lorlatinib, are also emerging in NSCLC. Like the EGFR-targeted therapies, these agents have better on target specificity for ALK with lower toxicity, better efficacy for patients with secondary resistance mutations in the ALK gene, and importantly, better penetrance of the drug into the central nervous system (CNS) for patients with brain metastases. Studies comparing 1st and 3rd generation ALK inhibitors, such as CROWN have shown significantly improved PFS, and like osimertinib, efforts are underway to move these advanced 3rd generation agents to an earlier space in the course of treatment. Sunvozertinib is a new targeted therapy for patients with advanced NSCLC with EGFR exon 20 type insertions (exon20ins), which has shown encouraging efficacy for patients who progress after platinum-based chemotherapy. This agent also shows efficacy in patients with baseline brain metastases and a phase III trial comparing sunvozertinib to platinum based chemotherapy is underway in patients with advanced NSCLC and exon20ins. These targeted therapies add to a growing number of TKIs, many of which are already approved for treatment of NSCLC tumors with other molecular alterations including ROS1, RET, TRK, and BRAF. In this regard, it should be noted that testing for these molecular alterations is becoming increasingly important, in order to identify patients who are candidates for targeted treatment.
Dr Shayma Kazmi from The University of Pennsylvania moderated a panel discussion on targeted therapy in NSCLC at the Total Health 2023 ‘Best of Lung’ Conference. The expert panel also included Dr Jaime Schneider from Massachusetts General Hospital Cancer Center, Dr Theresa Boyle from Moffitt Cancer Center, and Dr Coral Olazagasti from The University of Miami.
Immunotherapy has also been a pivotal addition to treatment for patients with advanced NSCLC. Some of the key findings over the past 2 years included results from KEYNOTE-671, which examined the use of neoadjuvant (pre-surgery) pembrolizumab in combination with platinum-based chemotherapy, followed by surgery and adjuvant pembrolizumab for patients with resectable stage II, IIIA, and IIIB NSCLC with no prior treatments. The key endpoint in the trial, event free survival (EFS), was significantly improved in the pembrolizumab arm relative to placebo, and a benefit of the combination was generally observed across all relevant patient subgroups. Other endpoints like pathologic complete responses (pCR) and complete responses were significantly improved over placebo, and although longer follow up will be needed, OS also appears to favor pembrolizumab treatment over placebo. There were no new safety signals with the regimen and rates of Grade 3 and higher AEs were low. An important question raised by the trial is which patients need adjuvant immunotherapy after surgery, and it has been suggested that those not achieving a pCR would benefit most, while those with a pCR might safely forgo continued pembrolizumab. We also saw data for the neoadjuvant use of another immunotherapy, nivolumab, in combination with chemotherapy which also improved both the endpoint of EFS and time to distant metastasis. These immunotherapy combinations may be an option for patients who do not have targetable molecular alterations. Patients with EGFR or ALKmutations do not derive meaningful benefit from immunotherapy, and as such they have been excluded from lung cancer immunotherapy trials.
Overall, for patients with metastatic NSCLC, it is estimated that survival has improved by about 1.5 to 2.0 years with the use of immunotherapies, either alone or in combination with chemotherapy, and this has become the standard frontline treatment. Tumor expression of programmed death ligand-1 (PD-L1) is the major predictive biomarker for immunotherapy benefit, with a level of >50% PD-L1 expression as a general threshold for efficacy of immunotherapy over chemotherapy. Immunotherapy is also transforming NSCLC treatment for the elderly and patients who would otherwise not be candidates for platinum chemotherapy, such as those with significant comorbidities or poor performance status (PS). Results from the IPSOS trial, for example, showed that atezolizumab immunotherapy significantly improved OS over investigator’s choice chemotherapy in stage III and IV NSCLC, importantly, with a markedly lower incidence of Grade 3 and 4 AEs. Results of this trial show that immunotherapy is a viable alternative to chemotherapy for the highly clinically relevant and frequently encountered population of elderly and frail patients with lung cancer.
Colorectal Cancer
For me, one of the most interesting developments to be reported this past year on the topic of colorectal cancer (CRC) is the impact of sidedness of the tumor in the colon. We learned that primary tumors originating on the right or left side have markedly different responses to targeted treatments such as panitumumab (an anti EGFR-directed therapy) and bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF). The underlying biology relates to the fact that the midgut and the hindgut actually derive from different embryonic origins during early development, and the colon itself therefore represents 2 organs fused together. The finding is reminiscent of my postdoctoral work with homeobox genes which function as master developmental regulators that can also be involved in cancer, and the hypothesis that many cancers can result from early developmental growth and differentiation processes gone awry. Structures in the right colon, such as the cecum, the ascending colon, and most of the transverse colon, are derived from the midgut, whereas the left colon, including structures like the descending colon, sigmoid colon, and the rectum are derived from the hindgut during early development, and we now know this distinction has implications for cancer treatment.
