ASCO 2023: Oncology Updates

ORAL: Late-Breaking Abstract Session

The session presented a series of abstracts and their findings.

The first abstract presented by Dr. Kathleen Moore presented the findings of the Phase III MIRASOL study-a randomized, open-label, phase III study of mirvetuximab soravtansine versus investigator’s choice of chemotherapy in advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate-alpha (FRα) expressionUntil today, no randomized phase III trial of a novel therapy demonstrated an improvement in overall survival in the platinum resistant ovarian cancer (PROC). Mirvetuximab soravtansine is an antibody drug conjugate that targets FRα and is conjugated with a very potent microtubule toxin known as DM4. FRα is expressed in almost 90% of  high grade serous ovarian cancer, but it is highly overexpressed in about 35% of platinum resistant ovarian cacner (PROC) cases. 

The benefit of mirvetuximab soravtansine demonstrated by the phase three single arm SORAYA study, which evaluated mirvetuximab soravtansine in the platinum resistant and bevacizumab pretreated population with a response rate of 32% and a median duration of response of 6.9 months. This led to accelerated approval and access to this medication in November of 2022. The MIRASOL study is a trial aimed at providing global regulatory approval for mirvetuximab in the platinum resistant ovarian cancer setting. The study enrolled 453 patients with platinum resistant ovarian cancer who had three prior lines of chemotherapy, could or could not have been treated with bevacizumab or Poly (ADP-ribose) polymerases (PARP) inhibitors and the tumors by central testing had to have a high expression of FRα (>75%). The patients were randomized 1:1 to receive mirvetuximab 6mg/kg adjusted ideal body weight Q3W or investigator’s choice chemotherapy which could include weekly paclitaxel, pegylated liposomal doxorubicin or topotecan. The primary endpoints were investigator assessed progression free survival. The key secondary endpoints were overall response rate by investigator, overall survival and patient reported outcomes. Around 60% of the population entered the trial with prior exposure to bevacizumab, and 55% had prior exposure to PARP inhibitors, which is very consistent with current regulatory approvals. Close to 50% patients enrolled in the study had three prior lines of chemotherapy. Weekly paclitaxel, pegylated liposomal doxorubicin or topotecan was given in 41%, 36% and 23% patients respectively. The Kaplan-Meier curve for the investigators choice chemotherapy, which demonstrated a median progression free survival of 3.98 months was very consistent with historical benchmarks and consistent with the statistical assumptions made when this study was designed. The Kaplan-Meier curve for patients randomized to mirvetuximab with a median of around 5.62 months demonstrated a hazard ratio of 0.65, which represents a 35% reduction in the risk of progression or death as compared to chemotherapy ( p < 0.0001). Mirvetuximab soravtansine doubled the response rate of patients (from 16 to 42%). This indicates an overall response rate difference of over 26% and an odds ratio of 3.81 which is highly statistically significant (p < 0.0001). The waterfall plots for mirvetuximab versus investigator’s choice chemotherapy showed that 80% of patients having tumors with some decrement in their dimensions with mirvetuximab versus 55% when treated with investigator's choice chemotherapy. A pre-planned interim analysis of overall survival was conducted. The overall survival Kaplan-Meier curve for the investigators choice chemotherapy and mirvetuximab had a median overall survival of 12.75 months and 16.46 months respectively (hazard ratio of 0.67, p = 0.0046) and a 33% reduction in the hazard of death. An exploratory analysis revealed that there was a consistent magnitude of benefit of mirvetuximab over investigators choice chemotherapy irrespective of a tumor or prior exposure to bevacizumab. Mirvetuximab was associated with a lower rate of serious adverse events and nearly 50% of treatment discontinuations were related to treatment emergent adverse events. There were very less incidences of hematological toxicity, neuropathy or alopecia associated with mirvetuximab . n summary, mirvetuximab is the first novel treatment to demonstrate an overall survival benefit in a phase III setting in the platinum resistant ovarian cancer patient population. It has demonstrated statistically and clinically significant improvements in progression free survival, overall response rate and overall survival compared to investigators choice chemotherapy with a continued, well-tolerated safety profile that consists predominantly of low grade, ocular and GI side effects. This is the only FDA approved biomarker directed therapy ever approved in PROC and the ADC for ovarian cancer.

