September 2022

Supported by pre-clinical work in animals, this phase 1 clinical trial in early stage-melanoma patients found that local injection of an antibody against cytotoxic T lymphocyte–associated protein-4 (CTLA-4) after removal of the primary tumor can increase the efficacy of immunotherapy while reducing side effects.

Summary: Systemic immunotherapy, including immune checkpoint blockage (ICB), has dramatically improved survival for patients with locoregional and metastatic melanoma. However, autoimmune side effects and toxicity limit the applicability of ICB to patients with early-stage melanoma who are unlikely to develop metastatic disease. Studies in animals have demonstrated that the local administration of ICB agents such as anti-CTLA-4 or anti-PD1/PDL1 can be as effective as systemic administration, with significant reductions in systemic toxicity. This study investigates whether such an approach is safe and effective in human patients with early-stage melanoma.

The authors of this study designed a Phase 1 clinical trial (NCT0427481) to inject patients undergoing wide local excision of melanoma primary tumors with low dose antibody against CTLA-4, a protein receptor that serves as an immune checkpoint. Patients were injected after surgical resection of the primary tumor and prior to sentinel lymph node biopsy. This allowed the authors to investigate responses to local anti-CTLA-4 in the tumor draining lymph nodes (TDLNs) at the time of sentinel node biopsy. Thirteen patients were injected with a single dose of tremelimumab (a fully humanized monoclonal IgG2 Ab against CTLA-4, dose range of 2 – 20 mg) intradermally at their primary tumor excision site 1 week prior to sentinel lymph node biopsy. 

The study demonstrated that intradermal drug delivery was safe, with no significant toxicity. Analysis of draining lymph nodes at the time of sentinel lymph node biopsy revealed activation of migratory DC subsets required for T cell activation in the lymph nodes. Futhermore, local anti-CTLA-4 treatment led to reductions in Tregs and increases in effector and central memory T cells both in the SLN and systemically. With only 13 patients and no placebo arm in the trial, it is impossible to draw conclusions about efficacy from the current study. However, this trial suggests that intratumoral or local injection of immunotherapy may induce robust immune responses in the locoregional lymph nodes without the limiting side effects of systemic administration. Such an approach could expand the pool of patients that could be safely treated with ICB in melanoma and has potential applicability in a variety of solid tumors accessible for local injection at the time of surgery. 

Bottom line: Local injection of immunotherapy allows for a more targeted effect on the tumor draining lymph nodes. Additional trials are currently under way to investigate the role of locally administered immunotherapy in the neoadjuvant and adjuvant setting.

This prospective, randomized phase II trial found that watch and wait is an efficacious management strategy for patients with locally advanced rectal cancer who have complete or near complete clinical response to total neoadjuvant therapy.

Summary: Total neoadjuvant therapy (TNT) has become standard for the treatment of locally advanced rectal cancer. Patients who have a pathologic complete response (pCR) to TNT have excellent outcomes, and observational studies have reported similar outcomes for those identified to have a complete clinical response (cCR; complete tumor regression) to TNT prior to surgery. These data suggest that patients who have a cCR may be able to have organ preservation (avoidance of removal of the rectum), and undergo a watch and wait (WW) surveillance strategy, in which they are surveilled intensely to identify early recurrence of their cancer. TNT can be administered either in the form of induction chemotherapy followed by chemoradiation, or with upfront chemoradiation followed by consolidative chemotherapy. Both are efficacious, but clinical trials specifically comparing the two TNT protocols are lacking. 

To address this knowledge gap, Garcia-Aguilar et al conducted a multicenter clinical trial comparing disease-free survival (DFS) and organ preservation rates between patients with locally advanced rectal cancer receiving either induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or WW on the basis of tumor response to treatment. 