Talking colorectal cancer with Dr Mark Lewis from Intermountain Health during one of our 2023 T-Talks segments.
Results from a sub analysis of the CALGB/SWOG 80405 study showed a much greater benefit of adding anti-EGFR treatments such as panitumumab to chemotherapy in left-sided tumors versus right. In contrast, there was a greater benefit of adding anti-VEGF treatments such as bevacizumab to chemotherapy for patients with right-sided tumors as compared to left-sided tumors. The molecular biology of right and left sided CRC is also markedly different with specific (and targetable) molecular alterations more (or less) common on one side versus the other. For example more BRAF and less HER2 gene alterations, and more microsatellite instability (MSI)-high status observed in patients with right sided disease versus left. Largely in agreement with these findings, results of the PARADIGM study (reported at ASCO 2022) also provide phase III clinical trial evidence supporting the efficacy of first line anti-EGFR treatment (in combination with established chemotherapy regimens such as mFOLFOX6) for patients with left-sided CRC. In comparison, we now know that patients with right sided CRC should not receive anti-EGFR therapies.
In the setting of advanced or metastatic CRC, for those patients who are positive for the HER2 biomarker, we saw from the MOUNTAINEER study this year that the combination of tucatinib, a HER2-targeted tyrosine kinase inhibitor (TKI) with another HER2-directed therapy, trastuzumab had significant activity in metastatic HER2+ CRC patients who did not have a RAS mutation. The combination has the potential to become a new standard of care, depending on findings of an ongoing randomized, phase III trial, MOUNTAINEER-3. Findings from the phase III SUNLIGHT study also showed the efficacy of TAS-102 (trifluridine/tiperacil) in combination with the VEGF-directed therapy bevacizumab in treatment refractory metastatic CRC with significant improvement in OS. Results from SUNLIGHT also have the potential to change the current standard of care in mCRC with better tolerability compared to existing treatment options such as regorafenib. This study also confirms an important benefit of continued VEGF inhibition after progression in the metastatic setting.
One of the more significant findings in CRC over the past year has also been the updated results from the KEYNOTE-177 trial, which demonstrated for the first time that some metastatic CRC patients might be safely spared any potentially harmful chemotherapy treatment. Specifically, for those mCRC patients whose tumors have specific molecular characteristics, including MSI-high status or defects in DNA mismatch repair (dMMR), immunotherapy with pembrolizumab improved PFS, with statistically similar OS, and notably fewer treatment related adverse events as compared with investigator’s choice of chemotherapy. In light of these findings, it is becoming increasingly important to assess a patient’s specific tumor characteristics, including MSI and MMR status, to determine if a chemotherapy free approach could be a treatment option for their metastatic CRC.
On the topic of biomarkers, the use of adjuvant chemotherapy after surgery as a means to prevent recurrence has been considered, at least by one expert, “the toughest sell in oncology”. This is particularly true for stage II CRC patients, who have an intermediate risk for recurrence, and for stage III CRC patients, who generally receive chemotherapy, despite the fact that as many as 50% might be cured with surgery alone. Circulating tumor DNA, or ctDNA, is a biomarker that can be used to evaluate the amount of residual cancer cells, or so-called “minimal residual disease” (MRD) that is present after surgical removal of their tumor. Previous findings have shown that ctDNA assessment after surgery is highly prognostic; patients with detectable ctDNA (ctDNA positive status) after surgery have a significantly higher risk for recurrence, as compared to those whose ctDNA is undetectable (ctDNA negative status). Moreover, the test is sensitive enough to detect disease recurrence as much as 1 year before it becomes detectable by conventional radiologic imaging methods, such as a CT scan.
Dr Samuel Klempner from Massachusetts General Hospital discusses the use of ctDNA testing in the gastrointestinal cancers at our 2023 ‘Best of GI Cancer’ conference.