Dr. Roisin O’Cearbhaill was the discussant for the practice changing late breaking Abstract 5507 The MIRASOL study. MIRASOL is the confirmatory study for the SORAYA study and has firmly established the role of mirvetuximab in FRα high expression, platinum resistant ovarian cancer. In the single-arm SORAYA study, mirvetuximab was given as monotherapy in patients with high expression of FRα who had received 1 to 3 prior lines of therapy requiring prior bevacizumab. The study showed a confirmed overall response rate of 32.4% with a progression free survival of 4.3 months and a median duration of response of 6.9 months. The randomized phase III MIRASOL study demonstrated improved response rate, progression free survival and overall survival in high FRα expression, platinum resistant ovarian cancer as compared to investigators choice of chemotherapy. For mirvetuximab, there was an incremental benefit of 1.6 months in terms of progression free survival, an incremental benefit of 3.7 months for overall survivalThe response rate was 42% compared to 16% in the investigators choice of chemotherapy. Among those responders, 5% of patients derived a complete response. An additional 37% patients had a partial response, compared to only 16% in the chemotherapy arm. If patients with stable disease were included, there was control rate of 80% with mirvetuximab. Mirvetuximab is well-established as an FDA approved treatment for recurrent, platinum resistant ovarian cancer. However, there is still a need for effective options that expressive response rates like mirvetuximab and translate into meaningful and durable responses for patients. The challenges encountered while treating platinum resistant ovarian cancer are both intrinsic and acquired resistance to our treatments, heterogeneous antigen expression, symptoms related to the disease burden and the toxicity related to these novel treatments. Another challenge is how to advance these technologies in a landscape that is rapidly changing with new agents and changes in approvals. An antibody drug conjugate is joined to a cytotoxic agent by a linker which allows a more focused drug delivery at the site of the tumor. There are great iterations and great improvements in this type of technology. However, it is important to know the optimal disease setting for these agents and how best to sequence them. There is a need to develop reliable predictive biomarkers that will be able to predict patients who are likely to respond as well as identify patients who will not respond to the treatment and would only be exposed to toxicity. It is essential to understand how best to deliver these agents safely and clinicians must educate themselves and educate the patients so that they too can implement strategies and minimize the toxicities related to these agents. There is a need to develop new partnerships with specialists (in this case, eye specialists) for us to be able to deliver these types of technologies safely. It is important to know the mechanisms of resistance and the ways to overcome or prevent them. There are ongoing efforts to explore novel combinations and combining these agents with other drugs, such as antiangiogenic agents. With respect to the current standard for treating ovarian cancer, mirvetuximab should be considered to be given early in the disease course keeping in mind that these patients have received prior 3 lines of chemotherapy. It is interesting that patients who had not received prior bevacizumab, derived a more substantial benefit from mirvetuximab. The GLORIOSA study is an ongoing study on mirvetuximab in combination with bevacizumab which may clarify the role of mirvetuximab in platinum resistant maintenance settings. There are ongoing trials exploring the role of antibody drug conjugates as a maintenance treatment in the platinum sensitive setting. In the United States, there are currently 6 antibody drug conjugates approved for solid tumors, and there are two additional approved worldwide. In ovarian cancer, there are four antibody drug conjugates (STRO-002, MORAb-202, Upifitamab and mirvetuximab) that are in the late stages of development. These different drugs vary according to the linker, the payload and the payload action. Upifitamab targets sodium transporter phosphate dependent 2b protein. An update needed in clinical practice is to investigate in patients if they have an expression of FRα. The FORWARD 1 study, a randomized Phase III study of mirvetuximab versus chemotherapy, demonstrated that there was no significant difference in median progression free survival for all corners group. However, subgroup analysis showed an improved medium progression free survival when enriching for high FRα expression. This is defined as immunohistochemical staining of 75% of the tumor cells, with at least 2+ membrane staining intensity. While designing newer trials, it is very important to consider these predictive biomarkers and their best cutoffs and then enrich that biomarker. It is observed that progression free survival outcomes can be improved when we enrich target antigen expression. The choice of antibody drug conjugate at the level of a target expression required, may depend on the choice of drugs As seen with SRTo-002, it is possible that a subset of patients who have lower FRα expression could still benefit from a targeted approach. Mirvetuximab has low hemotoxicity; its neuropathy is comparable to Paclitaxel and it has no alopecia.Gastrointestinal toxicity can be managed carefully with patient education. Eye toxicity, as seen in the MIRASOL study can be managed through mitigation strategies and establishing relationships with our eye specialists. There are several questions on how one can do better with respect to the challenges with the antibody drug conjugates in platinum-resistance ovarian cancer. The questions revolve around the best in class drugs, patient selection, optimizing disease settings, need for reliable biomarkers, optimal expression and cut-offs, minimizing toxicity through disease control and pre-emptive mitigation strategies, understanding the mechanisms of resistance, its association with antigen loss and rescue strategies. It is believed that translational correlatives will be a key to determining which patients may or may not derive benefits. 

Video No: SH02. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

ORAL: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

This session discusses the development of molecularly targeted agents in cancer therapy for HER2-expressing tumours and promising treatments for small-cell lung cancer (SCLC), peritoneal metastasis detection and CNS metastasis.

Trastuzumab Deruxtecan (T-DXd) is a highly effective and safe treatment for HER2-expressing solid tumours. It has become the standard of care for unresectable/ metastatic breast cancer, locally advanced/metastatic gastric/GEJ cancer, and unresectable/metastatic NSCLC with HER2 (ERBB2) mutation. Early studies have also shown promising results in colorectal, salivary gland, biliary tract, and endometrial cancers). The ongoing DESTNY-PanTumour02 trial, which includes 267 patients who have received at least two lines of treatment, has demonstrated clinically meaningful activity in a wide range of HER2-expressing tumours, including those that are difficult to treat. The overall response rate (37.1%; 61.3% in IHC 3+) and duration of response (11.8 months; 22.1 months in IHC 3+) have been encouraging. The safety profile of T-DXd aligns with expectations, with common side effects being nausea, fatigue, and neutropenia.

BL-B01D1, a first-in-class EGFRxHER2 bispecific antibody-drug conjugate (ADC), was evaluated for safety and efficacy in patients with advanced solid tumours. Targeting EGFR and HER3, which are highly expressed in epithelial tumours, BL-B01D1 showed a broad spectrum of anti-tumour activity. The study included 139 patients with different tumour types who received varying doses of BL-B01D1. The overall response rate was 45.3%, with a median follow-up of 4.1 months. treatment-related adverse events included leukopenia, anaemia, neutropenia, and thrombocytopenia, but no cases of interstitial lung disease were observed. The recommended dose for further studies was 2.5 mg/kg, administered every three weeks. BL-B01D1 exhibited promising anti-tumour activity, particularly in EGFR-mutated and wild-type non-small cell lung cancer and nasopharyngeal carcinoma.

ABBV-011, a seizure-related homolog protein 6 (SEZ6)-targeting ADC, was studied in patients with small cell lung cancer. It is highly expressed in SCLC and other neuroendocrine tumours with minimal expression in most normal tissues and non-neuroendocrine tumours. Current treatment options have limited effectiveness, with median progression-free survival (PFS) ranging from 3.5 to 5.1 months. In a study, the maximum tolerated dose (MTD) of ABBV-011 was not reached up to a dose level of 2mg/kg. The treatment was well tolerated at 1mg/kg administered every three weeks. Single-agent ABBV-011 at 1mg/kg every three weeks showed promising efficacy, with an overall response rate (ORR) of 25%, clinical benefit response (CBR) of 65% and a duration of response (DOR) of 4.2 months in patients with relapsed/refractory SCLC. Median PFS was 3.5 months. These results highlight the potential of SEZ6 as a valid target for SCLC, given its high tumour expression and minimal expression in normal tissues.

The DESTINY-PanTumour02 study focused on expanding the effectiveness of ADCs in various solid tumours. T-DXd demonstrated promising results with an ORR of 37.1% and a median duration of response of 11.8 months. Discordance between local and central HER2 testing was observed. ADCs target HER2, Trop2, Nectin4, TF, and FR alpha, with new targets being explored . Safety studies of ABBV-011 showed tolerability at a 1mg/kg dose administered every three weeks, with an ADC half-life of 4.6 days . In the dose escalation phase, patient selection was based on SEZ6 expression, specifically targeting well responders with expression levels below 25%. SEZ6 shows promise as a target, and defining specific cutoffs could enhance the response rate.