324 patients were included in the study, 158 of whom were in the INCT-CRT group, and 166 in the CRT-CNCT group. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. Patients with cCR or near-complete response were offered participation in a standardized WW protocol. Median follow-up for the study was 3 years. Three-year DFS rates did not differ between the two groups, and were 76% for the INCT-CRT group and 76% for the CRT-CNCT group. Of the 304 patients who underwent restaging following completion of TNT, 225 (74%) patients, 105/146 (71%) in the INCT-CRT and 120/158 (76%) in the CRT-CNCT, underwent WW, while the remainder were recommend for TME. Of these 225 patients who underwent WW, 42/105 (40%) in the INCT-CRT group and 33/120 (27%) in the CRT-CNCT group developed tumor regrowth during follow-up; all patients with tumor regrowth were recommended for TME. Three-year TME-free survival (organ preservation) was 41% in the INCT-CRT group and 53% in the CRT-CNCT group. The DFS rates were similar for patients recommended for TME after restaging and for those recommended for TME after regrowth. 

This trial is extremely important because it demonstrates that a treatment strategy including TNT and selective WW or TME on the basis of tumor response allows organ preservation in almost half of the patients with locally advanced rectal adenocarcinoma without an apparent adverse impact on oncologic outcomes. Furthermore, it corroborates prior studies (CAO/ARO/AIO-12 trial) which have found that CRT-CNCT protocols result in higher rates of complete treatment response as compared to INCT-CRT strategies.

This is a follow-up of the MSLT-II trial, which compared completion lymph node dissection (CLND) to surveillance for patients with cutaneous melanoma and positive sentinel lymph node (SLN) biopsy. Here, patients who were originally randomized to the surveillance arm were followed to 10 years. Specific risk factors for nodal recurrence were identified, but the majority (>80%) of these patients remained recurrence-free, suggesting that SLN biopsy alone can provide long lasting nodal disease control.

Summary: The MSLT-I and MSLT-II trials for of primary cutaneous melanoma both represented major paradigm shifts in the management of the regional nodal basin. The MSLT-I trial showed the SLN biopsy with reflex CLND was associated with improved recurrence-free survival (RFS) as compared to nodal observation alone. The MSLT-II trial is an international, multistage, phase 3 randomized clinical trial that examined the benefit of CLND in patients with SLN metastases by randomizing patients with positive SLNs to either CLND or observation using clinical exam and ultrasonography. The findings of this trial were published in NEJM in 2017, with the primary endpoint of melanoma-specific survival (which did not differ between the two treatment groups) and secondary endpoints including RFS (slightly improved in the CLND group, based on increased regional nodal control). 

This sub-study looked specifically at the patients who were randomized to observation, with the primary endpoint being nodal recurrence in the regional lymph node basin. These 823 patients (with 855 total positive SLN basins) were followed by exam and ultrasound at predetermined intervals to 10 years.

There were a total of 148 nodal recurrences in 855 basins (17.3%), and most of these recurred by year 3, with no nodal basin recurrences seen after 7 years. The mean 3-year and 10-year RFS rates were 83.2%, and 80.2%, respectively. On univariate analysis, RFS was associated with age <50, non-ulcerated and thinner primary lesions, axillary basin site, fewer positive SLNs, and lower SLN burden by area/diameter or metastasis. Except for ulceration status, these same factors were significant on multivariate analysis. When considering the risk factors of older age, ulceration, Breslow thickness greater than 3.5 mm, non-axillary basin, and greater tumor burden, basin disease-free rates at 5 years were 96% for patients with 0 risk factors, 89% for 1 risk factor, 86% for 2 risk factors, 80% for 3 risk factors, 61% for 4 risk factors, and 54% for 5 or 6 risk factors. This suggests that developing a predictive risk model based on number of risk factors may help guide individualized treatment strategies, including more personalized screening intervals.

Following the MSLT-II trial, nodal observation has become the standard practice for primary cutaneous melanoma patients with SLN metastases. This follow-up study demonstrates that more than 80% of these patients never have an in-nodal recurrence, suggesting that SLN biopsy alone achieves definitive nodal disease clearance for most patients, and spares patients a more morbid CLND.  SLN biopsy itself may be therapeutic rather than simply diagnostic, as once believed. Of final note, the MSLT-II trial preceded the widespread use of adjuvant systemic therapies, and only 6.5% pf patients in the study received adjuvant treatment. As multiple effective and generally well-tolerated treatments have since become available, the risk of nodal recurrence is expected to be even lower moving forward.