Although more data is needed to definitively change clinical practice, ctDNA assessments have a real potential to, as one expert put it, “first, do no harm” by safely sparing some stage II and III CRC patients the dangers of chemotherapy (i.e. prevent overtreatment), while also identifying patients (for example, those with ctDNA positive status after surgery) who might need some form of escalated treatment (i.e., prevent undertreatment). Results from a large Japanese study of stage I to IV CRC patients, CIRCULATE, have shown that patients with ctDNA negative status after surgery may not benefit from adjuvant chemotherapy (and are essentially cured with surgery alone) with nearly 100% disease free survival, whereas those with ctDNA positive status are at a much higher risk for recurrence, and clearly benefit with the use of adjuvant chemotherapy. The pitfall of using ctDNA assessment in clinical practice is the potential for significant psychological distress that could result from a positive test in the absence of any imaging evidence for recurrence. It has not been established that intervening in such patients would have any meaningful impact on survival. Nevertheless, with forthcoming results from clinical trials already underway, as well as an expanding base of registry data to draw upon, it is hoped that post-surgery ctDNA assessments can become another tool to aid in clinical decision making for CRC and other solid tumors.
Lastly, on the topic of CRC screening, I’m compelled to say I did get my first colonoscopy this past year. While stool based testing with things like ColoGuard are now available, and are certainly better than no testing at all (I had a negative ColoGuard test 3 years ago), it’s important to note that, by all accounts, colonoscopy remains the gold standard of CRC screening. The reason is the procedure is not only diagnostic, but also interventional for suspicious findings (i.e., precancerous polyps can be identified and removed/biopsied at the time of screening). I encourage everyone who is eligible to get their colonoscopy – it’s very simple, usually covered by your insurance, completely painless (even if polyps are found – I had one), and the prep is also much simpler than it was in the past – I didn’t even get a headache from the fasting the day before.
Melanoma
As the lesser known and appreciated, but still the 5th most common cancer, the incidence of melanoma continues to increase (I always remember the skin as being the largest organ in the body, and therefore having a lot of surface area for cancers to develop). Thankfully, however, the death rates from melanoma are stabilizing, and over the last decade, both immunotherapies and targeted therapy have helped to increase survival, even for patients with advanced disease. The field has also seen a flurry of drug approvals, beginning in 2011 with the approvals of the immunotherapy ipilimumab and the targeted therapy vemurafenib.
A colleague of mine during my graduate work, Dr Jedd Wolchok, is now Meyer Director of the Sandra and Edward Meyer Cancer Center at Weil Cornell Medicine, and one of the most recognizable names in the melanoma field. When I interviewed him several years ago, he reminded me that melanoma has always been one of the more immunogenic forms of cancer, that is, having a large complement of unique and diverse antigens capable of stimulating the immune system. As such, using the body’s immune system to target and kill melanoma has been a topic of clinical research for literally decades. It is appropriate, therefore, that melanoma would be one of the greatest success stories for immunotherapy. It turns out the reason why so many attempts to utilize approaches like anti-melanoma vaccines failed in the past is that melanoma (and apparently many other cancers) express molecules on the cell surface that act as “brakes” for the immune system, essentially saying to the angry immune cells “nothing to see here… everything is OK… move along”. By removing these brakes, or “checkpoints” using what are known as immune checkpoint inhibitors (ICIs), the cancer cells are laid bare to see for the immune system, to be subsequently attacked and destroyed. Pembrolizumab is one of several ICIs that inhibits one such checkpoint pathway, the interaction of the aforementioned programmed death ligand 1 (PD-L1) with its receptor, PD-1. Results from trials such as KEYNOTE 716, for example, have demonstrated that the use of adjuvant (post-surgical) pembrolizumab can significantly improve recurrence-free survival (RFS) over placebo for patients with high risk Stage II (IIB or IIC) melanoma. Updated results from this trial confirmed a significant benefit of pembrolizumab adjuvant therapy over placebo with longer follow up, including critical endpoints such as distant metastasis free survival.
It has also been recognized that the PD-L1/PD-1 pathway is only one of many “cancer-hiding” checkpoints that can be targeted with ICIs. Indeed, the first immunotherapy to be approved in melanoma, ipilimumab, is an inhibitor of a different immune checkpoint, termed CTLA-4, and it stands to reason that combining one type of ICI with another would lead to cooperative, or even synergistic anti-tumor activity. This is the exact approach that was examined in the CHECKMATE 067 trial, which examined the use of nivolumab (another anti-PD-1 ICI) and ipilimumab, either alone or in combination, for patients with inoperable, metastatic melanoma. The results have been described as “game-changing” for this population of patients, with nearly half of the patients on the combination treatment (the so-called “Ipi/Nivo regimen”) being alive after 90 months, whereas in the past, essentially none would have survived past one year. While immune-related adverse events (IRAEs), resulting from over activation of the immune system, are important to consider, especially in those patients receiving two distinct types of immunotherapy, with the expanded use of ICIs in clinical practice, oncologists are gaining the experience to better recognize and manage such events, so patients can remain on these life-prolonging treatments over an extended period. The efficacy of other checkpoint inhibitors such as the anti-LAG-3 antibody relatlimab, either alone or in combination with other ICIs, is also being explored in trials such as RELATIVITY 047. The combination of relatlimab and nivolumab was approved in 2023, and also reported at ASCO 2023 were results combining another anti-LAG-3 antibody, fianlimab, and cemiplimab (another anti-PD-1 therapy), in advanced melanoma. The availability of these and other checkpoint inhibitors and pathways, and the expanding potential for combining and sequencing different types of therapies is especially encouraging to increase therapeutic options in the setting of metastatic melanoma, which was once universally a fatal diagnosis.