A Phase II study evaluated Pegsitacianine, a pH-sensitive imaging agent, for detecting peritoneal metastases during cytoreductive surgery. Pegsitacianine is a micellar fluorescent imaging agent designed as an activatable probe with binary response to pH changes (acidin tumour environment). The study aimed to assess if fluorescence imaging could improve disease detection and completeness assessment of cytoreduction in peritoneal surface malignancies. 40 Patients received an infusion of Pegsitacianine at a dose of 1mg/kg with a flow rate of 10mL/min, followed by surgery performed within 24-72 hours. Surgical specimens were sent for pathology analysis. The results showed clinically significant events in 50% of patients, overall safety was well tolerated with no drug-related serious adverse events. Infusion-related reactions were observed in 28% of patients. Pegsitacianine imaging augmented the assessment of resection completeness in 50% of cases and has the application in diagnostic or staging setting.

In the American Cancer Society Cancer Prevention Study-3 cohort, the detection of methylated DNA biomarkers and incident cancer was investigated. The ability to detect cancer signals in the blood is influenced by cancer biology, with cancer shedding limiting early detection within a preclinical detection window. The large CPS-3 biobank, consisting of 300,000 volunteers, provided an opportunity to study preclinical cancer biology. The cohort was comprised of healthy, lovely female and never smoker volunteers aged 30 to 65 at lower than average risks of overall cancer and particularly deadly cancers. The cohort demonstrated lower cancer incidence and mortality rates than the SEER-expected rates. The detection rate of cancer signals was influenced by both cancer characteristics and the time between blood draw and diagnosis, with high accuracy (95% in year 1, 88% in year 2, and 81% in year 3) in predicting the origin of the cancer signal. The detection rates aligned with an average detectable window of one year. The shedding rate of eventually fatal cancers suggests the potential for early intervention and risk prediction. This finding indicates the possibility of annual screening intervals up to three years before conventional diagnosis, as significant changes in cancer biology occur before clinical diagnosis. Result should be reassessed in the intended use population aged 50 to 79 and ideally using MCED standard sample processing.

Patient selection for early-phase oncology clinical trials often lacks objective and reproducible biomarkers. Two scores, RMH and GRIm, have been used to predict survival in phase I patients, but a reliable biomarker is still needed. The circulating tumour fraction (TF), derived from tumour tissue and detected through liquid biopsy, has shown promise as a prognostic factor. A prospective evaluation revealed that a high TF is significantly associated with worse overall survival in both the BIP and STING prospective precision medicine studies. TF emerged as an independent prognostic factor in advanced solid tumours, surpassing the predictive ability of RMH and GRIm scores. The TIMES nomogram was developed as a reproducible tool to predict the 3-month survival probability and enhance patient selection for early phase studies Further investigations are needed to assess its predictive value in terms of response to systemic therapies.

Novel diagnostic methods have revolutionized tumour detection, with various imaging techniques proving valuable in visualizing tumours. These include PET imaging, US imaging, SPECT imaging, MR imaging, CT imaging, and Optical imaging. Among them, Optical imaging stands out for its high sensitivity in tumour detection and cost-effectiveness. It enables fluorescence-guided surgery, particularly aiding in nodular-complete resection while being less effective for identifying scirrhous tumours . Peritoneal metastases and cytoreduction surgery present challenges due to the low sensitivity of peri-operative imaging, extensive disease burden, wide distribution, and limited familiarity with parietal peritonectomy techniques. However, Pafolocianine (OTL38), administered one hour before cytoreductive surgery for ovarian cancer, has shown promising results. In 33% of cases, additional tumours were identified using this technique.

Achieving a high level of cytoreduction is essential, but the lack of a standardized measure for complete cytoreduction is a significant challenge. In lower-grade diseases, DNA shedding is less prominent. However, patients with a higher likelihood of survival and aggressive tumours can achieve remarkable long-term survival. DNA shedding is not solely determined by tumour size but is influenced by tumour histology and aggressiveness. It can serve as an indicator of tumour behaviour.

The novel BRAF inhibitor FORE8394, also known as Pilxorafenib, demonstrates specific activity against mutant BRAF while sparing wild-type RAF proteins. It effectively targets various BRAF complexes without inducing unwanted RAF dimer formation or paradoxical activation of the MAPK pathway. In a phase 1/2a study, the mPFS was 7.1 months for all patients, with MAPK-naive patients showing a longer PFS of 28.6 months compared to prior MAPKi-treated patients (3.6 months). The study also revealed favourable long-term tolerability, with infrequent grade 3 adverse events (commonly observed at a rate of ≤3.5%). Pharmacokinetic data and efficacy/safety profiles strongly support the recommended phase 2 dose (RP2D) of 900 mg once daily in combination with cobicistat 150 mg once daily.

A phase I study evaluated the safety and efficacy of KL590586, a next-generation selective RET inhibitor, in patients with RET-altered solid tumours. KL590586 showed promising results, including high selectivity for RET, greater potency against mutations, and improved exposure and survival in preclinical models The study reported no dose-limiting toxicities, with most treatment-related adverse events being grade 1-2. Clinical activity was observed across different tumour types and doses, with an overall response rate of 60% and a disease control rate of 94% . Intracranial responses were seen in 5 out of 6 patients, and complete clearance of ctDNA was observed in 90% of patients. KL590586 shows potential as a selective RET inhibitor for treating RET-altered solid tumours.

A phase 1 study investigated the efficacy of PRT811, a brain-penetrant inhibitor of protein arginine methyltransferase 5 (PRMT5), in patients with recurrent high-grade glioma or uveal melanoma. PRMT5 overexpression has been linked to tumour growth and poor clinical outcomes. PRT811 demonstrated potent and selective inhibition of PRMT5 in IDH1-mutant glioblastoma multiforme cells. The study showed clinical activity in patients with high-grade IDH-mutant glioma and metastatic uveal melanoma. IDH-mutant glioma's overall response rate (ORR) was 12.5%, with two durable complete responses. The clinical benefit rate was 31.3%, and the mPFS was 2.46 months. The ORR was 10% in metastatic uveal melanoma with one durable partial response. The clinical benefit rate was 30%, and the median PFS was 4.14 months. These findings suggest PRT811 has potential clinical activity in patients with high-grade glioma and uveal melanoma.

