MARIPOSA: Can Amivantamab and Lazertinib Replace Osimertinib in the Front-Line Setting?

Osimertinib is the current first-line treatment for EGFR-mutated NSCLC, however, patients frequently relapse due to acquired resistance mutations. Amivantamab is a bispecific antibody against EGFR and MET alterations. Lazertinib is a tyrosine kinase inhibitor active against EGFR mutations including common resistance mutations. The MARIPOSA trial was designed to study if the combination of amivantamab plus lazertinib in untreated epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients would provide improved progression-free survival. Here, we discuss the rationale for the study and the early results of MARIPOSA.

Taletrectinib for the treatment of ROS-1 positive non-small cell lung cancer: a drug evaluation of phase I and II data.

INTRODUCTION: While crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer (NSCLC), unmet needs remain. These unmet needs include treatment options for patients with resistance mutations and efficacious options even in the presence of brain metastasis while simultaneously avoiding unwanted neurological side effects. AREAS COVERED: Taletrectinib was designed to: improve efficacy; overcome resistance to first-generation ROS1 inhibitors; and address central nervous system penetration while conferring fewer neurological adverse events. All of these features are demonstrated and supported by data from the phase I and the regional phase II TRUST-I clinical trial. Here, we describe the preclinical and clinical characteristics of taletrectinib and evaluate the data from phase I and II studies and review the rationale and design of TRUST-II, a global phase II study of taletrectinib, which is enrolling patients in North America, Europe, and Asia. EXPERT OPINION: Taltrectinib has the potential to improve PFS based on its greater potency against ROS1+ tumors and high CNS penetration. By selectively inhibiting ROS1 wild-type and its resistant mutations over TRKB, taltrectinib has a better safety profile with minimal CNS-related AEs compared to other ROS1+ inhibitors.

The development of amivantamab for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) patients with sensitizing oncogenic driver mutations benefit from targeted therapies. Tyrosine kinase inhibitors are highly effective against classic sensitizing epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletions and exon 21 L858R point mutations. Conversely, EGFR exon 20 insertions (exon20ins) are resistant to the traditional EGFR tyrosine kinase inhibitors (TKIs). In May 2021, the US Federal Drug Administration (FDA) provided accelerated approval to amivantamab (Rybrevant) in adults with locally advanced or metastatic NSCLC with EGFR exon20ins after treatment with platinum-based chemotherapy. Amivantamab was the first EGFR/MET bispecific antibody to be approved specifically for EGFR exon20ins where there was an unmet need. Furthermore, amivantamab is being evaluated in additional settings such as post osimertinib in sensitizing EGFR mutations as well as in MET altered NSCLC. Here we discuss amivantamab in regard to its mechanism of action, preclinical and clinical data, and clinical impact for patients with EGFR exon20ins NSCLC and beyond.

Multiorgan Failure From Nivolumab and Ipilimumab: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) as standard of care have revolutionized the treatment of patients with metastatic melanoma. The combination of nivolumab and ipilimumab improves treatment efficacy and prolongs survival compared to monotherapy alone. However, combination therapy is also associated with an increased incidence of adverse events. We report an uncommon yet important case of multi-organ failure in a patient following a single dose of nivolumab plus ipilimumab. A 60-year-old male with a history of ulcerative colitis in remission and metastatic melanoma was admitted on February 25, 2021, for presumed sepsis, after presenting with neutropenic fever. His brain metastases were previously resected on January 14, 2021, and he was started on dexamethasone 4 mg BID for six weeks. On February 11, 2021, he received one dose of nivolumab plus ipilimumab, per the CheckMate-067 protocol. He presented 14 days later with fever, diarrhea, pancytopenia, renal failure, drug-induced hepatitis, and myocarditis. The infectious workup was negative. His neutropenia responded to growth factors. He was diagnosed with interstitial nephritis due to immunotherapy and treated with corticosteroids. His symptoms resolved with concomitant improvement of his renal, hepatic, and cardiac function. He was discharged home in a stable condition. Although these specific immune-related adverse events (irAEs) are uncommon and rarely occur simultaneously, ICIs can trigger non-specific immune system activation, resulting in widespread inflammatory effects. Since irAEs can lead to multi-organ failure, as evidenced in this case, early recognition and institution of high-dose steroids are critical to preventing rapid deterioration. Given that ICI therapy is the standard of care for several cancers and is often studied in clinical trials, increased education on irAE toxicity and updated algorithms on the management of febrile cancer patients are warranted.