Dr Marlana Orloff from Sidney Kimmel Cancer Center presented updates in melanoma and other cutaneous malignancies at the 2023 ASCO Direct conference in Philadelphia.
In a phase II study, KEYNOTE-942, also reported this year, a novel immunotherapy approach, combining a personalized, patient-specific melanoma antigen, mRNA-4157-P201 with pembrolizumab was compared with pembrolizumab alone. Results showed the treatment to be well-tolerated, with no increase in immune-related adverse events relative to pembrolizumab alone, and the combination reduced the relative risk for both recurrence (by 44%) and for distant metastasis (by 65%) at a median 2 year follow up. The trial has resulted in the strategy receiving both a ‘Breakthrough Therapy’ and ‘PRIME’ designations by the US and European regulatory agencies, respectively. Treatment approaches also continue to evolve for the important group of patients with resistance to anti-PD-1 immunotherapy. In the IGNYTE trial, for example, we saw that the combination of an intratumorally administered immune-stimulating protein, RP-1, with nivolumab immunotherapy was an effective treatment for patients who had failed prior immunotherapy using PD-1 inhibitors. Also important to mention are the results of SWOG1801, which demonstrated that using neoadjuvant (pre-surgery) immunotherapy (pembrolizumab) in patients with resectable melanoma was superior to surgery first followed by adjuvant (post-surgery) pembrolizumab. This was a highly impactful finding, as it suggests that immunotherapy may be more effective on lymphocytes present in the tumor (called tumor-infiltrating lymphocytes or TILs) while the tumor itself is still present in the body, as opposed to after the tumor (and the TILs) have already been removed from the body.
Our 2023 ‘Best of ASCO’ Conference also featured updates in melanoma/skin cancer with Dr Meredith McKean from Sarah Cannon Research Institute.
We also have seen important advances in targeted treatments for patients with metastatic melanoma whose tumors have identifiable molecular alterations, such as BRAF V600 mutations. Such patients are candidates for treatment with BRAF inhibitors such as vemurafenib and other drugs, in combination with inhibitors such as trametinib and others which target a different pathway, the MEK pathway. Use of these drugs in combination can lead to very rapid and robust responses in patients whose tumors harbor these alterations. We also saw promising results from this year’s ASCO meeting for tunlametinib, a targeted therapy for patients with the rarer but more clinically aggressive NRAS mutant subtype of melanoma for which there is no approved therapy at present.
Trials such as DREAMSeq are also helping to address the question of which type of therapy (i.e., a targeted therapy or an immunotherapy) should be used first for patients with metastatic melanoma. While results from DREAMSeq showed that using an immunotherapy combination (the Ipi/Nivo regimen) upfront led to significantly better progression free survival as compared to a BRAF/MEK inhibitor combination (dabrafeninb + trametinib) upfront, the latter combination nonetheless provides a targeted treatment option for patients who might not be able to tolerate the immunotherapy combination.
A Word About Racial Disparities in Cancer Care
Breast cancer has been one example of what can be done to improve outcomes in a specific subtype of cancer with a coordinated effort of education, screening and prevention programs, industry investment in research and development, patient participation in clinical trials, and rapid integration and application of newly approved therapies and diagnostic methodologies into clinical practice. The result is a dramatic improvement in highly relevant clinical outcomes, such as overall survival and breast cancer specific mortality in newly diagnosed patients over the last few decades. What is also being increasingly recognized, however, is that improved outcomes may not be uniformly observed across all subgroups of patients, particularly for minority populations. For example, it is now recognized that, despite the fact that breast cancer is more frequently diagnosed in White women, Black women with breast cancer have a 40% higher risk of death from breast cancer. The reasons underlying these disparate outcomes are certainly multifactorial, and can include such factors as racial and genetic predisposition (for example, we know Black women are more frequently diagnosed with more difficult to treat triple negative breast cancers), as well as socioeconomic factors, such as poor education, lack of insurance coverage or inadequate coverage, and less access to care. Accordingly, these factors can be categorized as both the modifiable (e.g. socioeconomic) and the non-modifiable (e.g., genetic predisposition). Another highly relevant factor which can impact cancer outcomes is the dramatic underrepresentation of Black and minority populations in cancer clinical trials. For example, even for some of the most impactful and practice changing clinical trials in breast cancer, the representation of Black individuals is frequently no more than 3 to 5% of the overall study population. The implications of minority underrepresentation are profound. For example both efficacy and safety results from what may be potentially practice changing clinical trials, and the resulting changes in major treatment guidelines and recommendations may not be applicable and evidence based for Black and minority patients if the results have been obtained in overwhelmingly White/Caucasian populations.