Brain penetrant small molecule inhibitors are breaking barriers in developing molecularly targeted agents. These inhibitors, such as FORE8394, KL590586, and PRT811, have shown good safety profiles and tolerability, addressing the challenges of side effects and patient selection. Although these drugs may not immediately change clinical practice, they lay the groundwork for future advancements. Moreover, clinical studies focusing on treating CNS metastasis have shown promising results, doubling patient survival rates. This highlights the importance of ongoing research and the significant contribution in this field.

To conclude, various molecules such as T-DXd, BL-B01D1, ABBV-01, Pegsitacianine, FORE8394, KL590586, and PRT811, demonstrated potential in targeted cancer therapy, including CNS metastasis. Ongoing research is crucial for further progress in this field.

Video No: M09. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

CSS: The Promise of Neo Adjuvant Immunotherapy Across Solid Tumors

In addition to accessing tumor response, these studies help to identify predictive biomarkers. Such studies also help to identify possible mechanism of resistance, providing a window of opportunity to understanding cold tumors.

The first studies on neoadjuvants was done on murine models of breast cancer where these mouse were treated with neoadjuvants or adjuvant PD-1 α or combined with α CD137. Mice treated with neoadjuvant IO had a significantly higher survival, and long survival in mice treated with combination, compared to both control and adjuvant treatment. Similar results were shown in pMMR/MMS colorectal cancer mouse models which were also treated with neoadjuvant anti- PD-1 + anti CTLA 4 versus adjuvant. The mouse treated with neoadujuvant did not have a reduction in the tumor, did have a significantly low risk of developing metastasis.

Early eradication of micro metastases in melanoma: S1801 study: Melanoma patients received standard of care adjuvant treatment with prembolizumab(18 cycles) or take three of these cycles in a neo adjuvant setting. Results of the study showed higher event free survival in the neoadjuvant group than in the adjuvant group highlighting the superiority of neoadjuvant therapy.

Higher rates of pathological response in NSCLC and TNBC: Checkmate 816 study (in non-small cell lung cancer) and the Keynote 522 (Triple negative breast cancer) studies: Both demonstrated that addition of anti PD 1 to chemotherapy compared to chemotherapy alone resulted in higher pathological completer response in the anti PD arm versus chemotherapy alone. A pooled analysis of pathological response in patients with melanoma treated with neoadjuvant IO showed benefits of neoadjuvant therapy.

Benefits of identifying biomarkers- NICHE 2 study (locally advanced MMR deficient colon cancer): Patients treated to short cycle of Nivolumad + Ipililumab and a second cycle of Nivolumab followed by surgery, showed 95% major pathological response (MPR). In BELLINI trial in TNBC patients received 4vweek of neoadjuvant immunotherapy prior to surgery or chemotherapy. Benefits were noted either as radiological response and overall benefits of not having viable tumor cells in subsequent biopsies. A large RCT, NADINA Trial currently underway in melanoma patients where patients undergo direct surgery or receive neoadjuvant immunotherapy

Neoadjuvant IO leads to higher pathological responses MPR and pCR in a variety of soild tumors and these are associated with excellent outcomes. There is a need for predictive biomarkers and de-escalation of systemic therapy, less extensive surgery or omission of surgery are options that can be considered. Immunotherapy prior to surgery is extremely effective in several tumor types, and patient whose tumor shrinks have excellent outcomes.

PD1 and PD L 1 inhibitors are standard of care therapy for advanced metastatic NSCLC. A perioperative approach that includes both neoadjuvant and adjuvant PD (L) 1 inhibition may be beneficial. Recently reported phase 3 AEGEAN and NEOTORCH studies have reported significant improvement in EFS for neoadjuvantPD-(L)1inhibition+ platinum-based chemotherapy followed by surgery and adjuvant PD-(L)1 inhibition compared with neoadjuvant platinum based chemotherapy and surgery alone for resectable NSCLC.

Statistically significant and clinically meaningful improvement in event free survival was reported with neoadjuvant pembrolizumab + chemotherapy followed by surgery and adjuvant pembrolizumab as compared with neoadjuvant chemotherapy and surgery alone. Pathological response rates were significantly higher in the pembrolizumab arm versus the placebo. Although the overall survival benefits of perioperative pembrolizumab was not found to be statistically significant, OS will be continued to be tested according to the statistical analysis plan. Over data suggests that perioperative pembrolizumab is a promising treatment option for resectable stage IIIA, or IIIB (N2) NSCLC.

Recent advances in immunotherapy for locally advanced NSCLC- should it be given pre-op, post-op or both? In recent years major advances have been made in immunotherapy and several studies have reported promising results. KN-671 reported event free survival with a HR 0.58, and overall survival with HR 0.73.  There are promising results for early-stage NSCLC. Results from major trials like KEYNOTE 671and other perioperative immunotherapy studies demonstrate major advances as new standard of care for treatment of resectable lung cancer. Additive impact of adjuvant immunotherapy after neoadjuvant chemotherapy must be considered. It is hoped that biomarker discovery and appropriate suitable therapeutic strategies will help to cure patients with early-stage NSCLC.

Comparison of 3-year data from PRADO and OpACIN-Neo on the impact of response directed treatment personalization on survival after neoadjuvant checkpoint blockade in stage III melanoma. A recent study showed that all patients do not need extensive surgery after neoadjuvant checkpoint blockade and can be omitted in patients with MPR without compromising survival outcomes. Also, it is not necessary that all patients will need systemic immunotherapy after neoadjuvant checkpoint blockade. Patients with MPR probably do not need systemic adjuvant therapy. However, patients with pNR benefit with systemic adjuvant therapy with effect being shown on their survival outcomes.

The best adjuvant treatment plan for patients with pNR indicate that adjuvant anti PD 1 can be preferred over adjuvant BRAF/MEK. Adjuvant radiotherapy appears to be beneficial for patients who are not eleigible for adjuvant systemic therapy eg, BRAF wt patients experiencing high grades of ir AE after neoadjuvant IT). 

