NEJM This Week — July 23, 2026

An ID-heavy issue. The headline for internists is a negative result: GoGoVax shows the 4CMenB meningococcal-B vaccine does NOT prevent gonorrhea in high-risk MSM, overturning years of observational signal. A high-yield antiretroviral therapy review and a superb Bartonella neuroretinitis teaching case round out the ID content. Two practice-changing but narrow oncology trials — daraxonrasib (first-in-class oral RAS inhibitor doubling survival in pancreatic cancer) and KEYNOTE-B15 (perioperative enfortumab vedotin–pembrolizumab beating cisplatin in bladder cancer) — are summarized for awareness, as is the pediatric SCOUT-HCM mavacamten trial.

Infectious DiseaseGoGoVax · RCTHigh yield · ID

Meningococcal B Vaccine to Prevent Neisseria gonorrhoeae Infection

In MSM at high risk for gonorrhea, does the 4CMenB vaccine vs placebo lower the incidence of N. gonorrhoeae infection?

Population: 654 randomized (587 per-protocol) MSM with a recent gonorrhea or infectious-syphilis diagnosis, either HIV-negative on PrEP or living with HIV; multicenter, double-blind, placebo-controlled. Quarterly NAAT screening (3 sites) for 2 years.
Intervention: Two doses of 4CMenB (4-component meningococcal serogroup B OMV vaccine).
Comparison: Placebo.
Outcome: No protection — 48.1 vs 47.8 events per 100 person-years (incidence rate ratio 1.01; 95% CI 0.80–1.26; P=0.97), vaccine efficacy −0.5%. No efficacy for symptomatic, asymptomatic, or any anatomic site. Serious AEs 4.7% vs 2.8%.

Clinical takeaway. A well-powered RCT shows 4CMenB does not prevent gonorrhea in high-risk MSM, directly contradicting observational studies (a meta-analysis had estimated ~38% risk reduction) that had already prompted 4CMenB-for-gonorrhea programs in Spain and the UK. The finding is concordant with the earlier randomized DOXYVAC signal (adjusted HR 0.78; P=0.06). What this changes: argues against deploying or expanding 4CMenB as a gonorrhea-prevention vaccine.

Heme / OncologyRASolute 302 · RCTNotable · narrow onc

Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer

In previously treated metastatic pancreatic cancer, does oral daraxonrasib vs chemotherapy improve survival?

Population: 500 patients (248 vs 252) with previously treated metastatic PDAC; 91.8% had RAS G12 mutations. Phase 3, international, open-label; dual primary OS and PFS in the RAS G12 subpopulation.
Intervention: Daraxonrasib — oral RAS(ON) multiselective inhibitor of the active GTP-bound state of mutant and wild-type RAS.
Comparison: Investigator's choice of standard chemotherapy.
Outcome: Median OS (RAS G12) 13.2 vs 6.6 months (HR 0.40; P<0.001); median PFS 7.3 vs 3.5 mo (HR 0.45). Grade ≥3 AEs 61.8% vs 69.6%; treatment-related discontinuation 1.2% vs 11.2%.

Clinical takeaway. The first phase-3 win for a first-in-class oral pan-RAS(ON) inhibitor, roughly doubling overall survival vs chemotherapy in a cancer where >90% of tumors are RAS-driven — a genuine pancreatic-oncology milestone. Per the editorial (Sivakumar), it validates targeting RAS(ON) directly rather than single KRAS variants. Awareness-level for the internist. What this changes: establishes RAS(ON) inhibition as a new paradigm for RAS-driven mPDAC.

Heme / OncologyKEYNOTE-B15 / EV-304 · RCTNotable · narrow onc

Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer

In cisplatin-eligible muscle-invasive bladder cancer, does perioperative enfortumab vedotin–pembrolizumab vs neoadjuvant cisplatin–gemcitabine improve event-free survival?

Population: 808 adults (405 vs 403) with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy and radical cystectomy; phase 3, open-label.
Intervention: Neoadjuvant enfortumab vedotin (nectin-4 ADC) + pembrolizumab → cystectomy → adjuvant enfortumab vedotin + pembrolizumab.
Comparison: Neoadjuvant cisplatin–gemcitabine → cystectomy.
Outcome: 2-yr event-free survival 79.4% vs 66.2% (HR 0.53; 95% CI 0.41–0.70; P<0.001); 2-yr overall survival 86.9% vs 81.3% (HR 0.65; P=0.006); pathological complete response 55.8% vs 32.5% (P<0.001). Grade ≥3 AEs 75.7% vs 67.2%.