While breast cancer is a prime example, the disparities in cancer outcomes clearly exist for other types of cancer, and will be increasingly recognized as research continues. At Total Health, our initiatives this past year have been focused not only on increasing awareness of cancer healthcare disparities, but more importantly, on discussions of what can be done in practical terms to start addressing the problem. There are certainly no easy solutions. Many faculty at our conferences over the past year are aware of and have vocalized the inherent distrust of medical research among minority populations, as a result of historical injustices in this country that I will admit I was not all that aware of (and which didn’t happen all that long ago). A coordinated effort of community outreach and engagement, building trust by recognizing and acknowledging our own inherent biases, and expanding access to clinical research for Black and minority populations will be needed. I’m also encouraged by efforts of national funding agencies including the National Cancer Institute (NCI) and others to require major cancer centers conducting clinical trials to have trial populations that are appropriately representative of the communities that they serve in order to obtain funding for cancer clinical research.
Conclusions – Looking Toward the Future
As we head into the busy meeting season of 2024, I expect to see emergent results from some of the most important clinical studies across all the “big five” cancers mentioned herein, with extended follow up for critical and practice-changing endpoints like overall survival, long term efficacy endpoints such as cancer specific survival and importantly, the impact of different treatments on survivorship and overall quality of life. Clearly, groundbreaking therapies such as immune checkpoint inhibitors, targeted therapies, antibody drug conjugates and PARP inhibitors will continue to move the needle and extend survival across the big five and other less common cancer types.
Another area I am personally most excited about is multi-cancer early detection, or MCED. Each year, as I walk into my annual physical and diligently endure all of the required tests (at least those covered by my insurance), at the age of 57, I wonder - am I doing all I can do to detect a cancer in its earliest and most treatable stage? Is that pain in my elbow arthritis, muscle strain, or metastatic cancer? The promise of MCED is a simple, once-a-year, non-invasive blood draw to detect a cancer signal – a signal in the blood that something isn’t right – and more importantly, if it’s detected, where is this cancer, and what tests could be more logically and appropriately performed to probe further? To be clear – the technology is not there yet. There are many promising tests available that continue to accumulate the volumes of clinical data that will be required for use in regular clinical practice, and more importantly, for cost-efficacy and coverage by insurance. The MCED prospect also brings up the sociologic issue of - would you want to know? And how do we make sure this technology can be used to detect cancer earlier, more effectively and specifically, without causing undue psychological stress or harm to people?
As we head into the future of cancer care, I along with many of our esteemed faculty, am indeed hopeful that the remarkable progress in understanding of cancer and its treatment will continue. Although it may sound like a contradiction in terms, there is certainly much hope for making cancer not “curable” per se, but rather, a “chronic condition”, like cardiovascular disease. I think it’s essential for the non-scientist to understand that cancer is as diverse as the people who suffer from it, and the diversity of diseases that constitutes cancer is precisely the reason that there will never be a single cure. But I do think we are on our way to making the experience of cancer far more tolerable, far more humane, and ultimately, a survivable human condition. It is also our hope that the enduring free educational conferences and content available on our website and across the Total Health social media platforms will be useful for patients to better understand their cancer and its treatment, promote better shared decision making with the cancer care team, and improve strategies for survivorship after cancer.
Acknowledgement
I am grateful to Sharon Gill, CEO & Founder, Sharon Gill International, Inc., Dr Elyse E. Lower, Professor Emerita, University of Cincinnati, and Dr Jedd D. Wolchok, Meyer Director, Sandra and Edward Meyer Cancer Center at Weil Cornell Medicine, for their review and comments on this article. My sincere thanks as well to all of our distinguished faculty contributors for their ongoing support and participation in these free educational conferences.
Peter J. Sciavolino is a freelance writer and consultant in medical education, and Director of Medical Writing and Scientific Content at Total Health.
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