Paradigm shift to neoadjuvant immunotherapy in melanoma. Although surgery continues to be the mainstay for early stage diaease, immunotherapy is preferred first line systemic therapy in most patients with metastatic disease. It is understood that adjuvant immunotherapy or targeted therapy (in patients with BRAF mutated tumors can extend relapse free survival. Neoadjusvant immunotherapy appears to be superior to adjuvant therapy. It is hoped that therapy can be personalised to individual patient’s response, and therapy programs can be scaled up only up to what is needed for long term disease control. This will minimize physical and financial toxicity and improve the quality and quantity of life. What needs to be done is that single agent PD-1 blokade must be compared with combinations. Evaluate and examine the requirement for surgery in patients with radiographic complete response and also, determine minimum necessary adjuvant therapies. The proposed mechanism of superiority for neoadjuvant versus adjuvant therapy needs to be validated. While neoadjuvant therapy brings in a lot of positive potentials, we need to learn more from studying refractort tumors. Therapeutic toxicities should be carefully considered and using only the treatment that is necessary.

Neoadjuvant immunotherapy is the standard of care for early-stage TN breast cancer. Sine since not all patients respond and IO carries risk of immune related toxicities , some of which may be permanent. Hence ther is a need for predictive biomarkers to enable appropriate IO allocation decisions. The I-SPY 2 trial for high risk early stage breast cancer (I-SPY 2.0) tested 22 agents in approximately 2500 patients, including 810 arms. Focus was given on 5 anti PD 1/PD L1 IO arms (plus taxane and anthracycline) Anti PD 1, anti PDL1/PARPi combination, anti PD-1/TLR 9 dual IO combination, and anti PD 1+/-LAG 3 dual IO combination. Biomarkers can help understand why certain patients respond while others do not. Tumor immune signalling signatures predict response to immunotherapy in both TN and HR+HER2. The ImPrint classifier predicts response to several IO regimens and identifies an uncharacterized subset of HR+HERb2 patients with a high likelihood of response. 

Preoperative immunotherapy + immunotherapy is a standard of care in early stage TNBC, although this is not yet approved in HR+ condition. Trials such as I-SPY 2 with robust cprrelative studies are critical in identifying biomarkers that differentiates response to IO. Treatment to increase immune response against tumor is regularly used before the surgery in patients with triple negative breast cancer. This increases likelihood that no disease remains at the time of surgery although it is associated with side effects some of which can be lifelong.

Video No S01. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

ED: Current Therapeutic Targets in Cancer Cachexia: A Pathophysiologic Approach

The Central Nervous System and Cancer Cachexia-

Kunal C Kadakia

The CNS is a major driver of failure of food intake. The pharmacologic agents like GDF15 antagonists, MC4R antagonists and Ghrelin antagonists which target signal mediators of appetite/satiety are in development. Studies have shown that significant impairment of food intake is common (>50% have moderately or severely reduced food intake at diagnosis) and anorexia is a major independent factor leading to weight loss and poor survival. GDF-15 levels are increased in cancers during platinum treatment and higher pre-tx GDF-15 levels are associated with increased weight loss. GDF-15 expression leads to centrally mediated anorexia and blocking GDF-15-GFRAL-RET signaling leads to increase in weight and food intake. Melanocortin-4 receptor antagonism leads to hyperphagia and increased body mass. Ghrelin is produced in the stomach and binds GHS-R1a in the arcuate nucleus. Anamorelin is a potent and selective ghrelin receptor agonist.

Skeletal Muscle and Cancer Cachexia

Vickie E Baracos

The skeletal muscle wasting is a defining feature of cancer cachexia. Muscle directed drugs are a part of the cachexia therapeutic plan, based on mechanisms of muscle regulation of anabolism and catabolism. These could be used in combination with appetite stimulating drugs in the future. JAK-STAT signaling (Ruxolitinib- JAK inhibitor) has been tried for cachexia as a target. The key aspects of muscle biology are understood, but more information is needed on the human muscle biology in the patients with cancer. The treatment-associated muscle wasting is quantitatively important. This under-recognized set of side effects lack any clinical management strategy at the present time and is an area for development.

Nutrient Signaling and Multimodality Approaches for Cancer Cachexia

Jill Hamilton-Reeves

It is very important to correct anorexia and excess satiety and mange nutrition symptoms in order to treat cachexia. 2020 ASCO cancer cachexia guidelines suggested the use of omega-3 fatty acids within foods as tolerated as they resolve inflammation and reduce the activation of proteolytic pathways and increase the appetite. Leucine increases muscle synthesis and decreases muscle degradation. Muscle is dependent on nutrient and contractile signaling for anabolism, hypertrophy and cellular proliferation. Physical activities help in maintaining lean mass, maintaining weight, improved effectiveness of nutrition therapy, appetite stimulation, and beneficial metabolic adaptations. Multimodality clinical trials (combining anti-inflammatory drugs, omega-3-fatty acids, ghrelin agonists along with nutritional counselling, oral nutritional supplements, exercise) suggest that baseline screening should be done for malnutrition risk using a validated instrument following cancer diagnosis and repeat screening during and after treatment. Those at risk for malnutrition should be referred to a Registered dietitian for more in depth nutritional assessment and intervention. There is a need for rigorous, well-defined nutritional intervention studies among adults with cancer to evaluate the effects on symptoms and cancer-specific outcomes. Robust data collection should be done during trials to assess cost effectiveness and inform coverage and implementation decisions. 

Video No: T03. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

ED: Artificial Intelligence for Drug Development: Fad or Future?

A Machine Learning Framework to Improve Treatment Selection

Arsela Prelaj

In the last decade, we have already pushed the standards of data use and analysis. We are in an exciting transition period where we have been able to use our mass of data until now, however, AI and ML approaches will improve the efficiency of our toolset. By harnessing the power of ML, we can revolutionize treatment selection and enable personalized interventions that were once unimaginable. By integrating ML methodologies into clinical practice, oncologists can navigate treatment options more efficiently leading to improved outcomes for patients and reduced healthcare costs. The integration of ML in treatment selection empowers oncologists and patients by bringing human expertise and machine insights in the same layer to create a synergy that enhances the art and science of oncology. To reach the other sector evidence we need to improve the overall quality of collected data and its volume. There is a need for more balance between progress of technology and its ethical and legal frameworks, that we can improve by producing more transparent algorithms, awareness and prediction of uncertainty and go for alternative AI-empowered tools and empower patients’ engagement on co-DM.