Clinical takeaway. Perioperative enfortumab vedotin–pembrolizumab beat the two-decade neoadjuvant cisplatin standard on EFS, OS, and pCR — in cisplatin-eligible patients — at the cost of more grade ≥3 toxicity. Per the editorial (Sridhar, "The End of the Cisplatin Era?"), it extends the regimen already approved in cisplatin-ineligible disease. What this changes: positions this regimen to displace neoadjuvant cisplatin–gemcitabine as standard of care in cisplatin-eligible MIBC.

Cardiology · PedsSCOUT-HCM · RCTLower yield · peds/surrogate

Mavacamten in Adolescents with Obstructive Hypertrophic Cardiomyopathy

In symptomatic adolescents with obstructive HCM, does mavacamten vs placebo reduce LVOT obstruction?

Population: 44 adolescents (12 to <18 yr; mean ~14.7) with NYHA II/III obstructive HCM; phase 3, double-blind, placebo-controlled.
Intervention: Mavacamten (cardiac-specific myosin inhibitor).
Comparison: Placebo.
Outcome: Week-28 change in Valsalva LVOT gradient −48.5 vs −0.5 mm Hg (difference −48.0; 95% CI −67.7 to −28.3; P<0.001). AE rates similar; no LVEF <50%; no deaths.

Clinical takeaway. Mavacamten markedly reduced provoked LVOT obstruction in adolescents, extending adult HCM efficacy to a population with no previously approved targeted therapy — but the endpoint is a hemodynamic surrogate over 28 weeks in only 44 patients, without symptom/outcome data. What this changes: an early signal, not yet practice-defining.

Infectious DiseaseReview · High yield · IM/ID

Antiretroviral Therapy

When do you start ART, what regimen is first-line, and what threshold defines "untransmittable"?

•Treat everyone with HIV regardless of CD4 (START: immediate ART cut clinical events even at CD4 >500; HR 0.43). •First-line = integrase inhibitor + NRTI backbone: bictegravir/TAF/emtricitabine or dolutegravir/TAF(TDF)/emtricitabine(lamivudine). Two-drug DTG/lamivudine if HIV RNA <500,000, known genotype, no HBV. •Baseline genotype recommended (up to 19% transmitted resistance); prior cabotegravir PrEP → integrase-resistance risk → start a boosted PI while awaiting genotype. •U=U: across PARTNER1/PARTNER2/Opposites Attract (>144,000 condomless acts), zero linked transmissions when HIV RNA <200 copies/mL. Life expectancy now approaches the general population.

Teaching Case · Case Records of the MGH

Case 21-2026: A 28-Year-Old Man with Headache and Vision Loss in the Right Eye · Infectious Disease / Neuro-ophthalmology

High yield · IM/ID

Key learning point. Final diagnosis: Bartonella neuroretinitis. The combination of optic disk edema + a macular star (radial lipid exudates deposited along Henle fibers) defines neuroretinitis, and ~two thirds of cases are caused by Bartonella henselae (cat-scratch); syphilis and TB stay in the differential. Diagnosis was serologic: B. henselae IgG 1:4096 (titer ≥1:256 suggests recent/acute infection). Bartonella's VEGF-driven vasoproliferative biology explains the optic-disk neovascularization. Pharmacology pearl: because he also started rifampin for presumed coinfection workup, his dolutegravir dose was doubled (rifampin induction lowers DTG levels).

Also in this issue. Perspectives — using clinical-trial plus observational data to evaluate vaccine protection; national hepatitis C elimination starting in prisons and jails; regulating celebrity/internet drug promotion; "Love and Death." Images in Clinical Medicine — neurocysticercosis; Koebner phenomenon from wet cupping. Correspondence — clinical long-read genome sequencing for rare-disease diagnostics; Klebsiella brain abscess and heterovirulence in the urinary tract; left atrial appendage closure in AF; daraxonrasib in advanced RAS-mutated pancreatic cancer; digital twin–guided ablation for ventricular tachycardia.

Summaries are original paraphrases prepared for educational use; figures are drawn from the published full text. Read the full articles at NEJM.org (subscription required). Trial registrations: GoGoVax (NCT04415424), RASolute 302 (NCT06625320), KEYNOTE-B15/EV-304 (NCT04700124), SCOUT-HCM (NCT06253221). Citations: N Engl J Med 2026; Vol. 395, No. 4. DOIs: 10.1056/NEJMoa2516739, 10.1056/NEJMoa2605555 (editorial 10.1056/NEJMe2606948), 10.1056/NEJMoa2601486 (editorial 10.1056/NEJMe2605872), 10.1056/NEJMoa2601103, 10.1056/NEJMra2511692, 10.1056/NEJMcpc2518086.