Lorlatinib Tolerability and Association With Clinical Outcomes in Patients With Advanced ALK- or ROS1-Rearranged NSCLC: A Brief Report.

Introduction: Treatment with lorlatinib for patients with advanced ALK- and ROS1-rearranged NSCLC (ALK+ and ROS1+ NSCLC) is associated with a unique set of adverse events (AEs) often requiring dose reduction. However, the impact of dose reductions on outcomes remains unclear and is mainly limited to analyses from prospective studies of lorlatinib in the first-line setting. Methods: We reviewed the course of 144 patients with advanced ALK- or ROS1-rearranged NSCLC treated with lorlatinib in the second-line or later setting to assess the frequency of dose reductions resulting from treatment-related AEs (TRAEs) and the association between dose reductions and progression-free survival (PFS) and overall survival (OS). Results: A total of 58 patients (40%) had TRAE-related dose reductions, most (59%) owing to neurocognitive AEs or neuropathy. Among all patients, the median PFS was 8.1 months (95% confidence interval [CI]: 6.4-11.8); the median OS was 20.7 months (95% CI: 16.3-30.5). Among patients who were started on lorlatinib 100 mg/d (n = 122), a Cox regression model with the occurrence of a dose reduction as a time-dependent covariate indicated no association between dose reduction and PFS (hazard ratio = 0.86, 95% CI: 0.54-1.39) or OS (hazard ratio = 0.78, 95% CI: 0.47-1.30). Conclusions: Lorlatinib dose reductions were not associated with inferior clinical outcomes in this multicenter analysis. Prompt identification of lorlatinib TRAEs and implementation of dose reductions may help maximize tolerability without compromising outcomes.

Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET fusion positive colorectal carcinoma as a unique molecular subset.

BACKGROUND: RET fusions are driver alterations in cancer and are most commonly found in non-small cell lung cancer and well-differentiated thyroid cancer. However, RET fusion have been reported in other solid tumors. MATERIAL AND METHODS: A retrospective analysis of RET+ solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ). RESULTS: As of March 22, 2022, a total of 378 RET+ solid malignancies were identified in 15 different tumor types and carcinoma of unknown primary (CUP) that underwent next-generation RNA sequencing. RET+ NSCLC and RET+ thyroid cancer constituted 66.9% and 11.1% of the RET+ solid malignancies, respectively. RET+ colorectal adenocarcinoma and RET+ breast adenocarcinoma constituted 10.1% and 2.6%, respectively. The estimated frequency of RET fusions within specific tumor types were NSCLC 0.7%, thyroid cancer 3.1%, colorectal cancer 0.2% and breast cancer 0.1%. KIF5B (46.8%) was the most common fusion partner followed by CCDC6 (28.3%) and NCOA4 (13.8%) in RET+ solid tumors. KIF5B-RET was the dominant fusion variant in RET+ NSCLC, NCOA4-RET was the dominant variant in RET+ colorectal carcinoma, and CCDC6-RET was the dominant variant in thyroid cancer. The most common single gene alterations in RET+ tumors were TP53 (34.8%), RASA1 (14.3%) and ARIAD1A (11.6%). RET+ CRC had a high median TMB of 20.0 and were commonly MSI-H. CONCLUSIONS: RET fusions were identified in multiple tumor types. With a higher median TMB and commonly MSI-H, RET fusion positive CRC may be a unique molecular subset of CRC.

The Additional Exclusions of ROS1 Fusions (In Addition to EGFR Mutation and ALK Fusions) in the Cemiplimab NSCLC FDA Indication (EMPOWER-Lung 1 and -Lung 3). Catching Up with Current Scientific View of Immunotherapy in Never-Smoker Predominant Actionable Driver Mutation Positive NSCLC?

Cemiplimab is one of seven immune checkpoint inhibitors (ICIs) approved for the first-line (1L) treatment of advanced NSCLC in the US based on EMPOWER-Lung 1 and -Lung 3 trials. In addition to exclusion of NSCLC patients harboring EGFR mutations and ALK fusion from 1L treatment with ICIs, exclusion of ROS1 fusion is an additional unique exclusion the use of criterion for cemiplimab in the US FDA indication based on the design of the EMPOWER lung trials. We review the effectiveness of ICIs in never-smoker predominant NSCLC with driver mutations (EGFR, ALK, ROS1, RET, HER2) and question whether exclusion of ROS1 fusion would put cemiplimab at a competitive disadvantage given the requirement for insurance to prove ROS1 fusion negativity. We further discuss whether the US FDA as a regulatory authority has the right and responsibility to harmonize the use of ICIs in these actionable driver mutations to standardize community practice for the benefit of patients and to advance the development of next-generation treatment for these driver mutations.