Using AI to Optimize Drug Combinations and Dosing

 Dean Ho

It is essential to address certain domains in order to incorporate AI in drug discovery, development and dosing. It is important to minimize off target effects and toxicity and enhance the drug exposure, optimize drug and dose selection, match patients to therapies and trials and overcome resistance with game theory. However, there are certain challenges like identifying optimal targets, improving trial outcomes, stratification with right patient data and more clinical validation is required. The digital avatar uses small data and uses only a patient’s own data to manage their own care. The steps to implement digital avatars include prospective calibration, construction of a digital avatar profile, dosage recommendation and personalized cancer therapy. CURATE.AI case recommended 50% dose reduction to increase efficacy in patients with advanced prostate cancer, while prior to this end of treatment was considered only. There are other studies who suggest integrating digital medicine into clinical workflow, however, large-scale validation is required, and regulatory considerations of AI remain an ongoing process. Data bias, security and other factors need to be addressed during platform development and human involvement is important during clinical workflows. AI can be applied to both diagnostic and interventional domains. It is important to incorporate user engagement, design, implementation sciences, health economics into early workflow development.

Pathology Image-based Detection of Clinically Actionable Genetic Alterations

Alexander T Pearson

To incorporate AI into pathology, it is important to collect data. A physical sample needs to be converted into a digital whole slide image and format for final analysis. Deep learning methods like pixel intensity of digital images extract information from the medical images. Many mode architectures exist with different properties and allow us to create imaging features which can process akin to statistical regression. A study showed an AI model can be used to detect mutated state directly from digitized H&E pathology slides and was trained >4000 patient samples in most common tumors. It could simultaneously return multiple model predictions without additional stains or tests. MSI indicates improved outcomes for immunotherapy over chemotherapy in MSI-high front line recurrent/metastatic CRC. Deep learning models can detect MSI-high cancers with excellent accuracy. AI biomarkers can improve accuracy of the traditional biomarkers, decrease testing complexity, reduce the cost and time for testing and fewer reagents would be required. However, AI biomarkers are susceptible to bias and to limit this, careful model building, trial development and reporting are required along with validation.

Video No: T06. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

Clinical Science Symposia: Role of the Microbiome in Immune Checkpoint Inhibitor Response and Resistance

The clinical science symposia session discussed the role of the microbiome in immune checkpoint inhibitor response and resistance.

Setting the Stage: What We Know About the Microbiome and Cancer

The presentation on gut microbiota in immuno-oncology highlighted antibiotics inhibited the clinical benefit of immune checkpoint inhibitors (ICIs) in patients with advanced cancer. Gut dysbiosis has been associated with intestinal and extraintestinal malignancies. It was shown that immunogenic commensals circumvent dysbiosis-related resistance to programmed cell death protein 1 (PD-1) blockade and could further enhance tumor progression. Hence, it was concluded that diagnosis tools for dysbiosis and microbiota-centered interventions are needed.

Friendly-user Score Assessing Gut Dysbiosis and Resistance to Immune Checkpoint Inhibitors (ICI).

Accumulating evidence pointed to the impact of the intestinal microbiota on ICI outcomes across various cancers. Although specific gut microbial species have been associated with beneficial responses (i.e., Akkermansia muciniphila (Akk)), no consensus exists on a gut fingerprint predicting immunoresistance to clinical routine use. A monodimensional score (TOPOSCORE) based on SIG1/SIG2 ratio combined with Akk relative abundance was calculated and compared to machine-learning (ML) algorithms. In n=245 and n=148 NSCLC pts, could classify pts into dysbiotic (SIG1+,33%) and eubiotic (SIG2+, 67%), using the TOPOSCORE. Pts falling within the SIG2+ exhibited a significantly prolonged OS than pts falling into SIG1+ (HR: (95% CI), 0.50 (0.36-0.71), p<0.0001). TOPOSCORE represents a user-friendly diagnosis tool to evaluate gut dysbiosis within 48 hours in each individual advanced cancer patient. TOPOSCORE also predicted OS in 277 ICI-treated NSCLC and GU pts and compared to the state-of-the-art ML algorithms, held the highest percentage of correct predictions (63%). Confirmed (n=323) that OS was superior in those pts harboring a 24-bacteria-qPCR-based TOPOSCORE falling within the SIG2+ category (HR: 0.65 (0.48 to 0.87), p=0.0005). It will also improve patient stratification and ICI success rates selecting dysbiotic patients and guiding microbiota-centered interventions. TOPOSCORE represents a robust biomarker predicting and following the dynamic of the immunoresistance to ICI across cancers on an individual basis.

Effect of CBM588 in Combination with Cabozantinib plus Nivolumab for Patients (Pts) with Metastatic Renal Cell Carcinoma (mRCC): A Randomized Clinical Trial.

Its previously demonstrated that the live bacterial product CBM588 may augment clinical outcomes in pts with mRCC receiving 1st-line (1L) therapy with dual immune checkpoint inhibitors. Results of a randomized study on the effect of the live bacterial product CBM588 in combination with cabozantinib (cabo) plus nivolumab (nivo) for patients with metastatic renal cell carcinoma (mRCC) were discussed. Patients were randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg oral daily and 480mg IV monthly, respectively) alone or with CBM588 dosed at 80mg oral twice daily. A total of 30 patients were recruited. It was shown that addition of CBM588 to cabozantinib plus nivolumab was associated with no significant change in Bifidobacterium spp., significant increase in PFS and higher response rate and no added signals of toxicity. Median PFS was not reached in pts receiving CBM588 vs 5.8 mos in pts receiving cabo/nivo along (P=0.03). Grade 3/4 toxicities were observed in 44% and 42% of patients on control and experimental arms, respectively. However, it was pointed out that results bolster previous clinical data associated with nivolumab/ipilimumab with CBM588 in metastatic RCC. In the second prospective trial assessing the addition of CBM588 to ICI-based therapy in mRCC, a consistent result with improved PFS and RR was observed. Further translational efforts are underway to characterize the mechanism through which CBM588 augments clinical activity.