CodeBreaK 200: Sotorasib (AMG510) Has Broken the KRAS G12C+ NSCLC Enigma Code.

Per the US FDA sotorasib approval summary, KRAS G12C mutation is found in approximately 14% of adenocarcinoma of the lung, primarily in patients with a history of smoking. Until recently, targeted therapies against KRAS G12C have been largely unsuccessful due to the small protein size of KRAS and thus lack of binding pockets in KRAS and rapid hydrolysis of GTP to GDP by KRAS enzymes from abundance of GTP in the cytoplasm. Sotorasib, a first-in-class covalent KRAS G12C inhibitor that binds to the switch pocket II in the KRAS G12C-GDP "off" state, received US FDA accelerated approval on May 21, 2021 in the US, based on a Phase II dose expansion cohort of CodeBreaK 100 trial. Sotorasib at 960 mg once daily achieved an ORR of 36% (95% CI: 28%, 45%), with a median response duration of 10 months (range 1.3+, 11.1) in 124 KRAS G12C+ NSCLC. At the European Society of Medical Oncology (ESMO) 2022 annual meeting, sotorasib achieved a statistically significant improved PFS over docetaxel (HR = 0.66; 95% CI: 0. 51-0.86; P = 0.002). The modest magnitude of PFS improvement of 1.1 months (from 4.5 months to 5.6 months) and the ORR of 28% led to a vigorous debate on whether sotorasib was indeed a true breakthrough. In this pros and cons debate, we argue thatsotorasib has achieved a true breakthrough.

SOHO State-of-the-Art Updates and Next Questions: A Modern Approach to the Systemic Treatment of Advanced CTCL.

The term cutaneous T-cell lymphoma (CTCL) is a general term for T-cell lymphomas that are found primarily in skin. The most common CTCL entities, mycosis fungoides and Sezary syndrome are incurable diseases with a plethora of conventional treatment options. In the past treatment options have been selected primarily according to stage. Given newer targeted therapies with varied response in different body compartments, we suggest a compartment-guided algorithm that may enhance response rates directing the selection of the most efficacious treatment options.

Genomic Alterations and Tumor Mutation Burden in Merkel Cell Carcinoma.

Importance: Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence. Cytotoxic chemotherapy and checkpoint inhibitors provide treatment options in the metastatic setting; however, there are no approved or standard of care targeted therapy treatment options. Objective: To identify actionable alterations annotated by the OncoKB database therapeutic evidence level in association with tumor mutation burden (TMB). Design, Setting, and Participants: This is a retrospective, cross-sectional study using data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange, a multicenter international cancer consortium database. Patients with MCC were enrolled in participating institutions between 2017 and 2022. Data from version 11.0 of the database were released in January 2022 and analyzed from April to June 2022. Main Outcomes and Measures: The main outcome was the percentage of patients with high TMB and OncoKB level 3B and 4 alterations. Results: A total of 324 tumor samples from 313 patients with MCC (107 women [34.2%]; 287 White patients [91.7%]; 7 Black patients [2.2%]) were cataloged in the database. The median (range) number of alterations was 4.0 (0.0-178.0), with a mean (SD) of 13.6 (21.2) alterations. Oncogenic alterations represented 20.2% of all alterations (862 of 4259 alterations). Tissue originated from primary tumor in 55.0% of patients (172 patients) vs metastasis in 39.6% (124 patients). TMB-high (≥10 mutations per megabase) was present in 26.2% of cases (82 patients). Next-generation sequencing identified 55 patients (17.6%) with a level 3B variation for a Food and Drug Administration-approved drug for use in a biomarker-approved indication or approved drug in another indication. An additional 8.6% of patients (27 patients) had a level 4 variation. Actionable alterations were more common among high TMB cases, with 37 of 82 patients (45.1%) harboring level 3 alterations compared with only 18 of 231 patients (7.8%) with low TMB. The most common level 3B gene variants included PIK3CA (12 patients [3.8%]), BRCA1/2 (13 patients [4.2%]), ATM (7 patients [2.2%]), HRAS (5 patients [1.6%]), and TSC1/2 (6 patients [1.9%]). The most common level 4 variants include PTEN (13 patients [4.1%]), ARID1A (9 patients [2.9%]), NF1 (7 patients [2.2%]), and CDKN2A (7 patients [2.2%]). Copy number alterations and fusions were infrequent. In 61.0% of cases (191 cases), a PanCancer pathway was altered, and 39.9% (125 cases) had alterations in multiple pathways. Commonly altered pathways were RTK-RAS (119 patients [38.0%]), TP53 (103 patients [32.9%]), cell cycle (104 patients [33.2%]), PI3K (99 patients [31.6%]), and NOTCH (93 patients [29.7%]). In addition, oncogenic DNA mismatch repair gene alterations were present in 8.0% of cases (25 patients). Conclusions and Relevance: In this cross-sectional retrospective study of alterations and TMB in MCC, a minority of patients had potentially actionable alterations. These findings support the investigation of targeted therapies as single agent or in combination with immunotherapy or cytotoxic chemotherapy in selected MCC populations.

Tiragolumab (Anti-TIGIT) in SCLC: Skyscraper-02, a Towering Inferno.

Small cell lung cancer (SCLC) is characterized by rapid progression and poor prognosis. Although the phase II CITYSCAPE-02 trial found objective response rate (ORR) and progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients improved when tiragolumab was added to atezolizumab and chemotherapy, the phase III SKYSCRAPER-02 failed to find PFS or OS benefit in patients with SCLC. Atezolizumab was the first immunotherapy to show survival benefit in extensive SCLC based on the phase III IMpower133 study. Given that immunotherapy has become the standard of care for SCLC patients, further research is needed into ways to augment the immune system to better treat these patients.

A Long Overdue Targeted Treatment for KRAS Mutations in NSCLC: Spotlight on Adagrasib.

KRASG12C is one of the most common oncogenes in non-small cell lung cancer (NSCLC) and is associated with a poor prognosis. Historically, KRAS mutations have been difficult to target due to lack of binding sites and exceptionally high affinity for guanosine triphosphate/guanosine diphosphate (GTP/GDP). Recently, KRASG12C selective inhibitors have shown promising results in Phase I/II studies. Here we discuss the mechanism of action, pharmacokinetic and pharmacodynamic properties, efficacy, and tolerability of adagrasib (MRTX849).

Non-small Cell Lung Cancer with EGFR or HER2 Exon 20 Insertion Mutations: Diagnosis and Treatment Options.

Molecular testing is performed upon diagnosis of non-small cell lung cancer (NSCLC) because of the large success of targeted therapies for oncogenic mutations. Epidermal growth factor receptor (EGFR) mutations are the most commonly identified mutation in NSCLC, and EGFR exon 20 insertion mutations (exon20ins) are the third most common mutation in EGFR following EGFR exon 19 deletions and exon 21 L858R mutations. EGFR exon20ins have regularly demonstrated resistance to classical EGFR inhibition. Two treatments-mobocertinib and amivantamab-have recently been the first drugs to be approved by the US Food and Drug Administration (FDA) for treatment of lung cancers with these mutations following platinum-based therapy. Research surrounding these two drugs demonstrates strong efficacy, but with an intense array of side effects. Another targetable driver mutation is the human epidermal growth factor receptor 2 (HER2) exon20ins, representing approximately 2-3% of NSCLC patients. This mutation has been heavily studied in vitro as well as clinically, and trastuzumab deruxtecan was just recently granted accelerated FDA approval based on the high efficacy demonstrated in the Destiny-Lung01 study. However, similar to their EGFR counterparts, HER2 inhibitors also have evidence of toxicity in clinical studies. In this paper, we discuss the limited response of EGFR and HER2 exon20ins to a wide range of standard treatment regimens, such as platinum-based chemotherapy and classic EGFR tyrosine kinase inhibitors, as well as immunotherapy. We also review recently approved and upcoming targeted therapeutic options, considering what research is presently being done regarding efficacy and the reduction of side effects, as well as the agents' risks and benefits for incorporation into an approved treatment regimen.

Stroke in sickle cell disease and the promise of recent disease modifying agents.