Fecal Microbiota Transplantation Combined with Anti-PD-1 Inhibitor for Unresectable or Metastatic Solid Cancers Refractory to Anti-PD-1 Inhibitor.

The gut microbiome is emerging as a key regulator of the immune system during immunotherapy. However, the effect of modulating the gut microbiome in patients (pts) with cancer refractory to immunotherapy remains largely unknown. Results of a prospective, single-arm clinical trial of fecal microbiota transplantation (FMT) plus anti-PD-(L)1 inhibitor in patients with advanced solid cancer refractory to anti-PD-(L)1 inhibitors were presented. Thirteen patients with metastatic gastric cancer (GC) (n=4), esophageal squamous cell carcinoma (ESCC) (n=5), and hepatocellular carcinoma (HCC) (n=4) were enrolled; male (77%), median age=60 years (range, 38-76), and median line of prior systemic therapy=3 (range, 2-5). All had confirmed disease progression on nivolumab monotherapy with primary (46.2%) or secondary resistance (53.8%) and underwent FMT with continued nivolumab of the 13 recipients, five showed stable disease (SD) and one achieved partial response (PR) after FMT with a disease control rate of 46.2% (6/13) and an objective response rate of 7.7% (1/13). Recipient #7 (R7), who had metastatic HCC with primary resistance to nivolumab, initially showed PD to the 1st FMT from donor #1 but achieved PR after the 2nd FMT from donor #5. Clinical response was accompanied by an increase in levels of cytotoxic T cells in the blood and tumor microenvironment, immune cytokines, and the relative abundance of a new species derived from donor #5 showing 97% whole genome nucleotide sequence similarity with Prevotella sp. Marseille-P4119. The species was isolated from feces of R7 and preclinical experiments showed that treatment with this species activated human CD4+ and CD8+ T cells with increased IFN-γ secretion, and suppressed tumor growth in a syngeneic mouse model by enhancing tumor infiltration of cytotoxic T cells. Moreover, the combination treatment with anti-PD-1 and this species reduced the tumor volume more than with anti-PD-1 alone. It was concluded that FMT containing the effective microbiota could overcome resistance to anti-PD-1 inhibitor by modulating the tumor microenvironment in advanced solid cancer patients.

Video No: S05. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

Pediatric Immunotherapy CARS Of The Future

Beyond Original CAR T-cell Therapy: Natural Killer CARs As An Alternate Platform

Katy Rezvani

The CAR-T cells have resulted in the paradigm shift in the treatment of certain types of cancer, most specifically certain subsets of hematologic malignancies with responses ranging from 48% to 90% depending on the type of the disease. All these FDA approved are autologous which means that they are generated from the patients for the patients and the process takes around 2-4 weeks. To reduce the costs and eliminate the logistical hurdles of autologous immune effector cells (IEC), these products can be derived from healthy allogeneic donors. There are several challenges to the use of allogeneic donors for CAR therapy like the risk of GVHD, limited persistence, choice of cell type and choice of donor. The NK cells are a better choice for CAR therapy as they have no CRS or ICANS or GVHD and thus lower the costs. First In-human trial of CAR19/IL15 CB-NK cells in lymphoid malignancies done in 2020 showed 7/11 CR, no CRS, no neurotoxicity, no GVHD and CAR NK cells were detectable up to 12 months post infusion. The NK cells derived from optimal cord vs suboptimal cord have distinct effector functionality potency. Pre-complexing NK cells with bispecific antibodies prior to infusion facilitates CAR-like responses by NK cells. The persistence of NK cells can be enhanced by pre-activation with cytokines to induce a memory phenotype. Clinical trials of AFM-13 complexed CAR-like memory CB-NK cells for refractory/relapsed CD30+ malignancies showed ORR 92.5% with CR 65%, no cases of CRS, ICANS or GVHD. Another study has shown that CD70 is a promising pan-cancer antigen as it is expressed on multiple blood cancers and solid tumors and has limited expression on normal cells. Phase I/II clinical trial evaluating the safety and efficacy of P+E CD70 CAR-NK cells for cancer immunotherapy demonstrated that around 250 patient doses were manufactured and frozen from 2 cord blood units and CAR transduction efficiency was 60%. Trophoblast cell surface antigen 2 (TROP2) is an attractive pan cancer target as it is over expressed in many epithelial cancers with low expression in healthy adult tissue. Its expression is associated with tumor aggressiveness and poor prognosis in many cancers like ovarian cancer. It plays an essential role in embryonic and fetal development. A combinatorial strategy is required in future wherein CARs target more than one antigen and CAR engineering can be combined with bispecific engager/antibody loading, combining CAR with CRISPR gene editing, checkpoint inhibitors/immunomodulatory drugs/radiotherapy.

Engineering the Next-generation CARs 

Yvonne Y Chen

CAR T cell therapies such as GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas, GD2-CART01 for relapsed or refractory high-risk neuroblastoma have shown promising results. Brain tumor microenvironment is a scary place. TGF-ꞵ in brain can be secreted by tumor cells or other cells. TGF-ꞵ CAR can activate primary human cells. IL-13Rα2/TGF-ꞵ CAR-T cells exhibit superior in vivo control of human GBM xenograft. TGF-ꞵ CAR recognized both human and murine TGF-ꞵ. Treatment with IL-13Rα2/TGF-ꞵ tanCAR reduces Treg and increases ILTCK in brain. It is important for T-cells to find the tumor to overcome immunosuppression. There are many strategies that are being explored involving chemical signatures with the idea of locally delivering tumors that can create the inflammatory microenvironment. Major challenge in solid tumors is identifying an antigen that is uniformly expressed on tumor cells but not on healthy cells.