Sickle cell disease (SCD) is an inherited hemoglobinopathy affecting approximately 100,000 individuals in the United States. Cerebrovascular disease is among the most common and debilitating complications of SCA, with 53% experiencing silent cerebral infarct by age 30 and 3.8% experiencing overt stroke by age 40 years. This review highlights the burden of cerebrovascular disease in SCD, including both stroke and silent cerebral infarct (SCI). We then discuss the pathophysiology of stroke and cerebral fat embolism in the absence of a patent foramen ovale. This review also reveals that options for primary and secondary stroke prevention in SCD are still limited to hydroxyurea and blood transfusion, and that the role of aspirin and anticoagulation in SCD stroke has not been adequately studied. Limited data suggest that the novel disease-modifying agents for SCD management may improve renal dysfunction, leg ulcers, and lower the abnormally high TCD flow velocity. Further research is urgently needed to investigate their role in stroke prevention in SCD, as these novel agents target the main stroke contributors in SCD - hemolysis and vaso-occlusion. This literature review also explores the role of healthcare disparities in slowing progress in SCD management and research in the United States, highlighting the need for more investment in patient and clinician education, SCD management, and research.

Eponyms in Malignant Hematology.

Eponyms have been traditionally used in the field of medicine to honor the contributions of an individual or group of individuals in understanding a disease. However, many eponyms have come under scrutiny given the personal backgrounds of individuals for whom they intend to honor. As we previously reviewed commonly used eponyms in medical oncology, we now aim to review commonly used eponyms in malignant hematology in order to highlight the individuals for whom they are named after. In this review, we discuss the pathophysiology of each disease, epidemiology, and the historical background for the individual or individuals for which the eponym honors.

Deconstructing ADAURA. It is Not Yet Time to Forgo Platinum-based Adjuvant Chemotherapy in Resected Early Stage (IB-IIIA) EGFR-mutant NSCLC.

Recently, the ADAURA study demonstrated statistically significant improved disease-free survival (DFS) with adjuvant osimertinib in patients with resected stage IB-IIIA non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A consistent improvement in disease-free survival (DFS) was shown, regardless of whether or not patients received adjuvant chemotherapy. Given benefit seen with and without adjuvant chemotherapy, some clinicians may be tempted to forgo chemotherapy and only offer osimertinib post surgical resection. Would this approach be appropriate? Here we carefully dissect data from the ADAURA trial and review how this may fit into the existing evidence on the treatment of early stage NSCLC by discussing five themes, the study design of ADAURA, attempts on adjuvant tyrosine kinase inhibitors, prior studies to support adjuvant chemotherapy, how adjuvant chemotherapy was administered in ADAURA and consideration of toxicities.

Spotlight on Tepotinib and Capmatinib for Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutation.

Mesenchymal-epithelial transition (MET) receptor tyrosine kinase is overexpressed, amplified, or mutated in 1-20% of NSCLC. MET dysregulation is associated with a poor prognosis. Recently, development of targeted therapies against MET exon 14 mutations has demonstrated efficacy and tolerability in early trials. Here we focus on tepotinib and capmatinib in regards to molecular characteristics, early preclinical and clinical data, and the emerging role in future studies and clinical practice.

The cure from within? a review of the microbiome and diet in melanoma.

Therapy for cutaneous melanoma, the deadliest of the skin cancers, is inextricably linked to the immune system. Once thought impossible, cures for metastatic melanoma with immune checkpoint inhibitors have been developed within the last decade and now occur regularly in the clinic. Unfortunately, half of tumors do not respond to checkpoint inhibitors and efforts to further exploit the immune system are needed. Tantalizing associations with immune health and gut microbiome composition suggest we can improve the success rate of immunotherapy. The gut contains over half of the immune cells in our bodies and increasingly, evidence is linking the immune system within our gut to melanoma development and treatment. In this review, we discuss the importance the skin and gut microbiome may play in the development of melanoma. We examine the differences in the microbial populations which inhabit the gut of those who develop melanoma and subsequently respond to immunotherapeutics. We discuss the role of dietary intake on the development and treatment of melanoma. And finally, we review the landscape of published and registered clinical trials therapeutically targeting the microbiome in melanoma through dietary supplements, fecal microbiota transplant, and microbial supplementation.

Eponyms in medical oncology.

Eponyms have historically been used to honor individual contributions or discoveries in the field of medicine. More recently, some eponyms have been criticized for imprecision or for being misnomers. Eponyms attributed to discoveries made by Nazi German scientists have also fallen out of favor. However, despite these criticisms, eponyms remain popular for their ease of use. Eponyms generate interest in medical history and may help humanize the study of medicine. Here, we describe several eponyms in medical oncology with a focus on basic disease pathophysiology, epidemiology, and brief background on the individuals for whom the eponym was named.