The Costs of CAR T: How to Assess the Value of Expensive Therapies in Pediatric Oncology 

Edward RS Cliff

Access to CAR-T cell therapy is a challenge both within the US and globally due to high cost, reimbursement/coverage, logical set-up and access. The major component of the cost of the CAR-T cells include manufacturing costs, pricing & negotiations and bundled hospital payments. It is very important to assess the value of expensive therapies using cost-effectiveness analysis. A transformational cancer therapy can only benefit those patients who can access it. The cellular therapies are extremely expensive, and all stakeholders need to tackle all elements of cost and price to make them more accessible to patients within the US and globally. The novel and decentralized manufacturing approaches are likely to be the key to increasing global access. It is essential to ensure that cellular therapies are included in the price negotiations. The independent cost-effectiveness analysis is a key tool to help payers decide what therapies to invest in. HTAs need to develop strategies to deal with uncertainty in CEA otherwise patients will miss out on access.

Video No: T09. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

CASE-BASED PANEL: Integrating Liquid Biopsies Into Patient Care And Clinical Trial Design

Liquid biopsies, specifically ctDNA (circulating tumour DNA), have emerged as a promising tool in various clinical scenarios. This case-based session with poll questions highlights the clinical applications and considerations surrounding ctDNA integration into patient care and clinical trial design.

Circulating tumour DNA: Clinical applications of emerging science

ctDNA has advanced significantly and is now applicable in various clinical scenarios. In this case, a 57-year-old African woman presented with rectal bleeding and underwent a colonoscopy, revealing a circular mass at the hepatic flexure. After surgery, it was determined that she had a moderately differentiated adenocarcinoma of the ascending colon, classified as T3N0, with no lymph node involvement or tumour deposits. The pathology report showed no evidence of lymphovascular invasion (LVI) or perineural invasion (PNI), and the surgical margins were clear. The patient did not experience any signs of obstruction or perforation and had a smooth recovery, returning to everyday eating habits, passing regular stools, and achieving an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 within three weeks. Now seeking advice, she wonders if adjuvant chemotherapy is necessary

The recommendation for adjuvant chemotherapy is not strongly supported in this case, considering the absence of significant risk factors and the patient's favourable post-surgical condition. If the tumour were classified as T4, it would be more likely to recommend adjuvant chemotherapy due to the higher associated risk. However, it's worth noting that no statistically significant evidence suggests a benefit at five years. Patients are advised to omit axaceparin due to its toxicity and lack of randomized controlled trial (RCT) data. Regarding a T3N0 tumour with high microsatellite instability (MSI-high), the recommendation for adjuvant chemotherapy is different. MSI-high tumours have a higher risk of recurrence, and some data suggest that adjuvant chemotherapy may be harmful in this subgroup. Therefore, it is not recommended in MSI-high cases due to its potential harm. MSI status has proven to be a valuable prognostic factor in the adjuvant setting and is also included in many multi-biomarker tests that demonstrate better predictive capabilities.

Utilizing a ctDNA (tumour-specific) test is beneficial in this case.If the test yields positive results, it strongly indicates the need for chemotherapy. The sensitivity level of the test plays a significant role in determining the appropriate management approach. Scientific data published in 2016 has demonstrated the predictive value of ctDNA, specifically in assessing the likelihood of cancer recurrence in stage 2 colon cancer cases. However, it does not provide information about the efficacy of chemotherapy in these instances. There is a noteworthy concordance between tissue-based and liquid-based DNA analysis, thus supporting the utility of ctDNA in diagnostic evaluations.

There are two types of ctDNA evaluations: tumour-informed and tumour-agnostic. Tumour-informed ctDNA platforms are used for early-stage cancer to detect the presence of molecular or minimal residual disease after curative surgery. On the other hand, tumour-agnostic platforms, which are NGS-based panels, are used for advanced and metastatic solid tumours .

After mastectomy for oligometastatic disease, ctDNA can play a role. In the early stage, ctDNA is a robust prognostic indicator and can help track residual disease. It is important to note that prognostic indicators may not provide predictive benefits. The actual value of circulating tumour minimal residual disease (MRD) lies in its management with proven efficacy therapeutics. However, it is not enough to demonstrate the predictive value of ctDNA in a specific setting. While it guides clinicians to some extent, it does not definitively answer whether an intervention based on ctDNA will be clinically beneficial.

In the case of a stage 3 colon cancer patient with a negative ctDNA value, it is not advisable to hold off on chemotherapy until the values turn positive. Several factors need to be considered in such cases. The negative predictive value of ctDNA after surgery can vary, and in many instances, ctDNA may be present but not detected due to the level of sensitivity used. It can take a few weeks after surgery for ctDNA to be detected. Therefore, the chemotherapy decision should rely not solely on ctDNA results but on early and late treatment considerations.

When discussing the potential benefits of ctDNA in low-risk stage II colon cancer, it is essential to thoroughly inform the patient about the levels of recurrence risk and consider the intensity of surveillance. While some oncologists may use ctDNA testing in this setting, guidelines do not yet support its routine use due to insufficient evidence. However, as assays become more sensitive, such as with third-generation tumour-informed assays, the detection time will likely extend, providing a larger window of opportunity to treat micrometastatic disease. The timing of the assay is also an important consideration.

After engaging in a thorough discussion with the patient, the results of the ctDNA test are received within a week, indicating a positive outcome. Considering the same clinical scenario of T3N0 with no other high-risk factors, the likelihood of recommending adjuvant chemotherapy in this setting is high. If the decision is made to proceed with adjuvant chemotherapy, the recommended course of treatment would involve either 3m XELOX or FOLFOX, followed by ctDNA testing to guide further therapy based on the test results . Following the completion of the recommended chemotherapy, the patient shows no lingering adverse effects, and the subsequent ctDNA testing yields a negative result. The patient expresses interest in serial ctDNA testing as part of surveillance alongside standard CEA and CT imaging. The approach to surveillance may vary, either intensively or less intensively, based on various factors such as scan results and laboratory values.

Two years after completing adjuvant therapy, the patient's overall condition is positive, with negative colonoscopy results, NED on CT scans, and normal CEA levels. However, for the first time since the initial post-surgery sample, the ctDNA test returns a positive result. In such a situation, conducting a PET or repeat CT scan after a three-month interval is advisable to facilitate additional imaging assessment.

To conclude, ctDNA (circulating tumour DNA) has advanced in clinical applications, providing valuable information in various scenarios such as prognosis and residual disease tracking. The choice of chemotherapy regimen, such as 3m XELOX or FOLFOX, would be followed by ctDNA testing to guide further therapy.

Video No: T09. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago